Quantitative electroencephalography in cerebral amyloid angiopathy.

OBJECTIVE: We investigated whether quantitative electroencephalography (qEEG) correlates with cognition and cortical superficial siderosis (cSS) in cerebral amyloid angiopathy. METHODS: We included patients with sporadic (sCAA) and hereditary Dutch-type CAA (D-CAA). Spectral measures and the phase lag index (PLI) were analyzed on qEEG. Cognition was assessed with the MoCA and cSS presence was scored on 3T-MRI. Linear regression analyses were performed to investigate these qEEG measures and cognition. Independent samples T-tests were used to analyze the qEEG measure differences between participants with and without cSS. RESULTS: We included 92 participants (44 D-CAA; 48 sCAA). A lower average peak frequency (ß[95 %CI] = 0.986[0.252-1.721]; P = 0.009) and a higher spectral ratio (ß[95 %CI] = -0.918[-1.761--0.075]; P = 0.033) on qEEG correlated with a lower MoCA score, irrespective of a history of symptomatic intracerebral hemorrhage (sICH). The PLI showed no correlation to the MoCA. qEEG slowing was not different in those with or without cSS. CONCLUSIONS: Spectral qEEG (but not PLI) reflects cognitive performance in patients with CAA with and without a history of sICH. We found no association between qEEG slowing and cSS. SIGNIFICANCE: qEEG could be a valuable biomarker, especially in challenging cognitive testing situations in CAA, and a potential predictive tool in future studies.

Spontaneous preoperative microembolic signals detected with transcranial Doppler are associated with vulnerable carotid plaque characteristics.

AIM: Carotid plaque composition is associated with ipsilateral cerebrovascular events. Among patients with carotid artery stenosis, presence of microembolic signals (MES) detected with transcranial Doppler (TCD) is associated with increased stroke risk. We aimed to investigate whether MES detected with TCD in the outpatient clinic among patients scheduled for carotid endarterectomy, was associated with underlying carotid plaque composition. METHODS: TCD was used to detect MES among 38 symptomatic patients scheduled for carotid endarterectomy. Measurements were performed for 30 minutes. Carotid plaques harvested during CEA were subjected to histopathological examination. Plaques from patients without spontaneous MES were compared with plaques from patients with ≥1 MES. RESULTS: Median time between TCD and surgery was 4 days. At least 1 MES was detected in 10/38 (26%) patients. Five of ten (50%) patients with spontaneous MES had lipid-rich plaques, compared with 5/28 (17.2%) plaques from patients without MES (P=0.048). Luminal thrombus was observed in 6/10 (60.0%) of plaques from patients with MES compared with 7/28 (25.0%) of plaques from patients without MES (P=0.045). CONCLUSION: Spontaneous MES were detected in 26% of symptomatic patients scheduled for CEA and were associated with unstable carotid plaque characteristics. TCD might be a useful tool to help identify patients with vulnerable plaques.

High versus standard clopidogrel loading in patients undergoing carotid artery stenting prior to cardiac surgery to assess the number of microemboli detected with transcranial Doppler: results of the randomized IMPACT trial.

AIM: The aim of this study was to compare the effects of 300 mg or 600 mg clopidogrel loading dose, prior to carotid artery stenting (CAS) on the number of transcranial Doppler (TCD)-detected microembolic signals (MES) and to investigate the relationship between the magnitude of platelet reactivity and MES. METHODS: In this prospective randomized, double-blind study, 35 consecutive asymptomatic patients (17.1% females), scheduled for CAS and cardiac surgery were included. The primary endpoint was the number of TCD-detected MES. The secondary endpoints were the absolute magnitude of on-treatment platelet reactivity and the adverse cerebral events. Negative binomial regression to find predictors for sum of single emboli, the student's t-test to assess the association between platelet function tests and randomized dose of 300 mg or 600 mg clopidogrel, and the R2 calculation for the assessment of the association between platelet function tests and embolic load, were used. RESULTS: No statistically significant difference in the number of TCD-detected MES, in the sum of all the single emboli or showers and platelet aggregation measurements between the two groups was observed (aggregometry: 21.7±18.3 versus 23±18%, P=0.8499 and 45.8±17.5 versus 46.5±14.5%, P=0.9003) (verifyNow P2Y12 assay: 231±93 PRU versus 222±86 PRU, P=0.7704). In one patient a transient ischemic attack occurred. CONCLUSION: A loading dose of 300 mg of clopidogrel in combination with aspirin is as effective as 600 mg of clopidogrel in achieving adequate platelet inhibition and preventing periprocedural events in asymptomatic patients undergoing CAS prior to cardiac surgery.

