Disclosure of paradoxical brain embolism in two stroke patients with ultrasound test for right-to-left shunt and diffusion-weighted MRI.
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Publications and source records attributed to M Kaps.
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Neurovascular coupling and cerebral autoregulation are important and fast mechanisms for maintaining an adequate blood supply to the brain. It was suggested that both mechanisms follow a common control system. The aim of our study was to describe neurovascular coupling and cerebral autoregulation in mathematical terms of a control system and to test the aforementioned hypothesis. We analyzed the input-output dynamics of neurovascular coupling (flicker light test) and cerebral autoregulation (leg cuff test) in terms of a control system, and compared both systems. A transcranial Doppler device was used to measure continuously the blood flow velocity changes in young healthy volunteers who lacked vascular risk factors. For both tests, a control system model with only four parameters was sufficient to allow the vascular reaction to be described in all (rate time, undamped natural angular frequency, attenuation, gain). All parameters were identical for both control systems, except for gain, which is not directly comparable because, in the flicker light test, input function was not measured but assumed as a unit step function in each volunteer. This new method permits description of the regulation of cerebral blood flow using a control loop with four parameters. For the first time, these parameters allowed a demonstration that cerebral autoregulation and neurovascular coupling could be governed by the same control system.
Neurovascular coupling (NC) adapts cerebral blood flow to cortical activity. Functional transcranial Doppler (f-TCD) investigations revealed a typical time course of evoked blood flow responses with an initial overshoot and a stabilization at a lower, but stable, level. This blood flow reaction can be described in terms of a control-system model. We tested reliability and validity of this new approach using different stimulation paradigms. The P2 segment of the posterior cerebral artery was insonated in 14 healthy volunteers and, subsequently, NC was stimulated using two tests, a checkerboard stimulus of 1 s with different repetition rates and a reading test. Data were analyzed according to algorithms of control-system theory. The reading test was used to measure test reliability and side differences. A second-order linear system can describe blood flow regulation of NC. Different stimulation protocols of the checkerboard test and the related evoked blood flow curves could be described by the same control-system model. Further, there were no differences between the checkerboard and reading test nor between right and left side or test and retest of the reading test. NC can be described in a much more detailed manner using control-system analysis. We were able to show that blood flow response due to different visual stimuli follow one common control-system model. Unlike quantification of NC using overshoot, parameters of the control system have smaller SDs, increasing the statistical power and, thereby, usefulness of f-TCD as a diagnostic instrument.
Transcranial Doppler sonography measures blood flow velocity in basal cerebral vessels with high accuracy. For quantification, time averaged mean blood flow velocities are used most because the peak systolic and end diastolic blood flow velocities mark the velocity extremes of one heart cycle. It is known, from hemodynamic measurements of the neurovascular coupling mechanism, that the end diastolic velocity is more sensitive for change in hemodynamics than the peak systolic velocity. Thus, we used a recently introduced control system approach to compare both indices for their use in functional transcranial Doppler tests focusing on hemodynamics of blood flow velocity change. We enrolled 65 healthy young volunteers without a medical history of cardiovascular risk factors, and performed a visual stimulation test. Peak systolic and end diastolic maximal blood flow velocities were used after transformation to relative data for control-system analysis. Due to Doppler artefacts, 95% of peak systolic and 86% of end diastolic data sets were analyzed. Results showed statistically significant differences for resting blood flow velocity and the control system parameter gain, attenuation and rate time, whereas the parameters' natural frequency and time delay were equal. Increase in relative blood flow velocity in the posterior cerebral artery due to visual-cortical stimulation was higher in end diastolic values than peak systolic data. Using a complex visual stimulation paradigm, the higher sensitivity of the end diastolic index is of no practical use. Being less influenced by Doppler artefacts, the peak systolic velocity index is more feasible for control-system analysis of dynamic blood flow regulation.
