J. Philip Kistler

Low Vitamin B6 but Not Homocyst(e)ine Is Associated With Increased Risk of Stroke and Transient Ischemic Attack in the Era of Folic Acid Grain Fortification

Background and Purpose— The introduction of cereal grain folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample. Methods— Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5′-phosphate (PLP), B12, and MTHFR 677C→T genotype were measured. Results— Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L, P <0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1;P <0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1). Conclusions— Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.

Carotid Doppler Ultrasound Criteria for Internal Carotid Artery Stenosis Based on Residual Lumen Diameter Calculated From En Bloc Carotid Endarterectomy Specimens

BACKGROUND AND PURPOSE Carotid duplex ultrasound is widely used to screen patients for carotid endarterectomy and if combined with MR angiography and transcranial Doppler may be an alternative to conventional angiography in the preoperative assessment. We have examined the correlation between Doppler velocities and the residual lumen diameters of internal carotid arteries from surgical pathological specimens to establish Doppler criteria for residual lumen diameter independent of percent stenosis. METHODS Ninety-one patients who underwent 99 carotid endarterectomies for internal carotid artery stenosis within 6 months of their carotid duplex ultrasound evaluation were studied. The endarterectomy specimens were removed en bloc, and the minimal residual lumen diameter was calculated by computer analysis. The sensitivity and specificity of the Doppler criteria for determining high-grade stenosis were calculated and receiver-operator curves generated. RESULTS Peak systolic velocity (PSV), end-diastolic velocity (EDV),and carotid index (peak internal carotid artery velocity/ common carotid artery velocity) correlated with the residual lumen diameter. PSV > 440 cm/s, EDV > 155 cm/s, or carotid index > 10 indicated a residual lumen diameter of < or = 1.5 mm (specificity of 100% and sensitivity of 58%, 63%, and 30%, respectively). When these criteria were combined, the sensitivity increased to 72%. A PSV > 200 cm/s combined with either an EDV > 140 cm/s or a carotid index > 4.5 has a sensitivity of 96% and a specificity of 61%. CONCLUSIONS Doppler criteria can be both specific and sensitive for detecting a significant stenosis, defined as a < or = 1.5 mm residual lumen diameter. By adjustment of the velocity criteria, it can be 100% specific or a highly sensitive test (96%).

Transcranial Doppler Ultrasound Criteria for Hemodynamically Significant Internal Carotid Artery Stenosis Based on Residual Lumen Diameter Calculated From En Bloc Endarterectomy Specimens

BACKGROUND AND PURPOSE Transcranial Doppler (TCD) is often used in conjunction with carotid duplex ultrasonography (CDUS) to evaluate the hemodynamic significance of internal carotid artery (ICA) stenosis. We examined the sensitivity and specificity of TCD criteria for detection of a hemodynamically significant stenosis (residual lumen diameter < 1.5 mm) at the origin of the ICA. METHODS We selected patients who underwent carotid end-arterectomy (CEA) and had preoperative TCD data available. Eighty-one patients underwent transorbital evaluation, 49 of whom also had transtemporal TCD performed. The endarterectomy specimens were removed en bloc and sectioned, and the minimal residual lumen diameter calculated by computer analysis. RESULTS For the transorbital approach, the strongest indicators of a residual lumen diameter < 1.5 mm were reversed flow in the ipsilateral ophthalmic artery and a > 50% peak systolic velocity difference between the carotid siphons (distal ICAs) in patients with unilateral ICA origin stenosis. They were 100% specific and 31% and 26% sensitive, respectively. For the transtemporal approach in patients with a unilateral stenosis, a > 35% difference in ipsilateral middle cerebral artery (MCA) peak systolic velocity relative to the contralateral MCA or a > 50% difference in contralateral anterior cerebral artery (ACA) peak systolic velocity relative to the ipsilateral ACA were 100% specific for identifying a residual lumen diameter of < 1.5 mm. Sensitivities were 32% and 43%, respectively. Irrespective of contralateral stenosis, a > 35% difference in ipsilateral MCA peak systolic velocity relative to the ipsilateral posterior cerebral artery had a 100% specificity and a 23% sensitivity for detecting a < 1.5 mm minimal residual lumen diameter. CONCLUSIONS Although the TCD sensitivity for detecting a hemodynamically significant stenosis is relatively low, it can be highly specific (up to 100%). We conclude that TCD enhances the specificity of highly sensitive CDUS criteria for detecting a hemodynamically significant ICA stenosis.