Prediction of cerebral hyperperfusion after carotid endarterectomy with transcranial Doppler.

OBJECTIVES: To determine the diagnostic value for predicting cerebral hyperperfusion syndrome (CHS) by adding a transcranial Doppler (TCD) measurement in the early postoperative phase after carotid endarterectomy (CEA). DESIGN: Patients who underwent carotid endarterectomy between January 2004 and August 2010 and in whom both intra- and postoperative TCD monitoring were performed were included. METHODS: In 184 CEA patients the mean velocity (V(mean)) preoperatively (V1), pre-clamping (V2), post-declamping (V3) and postoperatively (V4) was measured using TCD. The intra-operative V(mean) increase ((V3 - V2)/V2) was compared to the postoperative increase ((V4 - V1)/V1) in relation to CHS. CHS was diagnosed if the patient developed neurological complaints in the presence of a preoperative V(mean) increase >100%. RESULTS: Sixteen patients (9%) had an intra-operative V(mean) increase >100% and 22 patients (12%) a postoperative V(mean) increase of >100%. In 10 patients (5%) CHS was diagnosed; two of those had an intra-operative V(mean) increase of >100% and nine postoperative V(mean) increase >100%. This results in a positive predictive value of 13% for the intra-operative and 41% for the postoperative measurement. CONCLUSIONS: Besides the commonly used intra-operative TCD monitoring additional TCD measurement in the early postoperative phase is useful to more accurately predict CHS after CEA.

Longer time interval between carotid cross-clamping and shunting is associated with increased 30-day stroke and death rate.

BACKGROUND: The benefit of carotid endarterectomy (CEA) in patients with a significant (>70%) (a)symptomatic stenosis has been proven thoroughly in major trials. It is unknown whether, after cross-clamping the carotid artery, the time interval between determination that a shunt is needed and the actual functioning of the shunt, defined as the need for shunt-to-shunt time (NST), influences 30-day morbidity and mortality rate after CEA. METHODS: Experienced vascular surgeons performed 851 CEAs with a selective shunting protocol based on perioperative transcranial Doppler measurement and electroencephalographic findings, and data were analyzed retrospectively. The study included 156 shunted patients. RESULTS: Longer NST was associated with an increase in the 30-day stroke/death rate. A binary logistic regression model was used to determine a 2-tailed P value of .004 and an odds ratio of 1.5/min increase of the NST. There was no influence on stroke-death rate of gender, age, symptomatic or asymptomatic stenosis, the use of a patch or not, or the number of periprocedural microembolic signals. CONCLUSION: If CEA is performed with a selective shunting protocol, a longer NST increases the 30-day stroke/death rate. These results support a strong recommendation that shunt placement should be as quick as possible.

The reliability of transcranial duplex scanning in parkinsonian patients: comparison of different observers and ultrasound systems.

PURPOSE: To establish the inter-observer and intra-transducer reliability of "on-line" and "off-line" assessment of substantia nigra (SN) and raphe nuclei (RN) by transcranial duplex scanning (TCD) in a mixed study population. MATERIALS AND METHODS: Out-patient neurology department of the University Hospital Maastricht. In total 24 subjects were investigated: 9 patients with idiopathic Parkinson's disease, 10 with parkinsonism from yet unclear origin, 1 with essential tremor and 4 healthy volunteers. Each patient was assessed four times by two independent experienced sonographers using two different ultrasound devices: SONOS 5500 and iU22; both Philips, Eindhoven, The Netherlands. The echointensity of the SN is evaluated qualitatively and quantitatively and the RN only qualitatively. 1. In the "on-line" assessment we determined: a) the inter-observer agreement of the four possible combinations. b) the intra-observer agreement of both sonographers using two different ultrasound systems. 2. In the "off-line" assessment a third sonographer re-examined the stored images. We determined the inter-observer agreement of the third sonographer with the "on-line" assessment of the other two sonographers. Cohen's k value was calculated for the agreement. RESULTS: 1a) The "on-line" inter-observer agreement of the four possible combinations of sonographer and transducer was: kappa 0.23 - 0.39 for the qualitative evaluation of the SN, kappa 0.31 - 0.56 for the quantitative evaluation of the SN and kappa 0.03 - 0.15 for the evaluation of the RN. 1b) The "on-line" intra-observer agreement was: kappa 0.53 - 0.67 for the qualitative evaluation of the SN, kappa 0.55 - 0.76 for the quantitative evaluation of the SN and kappa 0.45 - 0.47 for the evaluation of the RN. 2. The "off-line" inter-observer agreement was: kappa 0.32 - 0.67 for the qualitative evaluation of the SN, kappa 0.53 - 0.61 for the quantitative evaluation of the SN and kappa 0.08 - 0.33 for the evaluation of the RN. CONCLUSION: For the SN we found mediocre accordance comparing both observers "on-line" with each other as well as comparing an "off-line" observer with both "on-line" observers. On the whole, the inter-observer and intra-observer agreement were moderate to substantial for the evaluation of the SN. "On-line" and "off-line" comparisons yielded comparable results. The agreement for the evaluation of the RN, on the contrary, was considerably lower. Our findings indicate that this TCD technique is not yet ready for the application in large population screenings.