OBJECTIVES: To investigate the influence of interferon (IFN) beta-1b on the serum levels of sTNF-R1, sTNF-R2 and TNF-beta in patients with multiple sclerosis (MS) in correlation with clinical and MRI activity. MATERIALS AND METHODS: Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN beta-lb every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine levels were measured by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease of every patient. RESULTS: In the treatment group we found an obvious increase of sTNFR1 and sTNF-R2 (P < 0.001) and relatively stable serum levels of TNFbeta with no statistical significance (P = 0.56). In the control group, sTNF-R1 showed a significant decrease (P < 0.001) during the same observation period of 15 months. During the 15-month observation period, the MRI-responders group had significant larger mean AUC (area under the concentration-time curve) values of sTNF-R1 (P = 0.04) and sTNF-R2 (P = 0.01) when compared to the group of MRInonresponders. CONCLUSION: The present data suggest that IFN beta-1b induces the expression and shedding of TNF-R1 and TNF-R2. The magnitude of an increase of sTNF-Rs may be a marker for the effectiveness of treatment with IFN beta-1b.
BACKGROUND AND PURPOSE: The authors investigated the safety and diagnostic potential of a new ultrasound contrast agent (SonoVue) using transcranial color-coded duplex sonography (TCCS). METHODS: Forty patients were enrolled in a multicenter, open-label (on-site), blind (off-site), randomized, dose-ranging crossover study. SonoVue was administered as an intravenous bolus injection of 4 different dosages (0.3, 0.6, 1.2, and 2.4 mL). Efficacy was evaluated as (1) off-site assessment of global quality of the Doppler investigation (based on color or power Doppler images and spectral analysis) at baseline and following each dose of SonoVue according to a 4-point scale (from very poor to excellent imaging of blood flow) and (2) duration of clinically useful signal enhancement and color or power Doppler visualization of blood flow. Additional on-site efficacy assessments performed following each dose of SonoVue included confidence in diagnosis and global consequences of contrast enhancement on diagnosis. Safety evaluations included clinical laboratory tests, neurological examination, injection site tolerability, and incidence of adverse events and their relationship to the study agent. RESULTS: All doses of SonoVue significantly improved the global quality of Doppler examinations (P < .05). The median duration of clinically useful enhancement was dose related (P < .001) and ranged from 2 to 6 minutes at the highest dose. The administration of the contrast agent changed a nondiagnostic study to a diagnostic one in 66% of patients and increased the confidence in diagnosis in 74% of cases. No serious adverse events were recorded following SonoVue administration. The observed adverse reactions were all transient and mild in intensity. CONCLUSIONS: The results obtained from this multicenter study demonstrate that the administration of SonoVue to patients with ischemic cerebrovascular disease who undergo TCCS examination of cerebral vessels improves the visualization of intracranial arteries, providing a dose-dependent contrast enhancement and a clinically useful duration of signal enhancement related to the dose. During this multicenter study, SonoVue proved to be a safe and well-tolerated compound.
Ultrasound contrast agents (UCAs) have a distinct diagnostic impact on transcranial Doppler (TCD) and duplex sonography. In addition to the properties of the UCA and ultrasound imaging modes, the duration of contrast enhancement depends on the administration mode. Infusion of UCAs may be appropriate for prolonging the diagnostically useful time of elevated Doppler intensity. Five sedated dogs were investigated by TCD during infusion with SonoVue, a new UCA consisting of sulfur hexafluoride microbubbles. The infusion rate was varied, and the time-intensity curves were analyzed. Infusion rate of 70 ml/h provided a stable mean level of increased Doppler intensity up to 24 to 26 dB over baseline, whereas a rate of 35 ml/h did not result in a stable plateau (range 8-19 dB over baseline [5 minutes after starting time]). The maximum increases in Doppler mean intensity (18.2 dB [35 ml/h] and 25.6 dB [70 ml/h]) were significantly different (P = .025). Pharmacokinetic analysis of SonoVue during inflow (by exponential functional fitting of the time-mean intensity curves) and elimination (by linear regression analysis) revealed no dose-related differences. This study demonstrated a dose-dependent level of increased Doppler mean intensity within the brain circulation during infusion of SonoVue. Unlike the bell-shaped course of Doppler signal enhancement seen after bolus injection, infusion generates a stable plateau, which is an important prerequisite for more advanced contrast applications.
