Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection.

OBJECTIVE: Acute coronary syndromes and ischemic cerebral stroke share similarities regarding elevated platelet activation. In coronary syndromes, the importance of inflammation with platelet-leukocyte interaction has been demonstrated. Recent infection is an established risk factor for ischemic stroke; the role of platelet-leukocyte interaction in these patients had not been investigated. METHODS AND RESULTS: Using a flow cytometric assay we investigated 58 stroke patients, 21 with and 37 without infection 1 week before acute cerebral ischemia, and compared them to 58 controls with regard to platelet-leukocyte aggregation and platelet activation on admission and on day 7. Patients with previous infection were significantly up-regulated with regard to platelet activation and platelet-leukocyte aggregation compared with patients without infection. On day 7, these increases in the postinfective group had drawn level with the lower values of the other patients. As reported previously, recent infection was associated with a more severe postischemic deficit. CONCLUSIONS: These results suggest an important role of intercellular platelet-leukocyte interaction in the pathophysiology of acute cerebral ischemia which may also contribute to the increased incidence and clinical severity of ischemic stroke following infection. This may lead to therapeutic considerations of blocking intercellular adhesion molecules like P-selectin or the P-selectin glycoprotein ligand.

Cerebral occlusive artery disease in Noonan syndrome.

Noonan syndrome is an autosomal-dominant inherited syndrome with variable expression of multiple malformations including cardiovascular and craniofacial anomalies. While cerebrovascular insults due to cardiogenic emboli, coagulation abnormalities or cerebrovascular malformations have been documented before, intracerebral occlusive artery disease is not well recognized as a cause of stroke in this syndrome. A 6-year-old girl with Noonan syndrome presented with repetitive transient ischemic attacks consisting of dysphasia and right-sided central facial and arm weakness. Neuroimaging showed acute ischemic lesions in the left putamen and caudate nucleus. Multiple intracranial stenoses were found during transcranial Doppler examination and MR angiography. Although hypertrophic cardiomyopathy was documented by transesophageal echocardiography, a cardioembolic origin of the ischemic attacks was unlikely in this case. The symptoms resolved and did not recur after antiplatelet and anticoagulant therapy was initiated. Stenoses of intracranial cerebral arteries should be considered among the causes of stroke in young patients with Noonan syndrome.

Activated protein C resistance and acute ischaemic stroke: relation to stroke causation and age.

OBJECTIVES: Resistance to activated protein C (APC) is the most frequent cause of thrombophilia and a well known risk factor for deep and cerebral vein thrombosis. Its causative role in ischaemic stroke is still a matter of debate. We undertook this study to determine the prevalence of APC-resistance in a cohort of consecutive patients with acute ischaemic stroke, especially with respect to patients' age and the underlying stroke causation. MATERIALS AND METHODS: 489 patients with proven ischaemic stroke were included in this study. Subtypes of stroke were classified according to the TOAST criteria, i. e. large artery artherosclerosis (LAA), small vessel occlusion (SVO), cardioembolism (CE), stroke of other etiology (SOE), and stroke of undetermined etiology (SUE). APC-resistance was determined with a functional method with high sensitivity and specificity for the factor V Leiden mutation. The results were compared with the prevalence of APC-resistance in healthy volunteers, all born in the same area. RESULTS: APC-resistance was found in 24 of 489 patients (4.9 %) and in 6 of the 112 (5.4 %) control subjects. In the stroke patients, APC-resistance was distributed as follows: LAA 6.5 % (9/138), SVO 3,9 % (4/104), CE 6.7 % (7/104), SOE 3.6 % (1/28), SUE 2.6 % (3/115). Prevalence of APC-resistance was not significantly different between young stroke patients (6-45 years) and older patients (7.7 % [5/65] versus 4.5 % [19/424]). CONCLUSIONS: Prevalence of APC-resistance is not increased in patients with ischaemic stroke. Additionally, no significant differences in the prevalence of APC-resistance are evident within the various stroke subtypes.

Maternal cerebral hemodynamics in pregnancy-related hypertension. A prospective transcranial Doppler study.

