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Background and Purpose: Recent evidence suggests current best medical treatment may be sufficient to prevent stroke in patients with asymptomatic carotid stenosis. If this is the case, then it is important to determine risk reduction provided by treatments. Using Asymptomatic Carotid Emboli Study (ACES) prospective data, the effect of current treatment and risk factors on future stroke and transient ischemic attack risk were determined., Methods: Four-hundred seventy-seven patients with asymptomatic carotid stenosis were followed-up every 6 months for 2 years. Changes in risk factors and stroke prevention therapies were reviewed at each visit. Using time-dependent Cox regression, the relationship between current treatment over time was determined and presented as hazard ratios and 95% confidence intervals for risk of stroke, transient ischemic attack, and cardiovascular death end points., Results: On multivariate analysis, antiplatelets (P=0.001) and lower mean blood pressure (P=0.002) were independent predictors of reduced risk of ipsilateral stroke and transient ischemic attack. Antiplatelets (P<0.0001) and antihypertensives (P<0.0001) were independent predictors of a lower risk of any stroke or cardiovascular death., Conclusions: Antiplatelet therapy and blood pressure control are the most important factors in reducing short-term stroke and cardiovascular risk in patients with asymptomatic carotid stenosis. More prospective data are required for medical treatments in asymptomatic carotid stenosis in particular for current statin usage.

Background and Purpose: Improved methods are required to identify patients with asymptomatic carotid stenosis at high risk for stroke. The Asymptomatic Carotid Emboli Study recently showed embolic signals (ES) detected by transcranial Doppler on 2 recordings that lasted 1-hour independently predict 2-year stroke risk. ES detection is time-consuming, and whether similar predictive information could be obtained from simpler recording protocols is unknown., Methods: In a predefined secondary analysis of Asymptomatic Carotid Emboli Study, we looked at the temporal variation of ES. We determined the predictive yield associated with different recording protocols and with the use of a higher threshold to indicate increased risk (≥2 ES). To compare the different recording protocols, sensitivity and specificity analyses were performed using analysis of receiver-operator characteristic curves., Results: Of 477 patients, 467 had baseline recordings adequate for analysis; 77 of these had ES on 1 or both of the 2 recordings. ES status on the 2 recordings was significantly associated (P<0.0001), but there was poor agreement between ES positivity on the 2 recordings (κ=0.266). For the primary outcome of ipsilateral stroke or transient ischemic attack, the use of 2 baseline recordings lasting 1 hour had greater predictive accuracy than either the first baseline recording alone (P=0.0005), a single 30-minute (P<0.0001) recording, or 2 recordings lasting 30 minutes (P<0.0001). For the outcome of ipsilateral stroke alone, two recordings lasting 1 hour had greater predictive accuracy when compared to all other recording protocols (all P<0.0001)., Conclusions: Our analysis demonstrates the relative predictive yield of different recording protocols that can be used in application of the technique in clinical practice. Two baseline recordings lasting 1 hour as used in Asymptomatic Carotid Emboli Study gave the best risk prediction.

The importance of lowering blood pressure (BP) in hypertensive subjects is well-known and recent studies suggest that lowering of BP in patients who may already be in the normotensive range further reduces the risk of vascular events, particularly stroke. Epidemiological data have also shown that lower BP and antihypertensive treatment may be associated with cognitive impairment once cerebrovascular disease is established. However, the relationship between hypertension and cerebrovascular disease is more complex than suggested by epidemiological or intervention studies. Cerebral imaging studies have shown that cerebral blood flow (CBF) is reduced in areas of small-vessel disease (SVD) and the degree of hypoperfusion correlates with disease severity. Furthermore, impaired neuropsychological performance has been found to correlate with cerebral hypoperfusion in patients with established SVD. These findings raise questions surrounding the desirability of lowering of BP beyond a certain level in such patients. It is conceivable that indiscriminate BP reduction may compromise cerebral perfusion and function in these patients, increasing the risk of cognitive decline and cerebrovascular disease progression. Randomized clinical trials addressing the relationship between antihypertensive treatment and vascular cognitive impairment are lacking. Further studies are therefore needed to assess the cognitive consequences of BP reduction in people with established cerebrovascular disease. This will help to direct appropriate protective strategies and treatments in a vulnerable group of people, many of whom have hypertension and cerebrovascular disease at the same time.

