Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. METHODS AND RESULTS: Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. CONCLUSIONS: In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis.

BACKGROUND AND PURPOSE: The goal of this study was to examine the hypotheses that retinal ischemia is caused more often by carotid atherosclerosis than by atrial fibrillation and that the odds of retinal events compared with hemispheric events increase with worsening carotid stenosis. METHODS: We used data from the Stroke Prevention in Atrial Fibrillation (SPAF) I through III trials and North American Symptomatic Carotid Endarterectomy Trial (NASCET), calculating hemispheric:retinal (H:R) odds for the territory of ischemic events during follow-up in patients with atrial fibrillation and medically treated 50% to 99% carotid stenosis or occlusion in the respective trials. RESULTS: The H:R odds were 25:1 in the SPAF aspirin-assigned patients and 2:1 for NASCET vessels. In NASCET patients, the H:R odds of recurrent ischemic events were 1:4 for vessels randomized initially for retinal symptoms compared with 6:1 for those randomized for hemispheric events (significant difference; P<0.001). Moreover, the H:R odds of first events in the territory of the contralateral asymptomatic artery were 1:1 if the randomized vessel had retinal symptoms compared with 4:1 if the randomized vessel had hemispheric symptoms (significant difference; P<0.01). Increasing carotid stenosis in the 50% to 99% range had no effect on H:R odds (P=0.8). CONCLUSIONS: These findings confirm that retinal symptoms are more typical of carotid stenosis. Hemodynamic effects do not appear to be more important in the pathogenesis of retinal events than hemispheric ones in carotid stenosis. The retinal versus hemispheric location of initial symptoms is strongly predictive of the location of subsequent events in patients with carotid stenosis, even when new symptoms are contralateral to the original ones.

Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. I. pH changes measured in states of altered PCO2.

The 11CO2 method for measuring local brain pH with positron emission tomography (PET) has been experimentally evaluated, testing the adequacy of the kinetic model and the ability of the method to measure changes in brain pH. Plasma and tissue time/activity curves measured during and following continuous inhalation of 11CO2 were fit with a kinetic model that includes effects of tissue pH, blood flow, and fixation of CO2 into compounds other than dissolved gas and bicarbonate ions. For each of ten dogs, brain pH was measured with PET at two values of PaCO2 (range 21-67 mm Hg). The kinetic model fit the data well during both inhalation and washout of the label, with residual root mean square (RMS) deviations of the model from the measurements consistent with the statistical quality of the PET data. Brain pH calculated from the PET data shows a linear variation with log(PaCO2). These results were in good agreement with previously reported measurements of brain pH, both in absolute value and in variation with PCO2. The interpretation of these pH values in normal and pathological states is discussed.

Frontal systems impairment following multiple lacunar infarcts.

To characterize cognitive impairments following multiple subcortical lacunar infarcts (lacunes), we prospectively compared the neuropsychological performance of 11 subjects with multiple lacunes with 11 medical control subjects matched for age and education who had no clinical or computed tomographic evidence of central nervous system disease. Subjects with multiple subcortical lacunes displayed neuropsychological signs of frontal system dysfunction, even though only 27% met the criteria for clinical diagnosis of dementia. They exhibited significant deficits in shifting mental set, response inhibition, and executive function. In addition, they were more often rated apathetic on a behavior-rating scale. We propose a continuum of cognitive impairments in lacunar states, ranging from frontal systems impairment to dementia.

Are multiple cerebral infarcts synergistic?

OBJECTIVE: The goal of this study was to characterize the cumulative effects of multiple strokes on cognition. DESIGN: We conducted a prospective, longitudinal case study with neuropsychological, neurological, and radiological evaluations. SETTING: Research was conducted at the Boston (Mass) Veterans Administration Medical Center, Neurology Service, on successive inpatient hospital admissions. PATIENT: We followed up a 66-year-old right-handed man with multiple subcortical lacunae during a 3.5-year period during which he suffered two additional cortical infarctions. MAIN OUTCOME MEASURES: Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cognitive domains (attention, language, memory, visuospatial functions, response inhibition, and mental flexibility), full neurological examination, and computed tomographic scan. RESULTS: The patient's stepwise cognitive decline was characterized by unexpected exacerbation of "frontal" neurobehavioral features following the occurrence of two posterior cortical lesions. At initial evaluation, the computed tomographic scan showed bilateral subcortical lacunae in basal ganglia and periventricular white matter, and symptoms included dysarthria and perseveration. The second evaluation, following a left posterior parietal lesion, revealed a range of new frontal features, including impulsivity, pull-to-stimulus, and difficulty shifting set. Following a subsequent right occipital infarct, further frontal lobe impairments emerged: forced grasp reflex and incontinence. CONCLUSIONS: We hypothesize that the cumulative effects of infarcts were synergistic. That is, the posterior cortical infarcts elicited frontal features that would not be expected from a simple sum of these lesions' effects.