Retinal embolization during carotid angioplasty and stenting: periprocedural data and follow-up.

The purpose of this study was to prospectively evaluate the incidence of retinal emboli during carotid angioplasty and stenting (CAS) and to correlate emboli with clinical findings and transcranial Doppler (TCD)-detected cerebral embolic load. Between 2001 and 2005, 33 CAS procedures in 32 patients (23 [72%] male, 19 [58%] symptomatic, mean age 72.5 years [range 54.6 to 83.9]) scheduled for CAS were included in this study. Bilateral fundoscopy with retinal photography was performed by an experienced ophthalmologist immediately before, immediately after (fundoscopy only), and 1 day after the procedure and again at long-term follow-up (mean 37 months). Visual field testing was performed before CAS and again at long-term follow-up. TCD-detected cerebral emboli were stratified to five procedural phases: wiring, predilatation, stent placement, postdilatation, and cerebral protection device (CPD) use (if applicable). To establish correlation between TCD data and retinal embolization, Mann-Whitney test was used, and P < 0.05 was considered statistically significant. All procedures were performed successfully. In five of 33 procedures (15%), new retinal emboli were found. Two of the procedures with emboli had small retinal infarcts. Three of five were performed using CPDs versus seven of 28 that had no retinal emboli (P = not significant). Two of four patients (50%) with previous radiation therapy to the neck had new retinal emboli versus three of 29 patients (10%) who had no previous radiation therapy (P = 0.038). None of the other patient characteristics was associated with retinal embolization. In 30 (91%) of patients with an adequate acoustic temporal window for TCD monitoring, there was no statistically significant correlation between TCD data and the incidence of retinal emboli. No visual field defects were found. On long-term follow-up, all retinal emboli and retinal infarcts had resolved. Retinal embolization during CAS is not uncommon, and it occurs in both protected and unprotected procedures. Most retinal emboli are clinically silent.

Inhibition of cortical laser-evoked potentials by transcutaneous electrical nerve stimulation.

Objectives. This study attempts to confirm the hypothesis that transcutaneous electrical stimulation (TENS) of peripheral Aß fibers inhibits nociceptive processing, by quantifying the change of laser-evoked potential (LEP) components, using a 980-nm diode laser. Materials and Methods. Cutaneous heat stimuli were delivered to the dorsum of the right hand in 13 volunteers. LEPs and pain intensity ratings were recorded before, during, and after the use of TENS (110 Hz) at the dorsolateral forearm. Area under the curve (AUC), LEP amplitudes (N2P2), and peak latencies (N2, P2) were calculated. The paired samples t-test was used for statistical analysis. Results. A significant reduction of LEP amplitudes and AUC was found during and after the use of TENS (p < 0.05). After 10 min of TENS this was associated with a clinically relevant decrease of pain intensity. Conclusions. Our data suggest that TENS inhibits nociceptive processing. Ten minutes of TENS exerts a clinically relevant pain reduction.

Detection of leukocytes in contact with the vessel wall from in vivo microscope recordings using a neural network.

Leukocytes play an important role in the host defense as they may travel from the blood stream into the tissue in reacting to inflammatory stimuli. The leukocyte-vessel wall interactions are studied in post capillary vessels by intravital video microscopy during in vivo animal experiments. Sequences of video images are obtained and digitized with a frame grabber. A method for automatic detection and characterization of leukocytes in the video images is developed. Individual leukocytes are detected using a neural network that is trained with synthetic leukocyte images generated using a novel stochastic model. This model makes it feasible to generate images of leukocytes with different shapes and sizes under various lighting conditions. Experiments indicate that neural networks trained with the synthetic leukocyte images perform better than networks trained with images of manually detected leukocytes. The best performing neural network trained with synthetic leukocyte images resulted in an 18% larger area under the ROC curve than the best performing neural network trained with manually detected leukocytes.