BACKGROUND AND PURPOSE: Venous transcranial color-coded duplex sonography is a new technique for noninvasive evaluation of the intracranial venous system. However, the interobserver and intraobserver reliability of this method is unclear. METHODS: In 23 healthy volunteers (30 +/- 7.3 years of age), the deep middle cerebral vein (dMCV), basal vein (BV), vein of Galen (VG), and straight (SRS), transverse (TS), and superior sagittal (SSS) sinuses in addition to the arterial segments of the circle of Willis were insonated through the temporal bone window on 2 consecutive days by 2 experienced examiners. The examiners were blinded to each other's results. The interobserver and intraobserver reliability was calculated using a method described by Bland and Altman, resulting in 2-SD confidence intervals. RESULTS: Non-angle-corrected and angle-corrected systolic and end diastolic venous flow velocities (FV) were in good accordance with published normal values, ranging between 8.6 and 19.2 cm/s. The interobserver reliabilities for non-angle-corrected systolic FVs in the dMCV, BV, VG, SRS, and TS were +/- 1.8, 2.4, 2.6, 3.3, and 4.6 cm/s; for angle-corrected systolic FVs, the interobserver reliabilities were +/- 2.5, 3.1, 13.9, 11.6, and 7.7 cm/s. The intraobserver reliabilities for non-angle-corrected systolic FVs in the dMCV, BV, VG, SRS, and TS were +/- 2.9, 3.2, 2.6, 3.2, and 6.1 cm/s; for angle-corrected systolic FVs, the intraobserver reliabilities were 3.2, 3.7, 13.9, 11.6, and 7.5 cm/s. Angle correction was not attempted for the SSS. The interobserver and intraobserver reliabilities for systolic FVs in the SSS were +/- 3.3 and +/- 3.3 cm/s, respectively. CONCLUSIONS: Intracranial venous FVs can be measured with a high interobserver and intraobserver reliability in healthy human subjects. Intraobserver reliability was higher for cerebral veins than for dural sinuses, predisposing them for follow-up examinations; however, angle correction for venous FVs in the VG and the SRS is not advisable.
The objective of this study was to investigate the effect of interferon (IFN) beta-1b on the serum levels of soluble tumor necrosis factor receptor 1 (sTNF-R1) and sTNF-R2 in patients with multiple sclerosis (MS) in correlation with clinical and magnetic resonance image (MRI) activity. Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN beta-1b every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine receptor levels were assessed by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease. In the treatment group, the MRI responders had significantly larger mean values for the area under the concentration-time curve of sTNF-R1 (p = 0.04) and sTNF-R2 (p = 0.01) when compared to the MRI nonresponders during the 15-month observation period. With regard to an increase in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment, we observed a sensitivity of 33 and 58%, respectively, a specificity of 90 and 60%, respectively, and a positive predictive value of 80 and 64%, respectively, for MRI response during the 15-month observation period. A decrease in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment had a sensitivity of 40 and 20%, respectively, a specificity of 100 and 100%, respectively, and a positive predictive value of 100 and 100%, respectively, for further MRI nonresponse (during the 15-month observation period). The present data suggest that assessment of sTNF-Rs may contribute to the identification of subgroups of patients who are likely to respond better than others to treatment with IFN beta-1b. This could help to establish a cost-effective prescription pattern for this expensive treatment, which is of importance for the future management of patients with MS.
BACKGROUND AND PURPOSE: Transcranial color-coded duplex sonography (TCCS) allows bedside imaging of intracranial hemodynamics and parenchymal structures. It provides reliable information regarding midline shift (MLS) in space-occupying hemispheric stroke. We studied the value of MLS measurement to predict fatal outcome at different time points after stroke onset. METHODS: Forty-two patients with acute, severe hemispheric stroke were enrolled. Cranial computed tomography (CCT) and extracranial duplex sonography were performed on admission. TCCS was carried out 8+/-3, 16+/-3, 24+/-3, 32+/-3, and 40+/-3 hours after stroke onset. Lesion size was determined from follow-up CCT. RESULTS: Twelve patients died as the result of cerebral herniation (group 1); 28 survived (group 2). Two patients received decompressive hemicraniectomy and were therefore excluded from further evaluation. MLS was significantly higher in group 1 as early as 16 hours after onset of stroke. Specificity and positive predictive values for death caused by cerebral herniation of MLS >/=2.5, 3.5, 4.0, and 5.0 mm after 16, 24, 32, and 40 hours were 1.0. CONCLUSIONS: TCCS helps to estimate outcome as early as 16 hours after stroke onset and thus facilitates identification of patients who are unlikely to survive without decompressive craniectomy. Because of its noninvasive character and bedside suitability, sonographic monitoring of MLS might be a useful tool in management of critically ill patients who cannot undergo repeated CCT scans.