Occlusive disease of the middle cerebral artery.

We studied 20 patients with severe occlusive disease of the mainstem middle cerebral artery (MCA) or its major division branches, and 25 patients with internal carotid artery (ICA) disease. MCA disease patients were more often black, female, younger, and had fewer TIAs than the ICA disease patients. Neurologic signs in patients with MCA disease evolved progressively during days to weeks, whereas ICA disease patients more often had an acute onset of nonprogressive deficits. CT commonly showed restricted subcortical or wedge-shaped infarcts in MCA disease patients. All MCA disease patients had stroke, but 40% of ICA disease patients had no infarction. MCA lesions usually affected the mainstem MCA or its major superior division. Patients with MCA disease seldom had recurrent ischemia in the same vascular territory as the stroke and had a low incidence of subsequent cardiac death.

Cerebellar hemorrhagic infarction.

We investigated 17 patients with 26 cerebellar hemorrhagic infarcts for their vascular anatomy, stroke mechanisms, and clinical course. Sixteen infarcts involved the superior cerebellar artery, nine the posterior inferior cerebellar artery, and one the anterior inferior cerebellar artery territories. The infarcts involved the full territory of the supplying arteries in 19 of 26 infarcts (73%). Sixteen of 17 patients were stable or improving when the hemorrhagic infarction was detected. All but one patient had an imaging study at the time of presentation that was negative for blood; hemorrhagic infarction was detected on routine serial scans performed during the first 15 days. Nine of the 17 patients were on anticoagulants when the cerebellar hemorrhagic infarct was detected; anticoagulation was maintained in eight of them with no clinical worsening. The stroke mechanism in all patients was considered embolic from cardiac and intra-arterial sources. The causes, imaging findings, and consequences of hemorrhagic infarcts in the posterior circulation are similar to those in the anterior circulation.

Effect of anticoagulation protocol on outcome in patients undergoing CABG with heparin-bonded cardiopulmonary bypass circuits.

BACKGROUND: We have demonstrated that the use of heparin-bonded cardiopulmonary bypass circuits (HBCs) combined with a lower anticoagulation protocol as an adjunct to an integrated blood conservation strategy decreases the incidence and magnitude of homologous transfusion and improves clinical outcome in patients undergoing primary coronary artery bypass grafting. It is not known whether it is the lower anticoagulation protocol that influences outcome in patients treated with HBCs. Furthermore, the thrombogenic risk of using lower anticoagulation with HBCs still is debated. METHODS: To answer these questions, a prospective randomized study was conducted in which 244 patients undergoing primary coronary artery bypass grafting were treated with HBCs and randomized to undergo either a full (activated clotting time, > 450 seconds) or a lower (activated clotting time, > 250 seconds) anticoagulation protocol. In addition to clinical outcome, levels of thrombin generation markers during and after cardiopulmonary bypass were assessed in a consecutive subset of 58 patients (full anticoagulation profile = 28, lower anticoagulation profile = 30) by measuring thrombin-antithrombin complexes and prothrombin fragment 1.2. Levels of these markers also were correlated with the activated clotting time during cardiopulmonary bypass. RESULTS: Preoperative and intraoperative risk profiles and other characteristics were similar in both groups, with more than 60% of patients undergoing nonelective operation. Compared with the full anticoagulation protocol group, patients in the lower anticoagulation protocol group were less likely to require blood products (24.2% versus 35.8%, respectively; p = 0.047) and received substantially fewer homologous donor units (0.50 +/- 0.92 versus 1.08 +/- 2.10 U, respectively; p = 0.005). Clinical outcomes were uniformly outstanding (but similar) in both treatment groups, with a modest reduction in the length of the hospital stay in the lower anticoagulation protocol group (5.26 +/- 1.23 versus 5.63 +/- 1.73 days, respectively; p = 0.05). The use of HBCs with a lower anticoagulation protocol was not associated with any adverse clinical events. Thrombin generation increased during cardiopulmonary bypass in both treatment groups, but was unrelated to the anticoagulation protocol or the activated clotting time (r2 = 0.03). No differences between the full and lower anticoagulation protocol groups were noted in the number of microemboli detected by transcranial Doppler analyses during cardiopulmonary bypass (n = 40) or in the postoperative neurologic and neuropsychologic outcomes (n = 30). CONCLUSIONS: This study definitively demonstrates that, when used appropriately, patients who are treated with HBCs and a lower anticoagulation protocol have a lower incidence and magnitude of homologous transfusion and are not at any added risk for clinical, hematologic (thrombin-antithrombin complex and fragment 1.2 measurements), or microscopic (transcranial Doppler analyses) thromboembolic complications or for neurologic or neuropsychologic deficits.