Background and Purpose: Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5' flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160)., Methods: Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO(x)) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis., Results: The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86; P=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (P=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO(x) levels were associated with the T-786C locus (P=0.03) but only in the presence of the intron 4a allele (P=0.07 for interaction)., Conclusions: The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.

Background and Purpose: Individuals of African Caribbean descent who live in the United Kingdom have an increased risk of stroke. The reasons for this are not fully understood, but differences in genetic predispositions or other novel stroke risk factors could play a role. US blacks have been reported to have increased common carotid artery wall thickness, or intima-media thickness (IMT), measured by ultrasound. We measured carotid IMT in UK African Caribbeans compared with UK whites and determined whether different distributions of polymorphisms in potential candidate vascular genes or differences in measures of chronic inflammation or infection could account for any difference., Methods: In a population study, common carotid artery IMT was measured in 202 white men and 89 African Caribbean men. The distribution of polymorphisms in ACE, paraoxonase 1, paraoxonase 2, and methylenetetrahydrofolate reductase genes was determined. Serum C-reactive protein and Helicobacter pylori seropositivity were determined., Results: Carotid IMT was increased in African Caribbeans even after controlling for cardiovascular risk factors, including homocysteine and social class: beta=0.113, 95% CI 0.036 to 0.189, P=0.004. There was a significant interaction with smoking and mean IMT (P=0.022), and the difference in both measures of IMT between ethnic groups was largely limited to individuals who had never smoked. There were significant ethnic differences in the distributions of 3 of the 4 candidate genes studied (ACE, paraoxonase 1, and methylenetetrahydrofolate reductase). H pylori seropositivity was increased in African Caribbeans (78.7% versus 53% in UK whites). However, neither the genetic polymorphisms nor H pylori seropositivity was related to IMT, and ethnic differences in their distribution did not account for the increased IMT seen in African Caribbeans., Conclusions: Carotid IMT is increased in UK African Caribbeans even after controlling for conventional risk factors. There are highly significant ethnic differences in the distribution of many potential cerebrovascular candidate genes. Although those we examined did not explain the ethnic differences in IMT, other genetic predispositions or environmental exposures could account for these differences.

Background and Purpose: Asymptomatic embolic signal detection with the use of Doppler ultrasound has a number of potential clinical applications. However, its more widespread clinical use is severely limited by the lack of a reliable automated detection system. Design of such a system depends on accurate characterization of the unique features of embolic signals, which allow their differentiation from artifact and background Doppler speckle. We used a processing system with high temporal resolution to describe these features. We then used this information to design a new automated detection system., Methods: We used a signal processing approach based on multiple overlapping band-pass filters to characterize 100 consecutive embolic signals from patients with carotid artery disease as well as both episodes of artifact resulting from probe tapping and facial movement and episodes of Doppler speckle. We then designed an automated detection system based both on these embolic signal characteristics and on the fact that embolic signals have maximum intensity over a narrow frequency range. This system was tested in real time on stored 5-second segments of data., Results: The value of peak velocity at maximal intensity discriminated best between embolic signals and artifact and allowed differentiation with 100% sensitivity and specificity. Relative intensity increase, intensity volume, area under volume, average rise rate, and average fall rate appeared to discriminate best between embolic signals and Doppler speckle. For the majority of embolic signals, the intensity increase was spread over a narrow frequency or velocity range. The automated system we developed detected 296 of 325 carotid stenosis embolic signals from a new data set (sensitivity, 91.1%). All 200 episodes of artifact from a new data set were differentiated from embolic signals. Only 2 of 100 episodes of speckle were misidentified as embolic signals., Conclusions: Using a novel system for automated detection, which utilizes the fact that embolic signals have maximum intensity over a narrow frequency range, we have achieved detection with a high sensitivity and high specificity. These results are considerably better than those previously reported. We tested this initial system on short 5-second segments of data played in real time. This approach now needs to be developed for use in a true online system to determine whether it has sufficient sensitivity and specificity for clinical use.