AIM: To compare maternal cerebral hemodynamics, as assessed by transcranial Doppler studies, with the clinical and radiological findings in different types of pregnancy-related hypertension and to determine their pathophysiology. METHODS: A prospective study of 66 consecutive pregnant women with hypertensive disorders (eclampsia, n = 3; pre-eclampsia, n = 41; isolated hemolysis, elevated liver enzymes, and low platelet count (HELLP)-syndrome, n = 12; pre-eclampsia superimposed on chronic hypertension, n = 5; chronic hypertension, n = 5) and 21 women with uncomplicated pregnancies. Mean blood flow velocities (Vmean) were assessed serially by means of transcranial Doppler in all basal arteries and correlated with changes in mean arterial blood pressure (MABP) and the clinical course. RESULTS: Patients with the pre-eclampsia/eclampsia syndrome showed significantly elevated Vmean values as compared to controls. In the course of the illness Vmean over the whole length of all insonated basal arteries rose simultaneously. The three eclamptic patients showed the highest Vmean values (156, 182, 192 cm/s, respectively), of the middle cerebral artery (MCA) while MABP was 135, 135, and 150 mmHg, respectively. In pre-eclamptic patients the maximal Vmean MCA ranged from 80 (67, 93) to 145 (114, 151) cm/s [median (25th, 75th percentile)] depending on the severity of clinical presentation. In patients with isolated HELLP-syndrome changes in Vmean were either mild (5/12 cases) or absent (7/12 cases). CONCLUSIONS: Considerable differences in cerebral hemodynamics were observed in the various types of pregnancy-related hypertensive disorders examined in this study. Our findings in patients with pre-eclampsia/eclampsia syndrome suggest a breakdown of autoregulation with hyperperfusion and vasogenic edema being the most probable pathophysiological mechanism.

Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke: relation to stroke etiology.

Recent studies suggest that high plasma levels of tissue-type plasminogen activator (tPA) and its inhibitor (plasminogen activator inhibitor-1, PAI-1) are markers of an increased risk of atherothrombotic ischemic events such as stroke and myocardial infarction. In this prospective study, we measured tPA antigen, PAI-1 antigen and activity, as well as tPA/PAI-1 complex in patients with acute stroke. Stroke subtypes were classified according to the TOAST criteria. From 132 consecutively screened patients, 89 (100%) were enrolled in this study, including 42 patients (47%) with large artery atherosclerosis (LAA), 32 (36%) with small vessel occlusion (SVO), and 15 (17%) with cardioembolism (CE). Nineteen age-matched neurologic patients without manifestations of cerebrovascular disease served as control subjects (CS). Patients with acute stroke had significantly higher plasma levels of tPA antigen (p < 0.001), PAI-1 antigen (p < 0.05) and PAI activity (p < 0.05) than patients in the control group. t-PA antigen, PAI activity and tPA/PAI-1 complex levels were similar regardless of stroke etiology. Only PAI-1 antigen was lower in patients with cardioembolic stroke than in stroke patients with LAA (p < 0.05). Plasma tPA antigen, PAI-1 antigen, and PAI activity are significantly increased in patients with acute ischemic stroke. Except for PAI-1 antigen, this increase appears not to be related to the underlying stroke etiology.

Spontaneous oscillations of arterial blood pressure, cerebral and peripheral blood flow in healthy and comatose subjects.