Lupus anticoagulant and cerebral infarction: therapeutic implications.

The clinical hematological and radiological findings in a patient with stroke and the lupus anticoagulant are presented, and therapeutic alternatives are reviewed. The importance of recognizing this association is stressed because of its potential therapeutic implications.

Importance of angle correction in the measurement of blood flow velocity with transcranial Doppler sonography.

BACKGROUND AND PURPOSE: The angle of insonation cannot be assessed with conventional transcranial Doppler sonography. Findings in healthy control subjects suggest that the angle is relatively small in routine clinical practice. Data regarding the angle in middle cerebral artery (MCA) stenosis are scarce. In this study, the angle and its effect on flow velocity measurements were assessed with transcranial color Doppler sonography in patients with MCA stenosis. METHODS: Eighteen patients (median age, 53 y; age range, 22-72 y) who satisfied qualifying criteria (eg, angiographically revealed unilateral MCA stenosis of > or =50%) were selected from 149 consecutive patients enrolled in a prospective study of transcranial color Doppler sonography and cerebral digital subtraction angiography. All had active neurologic symptoms. The angle of insonation and peak systolic and mean flow velocities in both MCAs were measured from videotapes generated at sonography. RESULTS: The mean angle of insonation was 47 +/- 11 degrees (range, 19-64 degrees ) on the stenotic side and 34 +/- 18 degrees on the contralateral side (P <.05). Angle-corrected velocities were higher than uncorrected ones. Differences between angle-corrected and uncorrected peak systolic and mean flow velocities on the stenotic side were 46.6% and 45.9%, respectively, of uncorrected values. Differences between corrected and uncorrected peak systolic and mean velocities were larger on the stenotic side compared with those on the contralateral side (P <.05). CONCLUSION: In patients with moderate or severe MCA stenosis, the angle of insonation can be substantial and cause large errors when flow velocities are measured without angle correction.

Collateral flow changes through the anterior communicating artery during carotid endarterectomy.

To evaluate early changes in collateral flow through the anterior communicating artery, 11 patients undergoing carotid endarterectomy were monitored. All had angiographically demonstrated collateral flow towards the hemisphere on the side of surgery. The middle cerebral artery ipsilateral to the operated side and the contralateral anterior cerebral artery were simultaneously insonated with a transcranial Doppler instrument equipped with dual transducers, and flow velocity values were obtained at specific surgical stages. Mean flow velocity in the contralateral anterior cerebral artery's A1 segment increased at clamp placement (p = 0.036), did not change during clamping, and decreased at clamp release (p = 0.004). The rise in velocity occurred within seconds of clamp placement in all patients with an increase, reaching the 10 cm/s threshold within 1 min. No consistent increase was detected after 5 min. A decrease in pulsatility index, indicating a drop in resistance, was detected at clamp placement in the middle cerebral artery on the side of surgery (p = 0.012). The index did not change during clamping, but increased at clamp release (p = 0.002). Our findings indicate that significant changes in anterior communicating artery collateral flow occur during carotid endarterectomy, starting within seconds of carotid artery clamping. These changes are associated with arterial resistance alterations in the territory of the middle cerebral artery on the endarterectomy side. Our observations should be useful to assess intracranial early collateral flow changes in surgical and non-surgical settings.

Cerebral microembolism during carotid endarterectomy.