Carotid Surgery Without Arteriography: Noninvasive Selection of Patients

All carotid noninvasive studies at our institution comprised of duplex scanning, spectral frequency analysis, and ocular-pneumoplethysmography-Gee supraorbital Doppler assessments from 1985–1987 were reviewed. Forty symptomatic and 104 asymptomatic internal carotid arteries, concomitantly studied noninvasively and arteriographically, were identified. All studies were rereviewed prospectively and in blinded fashion. Utilizing peak frequency—internal carotid artery >10 mHz and carotid index (Pf-ICA)/PF-common carotid) >5 as criteria for surgery, 39/40 symptomatic internal carotid arteries were considered appropriate for carotid endarterectomy by noninvasive study. All of these internal carotid arteries had arteriographic confirmation of >50% internal carotid artery stenosis; 22 of them met noninvasive criteria for surgery of peak systolic frequency-internal carotid artery 14 mHz, carotid index >7 and abnormal ocular-pneumoplethysmography-Gee supraorbital Doppler. All of these had arteriographic confirmation of >80% internal carotid artery stenosis. Eleven asymptomatic internal carotid arteries met spectral frequency criteria for carotid endarterectomy but had normal ocular-pneumoplethysomgraphy-Gee/supraorbital Doppler. Eight in this group had <80% stenosis on arteriographic exam. Carotid endarterectomy may be performed without prior arteriography, provided objective criteria are established in a reliable noninvasive lab and met by individual patients.

Correlation of spectral phonoangiography and carotid angiography with gross pathology in carotid stenosis.

Spectral phonoangiography, a noninvasive method for measurement of the residual-lumen diameter of carotid stenosis by bruit analysis, was compared with x-ray angiography and direct measurement of the pathological specimen at carotid endarterectomy in 39 bifurcations from 36 patients. In six studies, the bruit was too faint to analyze. In 31 of the other 33 studies, the phonoangiogram predicted the residual-lumen diameter to within 0.5 mm of the measured value. Of the 39 contrast angiograms, 35 showed residual lumens within 0.5 mm of the value measured in the specimen, two showed lumens between 0.5 and 1 mm, and the sizes of two could not be estimated because of vessel overlap in all planes. Spectral phonoangiography and contrast angiography are both accurate methods for evaluation of carotid stenosis. Since phonoangiography is noninvasive, it may be of particular value in determining the natural history in patients with carotid bruits.

Carotid endarterectomy revisited.

The importance of understanding the pathophysiologic basis of transient cerebral ischemia or ischemic stroke became clear with Fishers original description of stroke in patients with atherothrombo...

Techniques and approaches to proton NMR imaging of the head

The next few years will undoubtedly see a refinement of proton imaging technology and a broader data base will indicate to what extent proton relaxation parameters are able to detect and characterize disease. In addition, it is likely that imaging of other nuclei (e.g. 31P, 23Na, 19F) will become a reality, although it must be stated that due to their inherently lower sensitivity to NMR detection and/or lower physiological concentration, clinical images of nuclei other than 1H will undoubtedly have a low spatial resolution and may require relatively long imaging times [41]. Nonetheless, herein lies the exciting possibility of non-invasive metabolic or functional imaging [42]. The realm of NMR contrast agents is just beginning to be explored [43, 44], and developments in high-speed imaging [45] indicate useful applications in cardiology [46]. So whilst improvements in image quality can be expected, as was the case with X-ray CT, the application of NMR in medicine will diversify to yield information of a more specifically functional nature. This, together with the very low attendant biological risk [47], heralds a bright future for NMR in clinical diagnosis.

Patent Foramen Ovale Diameter and Embolic Stroke: A Part of the Puzzle?