Background and Purpose: Carotid percutaneous transluminal angioplasty (PTA) is a new method of treating carotid artery stenosis. There has been concern about restenosis after carotid PTA. This study was performed to ascertain the change in percent stenosis 1 year after carotid PTA., Methods: Twelve patients with symptomatic carotid stenosis were treated by PTA, and the anatomic result was studied by digital subtraction angiography at 1 year, supplemented by duplex ultrasound examinations at 1 month and 6 months., Results: The mean severity of stenosis treated, measured by the common carotid method, was 82% (range, 69% to 98%). The immediate result of PTA was a reduction in the severity of stenosis in all patients to a mean of 51% (P<.005). Six of the 12 patients showed a further improvement in lumen diameter of > or = 14% at 1-year angiographic follow-up from a mean stenosis of 47% (range, 24% to 76%) immediately after PTA to 28% (range, 0% to 52%) at 1 year. This indicates an active process of remodeling in response to carotid PTA. PTA initially reduced the stenosis by > or = 20% in 9 of the 12 arteries, and 8 of these remodeled or remained largely unchanged compared with only 1 of the 3 with a suboptimal initial dilation. In 3 patients the lumen diameter improved by < 5%. Three other patients restenosed with an increase in stenosis after PTA of 9%, 16%, and 66% at 1 year, but all were asymptomatic. The duplex findings showed that remodeling occurred at variable times between PTA and 1 year., Conclusions: Remodeling of the carotid artery after PTA has not been described before. Our results confirm that carotid angioplasty has an acceptable patency rate at 1 year. It has been suggested that endovascular treatment of carotid stenosis should include placement of a stent. Our results indicate that this may not be necessary unless the initial PTA result is a reduction in stenosis of < 20%.

Background and Purpose: There has been concern regarding the reproducibility of the detection of embolic signals, particularly in patients with carotid artery stenosis in whom the signals are of low intensity. No published studies have examined inter-center agreement in reporting specific embolic signals or the factors responsible for any lack of agreement. We examined reproducibility between two centers in which widely differing proportions of embolic signals have previously been reported in patients with carotid artery stenosis., Methods: Recordings from the middle cerebral artery of eight patients with ipsilateral carotid artery stenosis in whom embolic signals had been detected during a previously study were independently examined by three experienced observers in one center and by one experienced observer in another center. We calculated agreement within and between centers by estimating the probability that one observer would identify a specific embolic signal if other observers had identified it (a probability of 1 indicates complete agreement). The influence of different characteristics of the embolic signal on the probability of its detection as an embolic signal was determined., Results: A high level of agreement in the identification of specific embolic signals was found. This was similar between all observers (.90), between the three observers in one center (.89), and between observers in the two different centers (.94). The probability of detection was independently related to the relative intensity of the embolic signal (P<.0001). It was less (although significantly) independently related to the position of the embolic signal in the cardiac cycle (P=.02), with signals in systole being more reliably detected. There was no independent relationship between the probability of detection and either the duration of the embolic signal or the velocity at the maximum intensity increase. The use of threshold intensity as a criterion for embolic signal detection increased interobserver agreement but reduced the sensitivity in detecting signals., Conclusions: The high level of interobserver agreement suggests that the technique is sufficiently reproducible for clinical use.