Slow and rhythmic spontaneous oscillations of cerebral and peripheral blood flow occur within frequencies of 0.5-3 min-1 (0.008-0.05 Hz, B-waves) and 3-9 min-1 (0.05-0.15 Hz, M-waves). The generators and pathways of such oscillations are not fully understood. We compared the coefficient of variance (CoV), which serves as an indicator for the amplitude of oscillations and is calculated as the percent standard deviation of oscillations within a particular frequency band from the mean, to study the impairment of generators or pathways of such oscillations in normal subjects and comatose patients in a controlled fashion. With local ethic committee approval, data were collected from 19 healthy volunteers and nine comatose patients suffering from severe traumatic brain injury (n = 3), severe subarachnoid hemorrhage (n = 3), and intracerebral hemorrhage (n = 3). Cerebral blood flow velocities were measured by transcranial Doppler ultrasound (TCD), peripheral vasomotion by finger tip laser Doppler flowmetry (LDF), and ABP by either non-invasive continuous blood pressure recordings (Finapres method) in control subjects, or by direct radial artery recordings in comatose patients. Each recording session lasted approximately 20-30 min. Data were stored in the TCD device for offline analysis of CoV. For CoV in the cerebral B-wave frequency range there was no difference between coma patients and controls, however there was a highly significant reduction in the amplitude of peripheral B-wave LDF and ABP vasomotion (3.8 +/- 2.1 vs. 28.2 +/- 16.1 for LDF, p < 0.001; and 1.2 +/- 0.7 vs. 4.6 +/- 2.8 for ABP, p < 0.001). This observation was confirmed for spontaneous cerebral and peripheral oscillations in the M-wave frequency range. The CoV reduction in peripheral LDF and ABP oscillations suggest a severe impairment of the proposed sympathetic pathway in comatose patients. The preservation of central TCD oscillations argues in favor of different pathways and/or generators of cerebral and peripheral B- and M-waves.

Peripartal temporal course of endothelin 1, angiotensin II, and atrial natriuretic peptide in pre-eclampsia and normotensive pregnancy.

OBJECTIVE: To investigate the temporal peripartal course of plasma endothelin 1 (ET-1), angiotensin II (ANG II), and atrial natriuretic peptide (ANP) in patients with pre-eclampsia as compared to women with normotensive pregnancy. METHODS: Levels of ET-1, ANG II, and ANP were measured by means of radio-immunoassay twice a week in 17 patients with pre-eclampsia and in 17 women with normotensive uncomplicated pregnancy during four different periods: (a) from admission to 1 week before delivery, (b) 1st week before delivery, (c) 1st week after delivery, and (d) 2nd week after delivery. RESULTS: ET-1 levels were not statistically different between the two groups. ANG II concentrations were lower in the pre-eclampsia group than in the control group with statistical significance in period c (2.8 +/- 3.0 vs. 7.1 +/- 5.9 pg/ml, mean +/- SD). ANP levels were higher in pre-eclamptic women than in the control group, the difference being statistically significant in period a (54 +/- 46 vs. 11 +/- 16 pg/ml) and in period c (122 +/- 134 vs. 39 +/- 22 pg/ml). CONCLUSIONS: There are considerable differences in ANP and ANG II concentrations during the peripartal period between patients with pre-eclampsia and normotensive pregnant women. Decreased ANG II and elevated ANP levels in the 1st week postpartum may reflect the clinical observation that some women deteriorate in this period.

Intracranial vascular stenosis and occlusion: comparison of 3D time-of-flight and 3D phase-contrast MR angiography.

We compared the value of 3D time-of-flight (TOF) and phase-contrast (PC) MR angiography (MRA) for detection and grading of intracranial vascular steno-occlusive disease. Unenhanced 3D-TOF MRA and 3D-PC MRA (30-60 cm/s velocity encoding) were performed at the level of the circle of Willis in 18 patients, mean age 56 +/- 10 years. Postprocessed images using a maximum-intensity projection reconstruction with multiple targetted projections were analysed. A total of 126 vessels was assessed by PC MRA and 143 by TOF MRA, with digital subtraction angiography (DSA) in 15 patients and/or transcranial Doppler sonography (TCD) in 18 as a standard. Two blinded readers reviewed the MRA, DSA and TCD examinations retrospectively. On DSA and/or TCD the two observers found 32 and 28 steno-occlusive lesions. 3D-TOF MRA was more sensitive than 3D-PC MRA (87% and 86% vs. 65% and 60%) and had a higher negative predictive value (96% vs. 89%). Correct grading of stenoses was achieved in 78 % by 3D-TOF and 65% by 3D-PC MRA.

Cerebral hemodynamics during induced tachycardia in routine electrophysiologic studies: a transcranial Doppler study.