BACKGROUND: This study was designed to assess the intraoperative risk of cerebral microembolism, as detected by transcranial Doppler ultrasonography, during carotid endarterectomy. PATIENTS AND METHODS: Thirty-six patients (37 procedures) with symptomatic (n = 35) or asymptomatic (n = 2) internal carotid artery origin stenosis(> 50%) were monitored continuously during carotid endarterectomy. Special instrumentation was used to detect high-intensity transient signals (HITS) in the middle cerebral artery on the carotid endarterectomy side. All HITS satisfied a priori established criteria. RESULTS: The incidence of carotid endarterectomies with formed-element HITS increased at clamp release (23/37, P < 0.001) and shunt opening (7/11, P = 0.014), and during wound closure (13/22, P< 0.005) and shunting (5/11, P = 0.046). HITS with air microbubble characteristics were detected at clamp release (22/37, P < 0.001) and shunt opening (5/11, P = 0.025). CONCLUSIONS: HITS do not occur randomly during carotid endarterectomy. Shunting, unclamping, and wound closure are high-risk periods.

Recent developments in transcranial Doppler sonography.

Transcranial Doppler mapping, dual monitoring, color imaging, emboli detection, and insonation after administration of contrast media are recent technological advances that promise to bring new capabilities to transcranial Doppler ultrasonography, and are likely to change its applications in the near future. This article presents a critical review of these developments.

The transcranial Doppler standardization project. Phase 1 results. The TCD Study Group, American Society of Neuroimaging.

A project to pursue standardization of the performance and interpretation of transcranial Doppler studies was designed. Phase I consisted of a national survey of the current practice of transcranial Doppler in the United States. From 200 ultrasound laboratories surveyed about the use of transcranial Doppler, 60 completed questionnaires were returned. The results show that further standardization of transcranial Doppler performance and interpretation is necessary, and provide the foundation for phases II and III of the project.

Transcranial Doppler validation pilot study.

The use of transcranial Doppler sonography (TCD) for the evaluation of patients with ischemic cerebrovascular disease remains controversial. This study was organized to gather preliminary data regarding the sensitivity and specificity of TCD when compared to cerebral angiography in detecting stenosing lesions and collateral flow patterns of the anterior cerebral circulation. Forty-two patients from six medical centers were prospectively enrolled. Each received cerebral angiography and TCD testing within 24 hours of each other. Based on TCD criteria established a priori, the results were first analyzed by a blinded investigator and then by computer. Computerized analyses were then repeated with modified criteria. Collateral flow through the anterior communicating and ophthalmic arteries was detected with sensitivities of 62% and 100%, and specificities of 98% and 92%, respectively. Internal carotid artery proximal and distal severe ( greater than 70%) stenoses were detected with sensitivities of 79% and 100% and specificities of 88% and 97%. Middle and anterior cerebral artery stenoses and middle cerebral artery occlusion were detected with specificities exceeding 98%; however, the data were insufficient to determine sensitivity. Computerized analyses did not permit improvement of sensitivity and specificity of the baseline criteria. The selected TCD criteria are highly specific in detecting intracranial stenoses and collateral flow patterns of the anterior circulation. The criteria have limited but acceptable sensitivity and specificity in detecting internal carotid artery origin severe stenoses, and are highly sensitive in detecting ophthalmic artery retrograde flow. A study with a larger sample is necessary to provide definitive guidelines for diagnosis.

Longitudinal monitoring of intracranial arterial stenoses with transcranial Doppler ultrasonography.

The natural history of intracranial arterial stenoses remains relatively unknown. To monitor the progression of these lesions over time, the authors reviewed transcranial Doppler (TCD) laboratory reports at five hospitals for patients with angiographically documented intracranial arterial stenoses along the internal carotid artery distribution, and at least two TCD studies conducted more than 2 months apart. Twenty-two patients (19 men and 3 women; mean age, 64 years) with 29 stenoses were identified. The findings were compared to reproducibility data obtained from 11 age-matched control subjects with repeat TCD studies. During a mean follow-up period of 21 months, peak systolic flow velocities corresponding to the areas of stenosis increased in 9 arteries with lesions, and new collateral flow patterns, indicating further hemodynamic compromise distal to the lesions, developed in 2; one of the latter also had increased corresponding velocities. Thus, 10 (35%) arteries with lesions had TCD evidence of progression. Flow velocities remained the same in 13 (45%) stenotic vessels and dropped in 2 (7%). Findings were considered inconclusive for 4 lesions (14%). These findings suggest that intracranial arterial stenoses are dynamic lesions, and that they can evolve and cause further reductions of the arterial diameters after relatively short periods of time. TCD can noninvasively detect their hemodynamic effects.

Transcranial Doppler ultrasonography: year 2000 update.