Tumor angiogenesis factors reduce leukocyte adhesion in vivo.

Leukocyte-endothelium interactions are diminished in tumors. It is reported here that, in a tumor-free in vivo model, angiogenic factors can down-regulate leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a single intrascrotal injection of 1 microg/kg IL-1beta was given 4 h before vessels of the cremaster muscle were investigated for leukocyte rolling and adhesion by means of intravital microscopy. Exposure of normal tissue to either bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate enhancement of rolling by VEGF was found. The observed differences could not be explained by differences in fluid dynamic parameters or systemic leukocyte counts. In conclusion, evidence is presented that, in vivo, angiogenic factors significantly reduce leukocyte adhesion, the final step preceding leukocyte infiltration. This observation may explain why tumors escape from immune surveillance.

The influence of prostaglandins on leukocyte-endothelium interactions in rabbit mesenteric venules.

Contradictory results have been reported concerning the effects of prostaglandins (PGs) on leukocyte-endothelium interactions. Therefore, we investigated the in vivo effects of PGE1, PGE2, Iloprost (a stable PGI2-analogue), and also of a combination of these PGs on leukocyte rolling and FMLP-induced leukocyte adhesion in venules of rabbit mesentery. This preparation was used because of its low level of vasoactivity, eliminating hemodynamic effects on leukocyte-endothelium interactions. The mesentery was superfused with PGs or vehicle. After 30 min FMLP was added to the PG-solution for 15 min, whereupon the tissue was superfused with the PG-solution alone for another 30 min. Neither the PGs nor the cocktail influenced leukocyte rolling. During FMLP administration leukocyte adhesion increased and leukocyte rolling decreased; adhesion was highest in the presence of PGE2. The FMLP-induced decrease in leukocyte rolling was similar in all groups. After FMLP administration had been stopped the number of adherent cells almost returned to baseline and the level of leukocyte rolling increased, the baseline level being reached only in the presence of PGE2. In conclusion, these findings indicate that the effects of PGs on leukocyte-endothelium interactions are limited.

The role of mast cells and histamine in leukocyte-endothelium interactions in four rat strains.

The objective of the present study was to determine the role of mast cells and histamine in leukocyte-endothelium interactions in mesenteric venules of four rat strains: Brown Norway, Lewis, Sprague-Dawley and Wistar. Intravital microscopy showed that the mast cell stabilizer cromoglycate (5 mg/kg i.v. just before exteriorization of the mesentery) did not affect the baseline level and velocity of leukocyte rolling in any of the four strains. This finding is in agreement with the observation that cromoglycate pretreatment only slightly influenced mast cell degranulation in all strains except the Brown Norway. After mast cell stabilization, only in Sprague-Dawley did topical administration of histamine (10(-4) M) result in a significant increase in the level of leukocyte rolling and a decrease in the rolling velocity compared with the time control. Histamine induced leukocyte adhesion only in the Brown Norway strain. In conclusion, the hypothesis presented in other studies, that degranulation of mast cells, and more specifically the release of histamine, is of major importance for the induction of leukocyte-endothelium interactions in rat mesenteric venules is not generally applicable; the present study shows a clear strain dependency.

Angiogenesis modulates the tumour immune response.

Outgrowth of solid tumors and metastases is dependent on the process of angiogenesis. Tumors escape from the formation of an effective infiltrate by downregulation of endothelial adhesion molecules. This downregulation of adhesion receptors is governed by the exposure to angiogenic factors. In recent years proof for this has been provided by demonstrating that freshly isolated tumor endothelial cells exhibit a decreased expression of ICAM-1 and -2 as compared to endothelial cells in normal tissue. In addition, adhesion molecules are downregulated on normal tissue endothelial cells when cultured with angiogenesis stimulators such as basic fibroblast growth factor and vascular endothelial cell growth factor, while under these conditions endothelial cells become less responsive to cytokines such as tumor necrosis factor-alpha with respect to the upregulation of endothelial adhesion molecules. Very recently it has been demonstrated that this harmful endothelial cell anergy can be counteracted by inhibitors of angiogenesis.