Supraventricular and ventricular tachyarrhythmia are established causes of syncope. We investigated the mean blood flow velocities (Vmean) of the middle cerebral arteries (MCA) during routine cardiac electrophysiologic studies in patients with supraventricular and ventricular tachyarrhythmias in order to evaluate the changes in cerebral hemodynamics associated with pre-syncopal and syncopal states. Thirty-two patients with a history of supraventricular (n = 14) or ventricular (n = 18) tachyarrhythmias were investigated in the nonsedated, post-absorptive state in supine position. Vmean was assessed in both MCAs by means of transcranial Doppler under resting conditions, during atrial and ventricular pacing at constant rates (n = 28) and during induction of tachyarrhythmia (n = 4). Mean arterial blood pressure (MABP) and heart rate were also recorded. Seven patients suffered pre-syncope at a heart rate of 187 +/- 45 bpm (mean +/- SD) with an average drop of 44% in the Vmean MCA, and statistically insignificant changes in MABP. Five patients suffered syncope during tachyarrhythmia (mean heart rate 283 +/- 42 bpm) with a reduction of 69% in the Vmean MCA. MABP could be assessed in two of those patients and showed a drop of 15 and 43 mmHg, respectively. During tachyarrhythmia pre-syncope and syncope are associated with an average reduction in Vmean MCA by 44% and 69%, respectively. The decrease in MCA blood flow velocity is a more important predictive factor for the development of pre-syncope and syncope than the MABP.

Intracranial microembolic signals in 500 patients with potential cardiac or carotid embolic source and in normal controls.

BACKGROUND AND PURPOSE: We undertook this study to evaluate the prevalence and clinical correlations of Doppler microembolic signals (MES) in stroke-prone patients. METHODS: Patients with potential cardiac (n = 300) or carotid (n = 100) embolic source and control subjects (n = 100) were monitored with transcranial Doppler sonography for MES. Transthoracic (n = 192) and/or transesophageal (n = 134) echocardiography and carotid studies (continuous-wave Doppler, n = 181; color-coded duplex, n = 47) were performed in all patients with potential native cardioembolic source. Carotid disease was evaluated by means of continuous-wave Doppler (n = 87), color-coded duplex (n = 70), or intra-arterial angiography (n = 24) in patients with potential carotid embolic source. RESULTS: Overall MES prevalence was 23% in patients with potential native cardioembolic source (infective endocarditis [n = 7] 43%, left ventricular aneurysm [n = 38] 34%, intracardiac thrombus [n = 23] 26%, dilative cardiomyopathy [n = 39] 26%, nonvalvular atrial fibrillation [n = 24] 21%, valvular disease [n = 80] 15%), 55% in patients with prosthetic cardiac valves (mechanical [n = 77] 58%, porcine [n = 7] 43%, homografts [n = 5] 20%), 28% in patients with carotid disease (symptomatic [n = 46] 52%, asymptomatic [n = 54] 7%; P < .01), and 5% in control subjects. No relationship between MES counts and patients' age, sex, or actual medication was noted. The sensitivity and specificity of MES detection in identifying patients with potential embolic sources were 31% and 95%, respectively. CONCLUSIONS: Our study confirmed the reported clinical significance of MES in patients with carotid disease and the high specificity of this technique. The demonstrated low sensitivity of MES detection could be due to short monitoring duration or application of antihemostatic treatment. Prospective large-scale studies are needed to determine the definitive value of MES detection as a diagnostic method in patients with potential cardioembolic source.

Detection of microembolic signals in patients with middle cerebral artery stenosis by means of a bigate probe. A pilot study.