Background and Purpose: The detection of asymptomatic embolic signals by Doppler ultrasound may offer a powerful investigational tool in the management of cerebrovascular disease. However, early studies, particularly in patients with carotid artery disease, have reported very different frequencies of embolic signals. While this may reflect differences in patient groups and the criteria used for embolic signal identification, the degree of time-window overlap may be important. If this is insufficient, some embolic signals may fall between two time windows and not appear on the spectral display. Furthermore, the use of nonrectangular time windows, such as the Hanning window, may result in variation of the intensity of an embolic signal depending on where it is detected within the time window., Methods: To test the importance of this potential problem, the same 25 embolic signals recorded as the audio signal on digital audiotape were each played repeatedly through a transcranial Doppler ultrasound (TCD) system using fast Fourier transform analysis. An older system with no time-window overlap was used, and a more modern system was also used in which three different degrees of overlap were used: -9%, 27%, and 57%. The number of signals audible but not appearing on the spectral display was recorded. The variability in the relative intensity increase for the same embolic signal played repeatedly was estimated by calculating the coefficient of variation of the relative intensity increase., Results: With the older system, 39/500 (7.8%) of embolic signals were missed. With the newer system, the number of embolic signals missed was fewer and decreased with increasing degrees of overlap (10/500 for -9% overlap, 1/500 for 27% overlap, and 0/500 for 57% overlap). For those setups in which embolic signals were missed, there was a highly significant relationship between duration of embolic signal and number of signals missed. In parallel with these results, the coefficient of variation of the relative intensity increase became progressively less with increasing degrees of time-window overlap. For all processing setups, the coefficient of variation was greater for the less intense and shorter duration signals, but this dependence, as estimated by the slope of the regression line, became less strong with higher degrees of overlap., Conclusions: Inadequate degrees of fast Fourier transform time-window overlap will result in the failure of current TCD machines to detect embolic signals. Furthermore, this and the time windowing currently usually used may result in variability in the relative intensity increase of identical embolic signals. These factors need to be taken into account when comparing data on the frequencies of embolic signals recorded by different researchers and in the design of future TCD equipment.

Background and Purpose: Transcranial Doppler ultrasound can detect circulating cerebral emboli. Monitoring of patients with potential embolic sources may allow identification of high-risk patients who can then be selected for prophylactic treatment. However, practical patient monitoring will require automated programs that can detect emboli and differentiate them from artifact., Methods: A new off-line algorithm for the detection of emboli, which detects the characteristic relative power increase occurring with an embolus, was evaluated in both an animal model and in patients. (1) In a sheep model, solid embolic materials (thrombus, platelet aggregates, and atheroma) were introduced into the proximal carotid artery while the distal carotid artery or a major branch was insonated. The signals resulting from 77 emboli (mean size, 1.77 mm) were studied and compared with the Doppler signals resulting from artifact. (2) In patients, 100 embolic signals occurring in three patients were analyzed and compared with signals associated with artifact in the same patients., Results: (1) In the sheep model, emboli resulted in a short-duration, high-intensity signal, but intensity increase alone did not distinguish between emboli and artifact. In contrast, the algorithm discriminated embolus from artifact with a sensitivity of 98.7% and a specificity of 98.0%. (2) In patient studies, embolic signals were differentiated from artifact with a sensitivity of 97.2% and a specificity of 97.0% by the algorithm., Conclusions: Using such an algorithm, detection of cerebral emboli and discrimination from artifact are possible with a high sensitivity and specificity. Incorporation of such an algorithm into an on-line system should make prolonged patient monitoring practical.

Background: The identification of gaseous emboli using Doppler ultrasound was described as early as the 1960s. Recently it has been demonstrated that this method can also detect solid emboli such as thrombi and platelet aggregates. This may make this technology useful in a large number of patients with, or at risk of, embolic stroke., Summary of Review: Emboli appear as short-duration, high-intensity signals in the Doppler spectrum. The intensity of the Doppler signal from an artery containing an embolus depends on the density difference between the embolic material and blood. This difference is greatest for gaseous emboli, which are therefore the most easy to detect. Gaseous emboli have been demonstrated during deep-sea diving, and their presence correlates with the occurrence of decompression sickness. Similar signals have been detected during cardiopulmonary bypass. A relation has been demonstrated between the number of emboli detected by transcranial Doppler and a decline in neuropsychological function after cardiopulmonary bypass. Solid emboli such as thrombi and platelet aggregates result in less intense signals than air emboli. Their detection, using Doppler ultrasound, has recently been described in patients with prosthetic heart valves, atrial fibrillation, and carotid artery disease. It may also help in the detection and localization of embolic sources in patients with stroke. Studies in in vitro and in vivo models demonstrate that this technique provides information on the size and type of emboli. Larger emboli produce signals of greater intensity and duration. Practical patient monitoring will require automatic emboli detectors incorporated into the Doppler machine; such programs are being developed., Conclusions: Detection of solid emboli using Doppler techniques offers an exciting new diagnostic tool. It has been demonstrated that the technique can detect solid emboli. The prognostic significance of such emboli remains to be determined. It is hoped that the technique will allow detection of patients at high risk of embolic stroke in whom appropriate prophylactic treatment can then be instituted.