Neurologic injury subsequent to decompression from diving may be due to paradoxical arterialization of venous gas emboli. Of 40 divers who performed 53 open water dives after being tested for a patent foramen ovale (PFO), arterial gas emboli were detected in 7 of 13 dives, which resulted in venous bubbles. In five of these seven dives, there was evidence of a PFO by contrast transcranial Doppler sonography, indicating an increased risk of arterializing venous bubbles in divers with a PFO.
OBJECTIVES: Ultrasound of the brain supplying arteries is a standard diagnostic procedure in patients with suspected and definite acute and chronic cerebrovascular occlusive disease. Anatomical and pathological limitations led to the development of echocontrast agents which are able to survive pulmonary and capillary transit and improve the echogenicity of the flowing blood. MATERIAL AND METHODS: This article reviews present and future applications of echocontrast agents in conjunction with personal experiences. RESULTS: Currently, echocontrast is used for the differentiation of internal carotid artery occlusion and pseudoocclusion, better delineation of the maximal narrowing in high-grade stenoses, and better visualization of the extracranial vertebral artery and its collaterals. Transcranial applications include the insufficient foraminal or temporal window, assessment of arteriovenous malformations, thrombosis of cerebral veins and sinuses, and intracranial aneurysms. The use of echocontrast can have direct diagnostic and therapeutic consequences. Harmonic imaging, perfusion imaging, stimulated acoustic emission, and drug delivery are possible future domains of the technique. DISCUSSION: Besides the support of conventional neurovascular ultrasound in poor examination conditions due to the patients' anatomy or pathology, echocontrast agents may allow for novel applications in the diagnosis and treatment of cerebrovascular patients.
OBJECTIVES: In this study the frequency of inherited thrombophilic risk factors in a population of German CVT patients and their influence on clinical outcome were evaluated. MATERIAL AND METHODS: Twenty-five patients (age 37.1 +/- 16.3 years) with CVT were screened for inherited coagulation disorders. All participants received a full clinical follow-up (mean follow-up period 4.8 +/- 6.4 years). RESULTS: Inherited thrombophilic risk factors were identified in 9 (36%) of the 25 patients studied. Four were found positive for the heterozygous factor V Leiden mutation, 2 were heterozygous carriers of the prothrombin-G20210A-polymorphism. APC resistance proved to be a reliable screening method for factor V Leiden mutation, whereas genetic evaluation for protein S and C deficiencies failed to demonstrate any mutations despite the identification of 1 patient with a protein C and protein S deficiency each. One patient suffered from a familial plasminogen deficiency. These 9 patients had a less favorable outcome (P < 0.05). CONCLUSION: Our results demonstrate that screening for inherited thrombophilia should be an integral part in the diagnostic work up of CVT patients. Patients with inherited coagulopathies tended to have a less favorable outcome, corroborating recommendations for a longer period of oral anticoagulation.