BACKGROUND AND PURPOSE: Middle cerebral artery (MCA) stenosis is a relatively rare occlusive disease with an annual stroke risk of approximately 7% to 8%. However, the frequent coincidence of cardiac or ipsilateral carotid artery disease may lead to difficulties in identifying the relevant embolizing source in symptomatic patients. We undertook this study to evaluate the prevalence of microembolic signals (MES) as well as the potential and limitations of bigate monitoring in patients with MCA stenosis. METHODS: Fourteen patients aged 33 to 87 years with angiographically demonstrated symptomatic (acute, n = 2; chronic, n = 8) or asymptomatic (n = 4) MCA stenosis were examined. Six patients (43%) had additional cardiac (n = 3) or carotid artery (n = 3) disease. By means of a bigate probe, simultaneous insonation of prestenotic and poststenotic vessel segments was attempted. RESULTS: In 10 patients (71%), MES detection could be performed sufficiently at target vessel sites. In the remaining patients, either prestenotic (n = 3) or poststenotic (n = 1) monitoring was not satisfactory due to insufficient transtemporal bone window or the great length or extent of MCA stenosis. Poststenotic MES were detectable in 2 acutely symptomatic and 1 asymptomatic patient (prevalence, 21%). In the latter case, the sequential appearance of MES in both prestenotic and poststenotic channels excluded MCA stenosis but strongly favored coexisting carotid artery stenosis as the active embolic source. CONCLUSIONS: MES are detectable in patients with MCA stenosis. Bigate monitoring in this setting is feasible and allows identification of the active source among "competing" embolizing conditions.

A novel technique for identification of doppler microembolic signals based on the coincidence method: in vitro and in vivo evaluation.

BACKGROUND AND PURPOSE: The applicability of a novel differentiation technique in embolus detection based on the coincidence principle and using a multigate probe was evaluated in this study. METHODS: According to the coincidence method, high-intensity transients should only be classified as microembolic signals if they appear sequentially in the two sample volumes monitored and within a defined time window calculated from the blood velocity and the spatial distance between the insonation depths. Part A: microbubbles were introduced in a continuous flow bench model of the middle cerebral artery to evaluate the accuracy of the multigate probe in embolus detection. Part B: in the subjects and patients, the minimal and maximum time delays in the appearance of microembolic signals in the two middle cerebral artery sample volumes were calculated as 0.01 second and set at 0.1 second, respectively. The multigate probe was used to monitor (1) 5 normal volunteers in whom 1008 artifact signals were produced,(2) 2 patients undergoing aortic valve replacement surgery, and (3) 12 patients with potential cardiac or carotid embolic sources. RESULTS: In the bench model, 95.5% of microembolic signals produced by microbubbles appeared in the two sample volumes with a time delay between 0.02 and 0.05 second, while in the remaining 4.5% a shorter passage time of 0.01 second was measured. A total of 1968 high-intensity signals were recorded in subjects and patients. All but 20 of these (99%) appeared in both monitoring channels within the above time frame. To summarize, 996 (98.8%) of the 1004 artifact signals and 943 (98.1%) of the 961 microembolic signals were correctly classified. CONCLUSIONS: Application of the coincidence theory to distinguish microembolic signals from artifacts provides a promising new technique with high sensitivity and specificity that could decisively improve the validity of embolus detection.

Hyperinsulinism and cerebral microangiopathy.

BACKGROUND AND PURPOSE: High insulin levels are a recognized risk factor for atherosclerosis. Microvascular endothelium is more susceptible to metabolic and mitogenic effects of insulin than large-vessel endothelium. Besides their atherogenic effect, high insulin levels impair fibrinolysis by enhancing plasminogen activator inhibitor-1. We undertook this study to evaluate the hypothesis that elevated serum insulin and C-peptide levels are related to cerebral small-vessel disease rather than large-vessel pathology. METHODS: One hundred ninety-four consecutive patients presenting with symptomatic cerebrovascular disease were assigned to three subgroups that were differentiated by clinical presentations, brain imaging studies, and extracranial as well as transcranial vascular ultrasound findings: (1) patients with lacunes (n = 20), (2) patients with subcortical arteriosclerotic encephalopathy (n = 35), and (3) patients with strokes due to large-vessel disease (n = 99). Patients who had suffered a cryptogenic (n = 9) or cardioembolic (n = 16) stroke or who showed characteristics of the microangiopathy and macroangiopathy groups (n = 15) were not further evaluated. Thirty patients without manifestations of cerebrovascular disease were also examined. Fasting blood glucose, insulin, and C-peptide levels were determined in all subjects. RESULTS: There were no significant differences in age or sex among the three groups and control patients. Insulin levels were significantly higher in the lacunar group compared with the subcortical arteriosclerotic encephalopathy group, the macroangiopathy group, and the control patients (median [interquartile range]: 103.8 [198.6], 72.0 [103.2], 66.0 [57.0], and 52.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney test). There was a statistically significant difference in insulin concentrations between the microangiopathy group (subcortical arteriosclerotic encephalopathy and lacunes) and the macroangiopathy and control groups (81.0 [110.4], 66.0 [57.0], and 55.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney). The same was true for the distribution of C-peptide levels and to a minor extent blood glucose values, but these differences failed to reach statistical significance. CONCLUSIONS: Elevated insulin levels potentially represent a pathogenetic factor in the development of cerebral small-vessel disease, predominantly in patients presenting with lacunes. Whether this is due solely to atherosclerotic changes of the small penetrating arteries or whether changes in hemorheology are operative as well remains to be evaluated.