In this update, the main clinical applications of transcranial Doppler ultrasonography are reassessed. A specific format for technology assessment, personal experience, and an extensive review of the literature form the basis of the evaluation. The document is approved by the American Society of Neuroimaging and the Neurosonology Research Group of the World Federation of Neurology.

Diagnosis of hyperlipidemia and treatment with a statin in the outpatient stroke clinic.

The aim of this study was to assess a stroke clinic's performance in the diagnosis of hyperlipidemia and more specifically to evaluate the effectiveness of statins in patients with cerebrovascular disease not enrolled in a research study. The records of 370 consecutive patients seen at a stroke clinic over a 4-year period were reviewed, and information regarding neurologic diagnosis, lipid profile, and use and type of cholesterol-lowering medication was abstracted. Hyperlipidemia was defined as a total cholesterol level equal to or more than 200 mg/dL. Forty-eight patients meeting specific criteria were further analyzed to monitor the effects of statins. Cholesterol testing was obtained in 324 patients (88%) and 178 (55%) were hyperlipidemic, but only 86 (48%) patients received treatment. The mean cholesterol level of the 48 patients dropped from 246.2 mg/dL to 197.1 mg/dL (P < .0001) after the initiation of statin therapy, and significant reductions were present in subgroups with pretreatment levels of 200 to 249 mg/dL and 250 to 299 mg/dL. Of the 21 patients with repeated cholesterol testing more than 6 months after the first posttreatment test, only 11 (52%) maintained a level below 200 mg/dL. Effective control of hyperlipidemia can be achieved in patients with cerebrovascular disease, but not all are adequately tested or treated. Improved physician awareness and more effective health care delivery systems are needed.

[Detection of microembolus with transcranial doppler]. / Detección de microémbolos con Doppler transcraneal.

OBJECTIVES: To review techniques and the most important clinical applications of microembolus detection with transcranial Doppler. DEVELOPMENT: Technical aspects of microembolus detection are discussed initially; clinical circumstances in which embolus detection is currently used follow, such as carotid stenosis, cardiac pathology, monitoring during neuroangiography, coronary revascularization surgery and endarterectomy. Lastly, the potential clinical applications of this technique are reviewed: localization of an embolic source, risk of recurrent ischemia in patients with unstable atherosclerotic plaques, intraoperative monitoring and potential surgical technique modifications based on this information, contributions to the understanding of the pathophysiology of the fat embolism syndrome, and monitoring therapeutic efficacy of antithrombotics and thrombolytics. CONCLUSIONS: The ability to detect cerebral emboli with transcranial ultrasound has increased significantly our understanding about the pathogenesis of cerebral ischemia. Microembolus detection with transcranial Doppler is a powerful and novel diagnostic technique that allows to study the embolic process in vivo and in real time, instead of using indirect indicators of embolism (clinical and radiological features, possible embolic sources, etc.).

[Overestimation of the degree of stenosis in the intracranial internal carotid artery determined by magnetic resonance angiography compared to conventional arteriography]. / Sobreestimación del grado de estenosis de la arteria carótida interna intracraneal por la angiorresonancia respecto a la arteriografía convencional.

INTRODUCTION: In the evaluation of stenoses of the extracranial internal carotid artery (ICA), there are studies that suggest that magnetic resonance angiography (MRA) can be a substitute for conventional arteriography (CA), although it seems it has a tendency to overestimate the degree of stenosis. No similar comparison of the two techniques has been conducted in intracranial ICA. We report the case of a patient suffering from an acute ischemic stroke and symptomatic intracranial stenosis that was overestimated when MRA was used, compared to the results obtained using CA. CASE REPORT: We report the case of a 64-year-old male with a history of arterial hypertension, hypercholesterolemia and intermittent claudication who visited the emergency department because of the sudden onset of paresthesias in the left hemiface and hand. The cranial tomography scan performed in the emergency unit ruled out any acute bleeding or early signs of a stroke. Magnetic resonance (MR) diffusion imaging showed an acute ischemic stroke in the right parietal cortex. Extracranial MRA was normal and in the intracranial area a 73% stenosis was detected in the cavernous segment of the right ICA, whereas the use of CA showed the stenosis to be only 55%. On repeating the MRA to rule out a possible rechanneling of the ICA, the image obtained was exactly the same as the earlier one. CONCLUSIONS: Our observations suggest that, as occurs with the extracranial part, MRA tends to magnify the degree of stenosis in the intracranial vessels, and this technique would therefore appear to be less efficient than CA in the evaluation of intracranial stenoses.