OBJECTIVES: Autoreactive T cells targeted against antigens of the myelin sheath are suggested to play an important role in the pathogenesis of multiple sclerosis (MS). Naive (CD45RA+) T cells and intercellular adhesion molecule-3 (ICAM-3) are markers for un-activated lymphocytes. This study was performed to investigate, whether the expression levels of these antigens both on cerebrospinal fluid (CSF) and peripheral blood lymphocytes can be used as activity markers in MS. MATERIALS AND METHODS: Corresponding blood and CSF samples were obtained from 31 patients with relapsing-remitting MS. Of the 31 MS patients 23 were suffering from acute relapses at the time of examination and all of them were treated with high-dose methylprednisolone (MP). Blood was collected again on the 10th day of therapy and after 3 months. The control group consisted of 12 healthy persons. Two-color flow cytometry was performed to evaluate the percentage of both CD45RA+ and ICAM-3+ cells within the lymphocyte population. RESULTS: The percentage of CD45RA+ ICAM-3+ cells in the CSF of MS patients with relapses was significantly increased compared to patients in remission (P<0.05). In blood, a significantly lower percentage of CD45RA+ ICAM-3+ lymphocytes was found in both patient groups compared to healthy controls (Relapse: P<0.05, Remission: P<0.10). Additionally, we found a significant increase (P < 0.01) in the percentage of CD45RA+ ICAM-3+ lymphocytes in blood of MS patients suffering from acute relapse on the 10th day of high-dose MP treatment. CONCLUSION: Our data suggest that the percentage of CD45RA+ ICAM-3+ lymphocytes in CSF can be used as marker of disease activity in MS patients.
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.
BACKGROUND AND PURPOSE: It is unclear which harmonic imaging mode (power Doppler or gray-scale imaging) is superior and which measuring method is the most robust for the description of brain perfusion. METHODS: We performed an animal study on 6 beagles through the intact skull using a SONOS 5500 device and Optison injected intravenously in 3 different doses (0.15, 0.3, and 0.6 mL). Intensity versus heart-cycle plots for the brain parenchyma and the basal cerebral arteries were generated to evaluate the peak increase (PI) from baseline and the area under the curve (AUC). RESULTS: With harmonic gray-scale imaging, a homogeneous increase in echo contrast of the brain parenchyma was observed. The effect was dose dependent, resulting in a significant increase in PI as well as an insignificant increase of the AUC with 0.3 mL versus 0.15 mL contrast agent (P=0.03 and P=0.65, respectively; n=5). With harmonic power Doppler, injection of the 3 different doses resulted in a nonsignificant increase in PI and AUC P=0.17, n=6 for both). After normalization of the brain signal to the peak arterial signal in individual dogs, a significant increase could be demonstrated (P=0. 03 and P=0.01, respectively; n=6). The signal pattern of harmonic power Doppler was inhomogeneous, with stronger signal increases in the anterior part of the brain. CONCLUSIONS: Gray-scale imaging leads to a more homogeneous increase in echo contrast of the brain tissue and may be more suitable for displaying brain perfusion. The PI of the signal intensity seems the most robust parameter for the description of cerebral perfusion with both imaging modes under investigation.
Direct and maternal genetic and environmental variances and covariances were estimated for weaning weight and growth and maturing traits derived from the Brody growth curve. Data consisted of field records of weight measurements of 3,044 Angus cows and 29,943 weaning weight records of both sexes. Growth traits included weights and growth rates at 365 and 550 d, respectively. Maturing traits included the age of animals when they reached 65% of mature weight, relative growth rates, and degrees of maturity at 365 and 550 d. Variance and covariance components were estimated by REML from a set of two-trait animal models including weaning weight paired with a growth or maturing trait. Weaning and cow contemporary groups were defined as fixed effects. Random effects for weaning weight included direct genetic, maternal genetic, and permanent environmental effects. For growth and maturing traits, a random direct genetic effect was included in the model. Direct heritability estimates for growth traits ranged from .46 to .52 and for maturing traits from .31 to .34. Direct genetic correlations between weaning weight and weights and growth rates at 365 and 550 d ranged from .56 to .70. Correlations of maternal weaning genetic effects with direct genetic effects on weights at 365 and 550 d were positive, but those with growth rates were negative. Between weaning weight and degrees of maturity at both 365 and 550 d, direct genetic correlation estimates were .55 and maternal genetic correlations estimates were -.05, respectively. Direct genetic correlations of weaning weight with relative growth rates and age at 65% of mature weight ranged from .04 to .06, and maternal-direct genetic correlation estimates ranged from -.50 to -.56, respectively. These estimates indicate that higher genetic capacity for milk production was related to higher body mass and degrees of maturity between 365 and 550 d of age but was negatively related to absolute and relative growth rates in that life stage.