Cerebral hemodynamics in pre-eclampsia/eclampsia syndrome.

Pre-eclampsia and eclampsia represent a syndrome with progressive pregnancy-induced hypertension. They are associated with considerable morbidity and mortality. The pre-eclampsia/eclampsia syndrome has been hypothesized to reflect a subtype of hypertensive encephalopathy. Additionally, an endothelial dysfunction with impaired cerebral autoregulation has been proposed. Neurological symptoms in hypertensive encephalopathy have been attributed to marked vasospasm or forced vasodilatation. This study was undertaken to evaluate the changes in cerebral hemodynamics due to this syndrome. Twelve patients with pre-eclampsia/eclampsia syndrome, five of them with a concomitant syndrome involving hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), were investigated. Mean blood flow velocities of the middle, anterior and posterior cerebral arteries were assessed bilaterally by means of a 2-MHz, pulsed Doppler ultrasound device. After the initial diagnosis, follow-up examinations were performed twice a week until delivery, and then weekly over a 4-week period postpartum. Intracranial arterial blood flow velocities were elevated in ten out of 12 patients. Values of up to twice the normal flow velocities were observed in individual cases. Flow velocities correlated with the systemic arterial blood pressure (r = 0.75, p = 0.008). Eight patients showed pathologically increased flow velocities despite a mean arterial blood pressure below 150 mmHg. Our preliminary findings suggest that a forced vasodilatation, probably due to passive overdistension of cerebral arterioles and vasogenic edema rather than vasospasm, is responsible for the observed high cerebral flow velocities. We hypothesize that endothelial dysfunction plays a crucial role in the altered cerebral hemodynamics in the pre-eclampsia/eclampsia syndrome.

Variability of Doppler microembolic signal counts in patients with prosthetic cardiac valves.

BACKGROUND AND PURPOSE: The purpose of this study was the evaluation of intraobserver, interobserver, and intrasubject variability in the Doppler detection of microembolic signals in patients with mechanical prosthetic valves. Simultaneously, the feasibility of automated embolus detection by means of a neuronal network was investigated. METHODS: From 25 patients with mechanical prosthetic heart valves, single transcranial Doppler monitoring sessions of 30 minutes' duration were recorded on videotape, randomized, and subsequently analyzed by eight independent trained observers from three centers. Three observers evaluated these tapes on three separate occasions, blinded to their previous results. An additional 48 patients with prosthetic heart valves were repetitively monitored with transcranial Doppler ultrasonography for 30 minutes three times within 1 year to examine the long-term variability in the occurrence of microembolic signals. Finally, in an effort to assess the short-term intrasubject variability, 20 patients were examined for 90 minutes, and the results of the three 30-minute periods were compared. The interobserver, intraobserver, and intrasubject (both short- and long-term) variability was evaluated. RESULTS: No significant differences in microembolic signal counts were found among the different observers, between the human observers and the neuronal network, or among the three separate evaluations of stored data by the same observer. The same was true for repeat examinations of the same patient (P > .05, Student's two-paired t test and Friedman's test). CONCLUSIONS: The detection of microembolic signals in patients with prosthetic cardiac valves is a reproducible technique. The reliable performance of the neuronal network argues for a broader use of this device. The intrasubject stability of the microembolic rate over 1 year supports the concept that the underlying emboligenic process is associated with intrinsic mechanical properties of the valve implant and not due to a thromboembolic process in the heart.