Understanding the pathological basis of cerebral ischemia is critical when considering whether embolism is the cause of a transient ischemic attack or nonhemorrhagic stroke (1). Data from the Stroke Data Bank of the National Institutes of Health (NIH) suggest that cerebral emboli account for 60% of all ischemic strokes. To make the diagnosis, the other major causes of stroke—large vessel atherothrombotic disease (15%), small vessel lacunar stroke (25%), and other mechanisms, such as dissection or arteritis (3%)—must be excluded by determining that the stroke topology is not lacunar and that the parent vessels supplying the territory of the ischemic stroke are free of intrinsic atherosclerosis, dissection, or other causes of stenosis (2). It then becomes essential to identify the source of the embolus. The NIH Stroke Data Bank distinguishes two major categories of embolic stroke. About one-third are from a definite, clinically apparent, cardiac causes, such as atrial fibrillation, valvular heart disease (prosthetic or rheumatic), post-myocardial infarction, and infective endocarditis; the remainder have no clinically apparent cardiac cause (2). The advent of reliable transthoracic and transesophageal echocardiography has enabled a more clinically relevant and precise classification. We favor a classification scheme based on commonly accepted standards of preventive therapy (3), and classify the clinically apparent cardiac sources into those for which antithrombotic therapy is the standard of care—atrial fibrillation, valvular heart disease, and post-myocardial infarction— and those in which it is contraindicated, such as infectious endocarditis and myxomatous disease. We then classify the larger category of “unknown source” based on the echocardiographic findings as either a possible cardiac source (patent foramen ovale, mitral annular calcification, left ventricular dysfunction, left ventricular thrombus); a possible ascending aortic atheromatous source as diagnosed by transesophageal echocardiography; or a truly unknown source, when the transthoracic and transesophageal echocardiograms and cardiac monitoring are nondiagnostic. With the exception of the rate of secondary embolic strokes in patients with a 4 mm or greater plaque in the aorta, there are few data on the cumulative risk of stroke associated with these conditions (4), nor have there been any randomized trials to assess the efficacy of stroke prevention strategies in patients with these potential cardiac sources of embolism. Of all the possible cardiac causes of embolic stroke, a patent foramen ovale is perhaps the most clinically perplexing in terms of stroke prophylaxis. An anatomical marker of stroke risk in patients with a patent foramen ovale would allow the identification of a high-risk group of patients whose annual stroke risk would be high enough to warrant a randomized trial of preventive therapy. In this issue of The Green Journal, Schuchlenz and colleagues have been able to identify such an anatomical marker, just as Amarenco and colleagues accomplished in ascending aortic atheromatous disease (the .4 mm plaque) (5). If it can be confirmed that a mean diameter of a patent foramen ovale greater than 4 mm conveys an odds ratio of 12 for embolic stroke, this could well be the feature used in future clinical trials to identify high-risk patients. Homma and others have suggested that the size of a patent foramen ovale, as measured by agitated saline contrast, is important in determining stroke risk (6). Using a state-of-the-art 5 MHz multiplanar transesophageal probe, and excluding other stroke subtypes and other possible sources of embolism, the results of the study by Schuchlenz et al suggest that it is reasonable to conclude that a patent foramen ovale with a diameter .4 mm was the likely embolic source. Because computerized tomographic scans were the only imaging technique used to identify strokes in many patients, there may be a slight bias for supratentorial strokes. But the decision to include only patients with an infarct greater than 1.5 cm in diameter in an arterial territory with a patent arterial supply reliably assures an embolic cause for the stroke. Recently, Lock (personal communication, June 2000) suggested that the volume of a patent foramen ovale may be a determinant of “local thrombus” formation and thus may affect the rate of embolism. Rosenberg has advanced the concept that vascular bed-specific hemostasis is important in thrombus formation in atherothrombotic cardiovascular disease, as well as in venous thromboembolism (7). It may be that local cardiac endothelial factors, in relation to the size of the patent foramen ovale, influence the propensity to form an unstable thrombus and thus affect the risk of embolic stroke. In collaboration with Rosenberg and colleagues, we have determined that the level of activity of the hemostatic system increases with age in patients with atrial fibrillation (8). Moreover, the increased activity is reduced Am J Med. 2000:109:506 –507. From the Neurology Service, Massachusetts General Hospital, Boston, MA Requests for reprints should be addressed to J. Phillip Kistler, MD, Massachusetts General Hospital, Neurology Service, 32 Fruit Street, (VBK 802), Boston, MA, 05114-2695.

Stroke Due to Large Artery Atherosclerosis

Chiari recognized atherosclerotic disease of the internal carotid artery (ICA) as a cause of stroke as early as 1905. In 1937, Moniz described four cases of carotid occlusion with transient ischemic attack (TIA) preceding stroke. In the 1950s, Miller Fisher described the clinical syndrome of transient deficits preceding stroke above an occluded carotid. Carotid atherosclerosis is associated with conventional vascular risk factors: hypertension, hyperlipidemia, diabetes, and smoking (1–5).

Stroke Prevention With Antiplatelet Therapy

Community-based stroke studies have shown that approx 80% of all strokes are ischemic (1,2). The majority of patients survive their first ischemic stroke, with 95% alive at 7 days poststroke and 90% alive at 1 month (3). These patients subsequently have an increased risk of stroke recurrence of approx 5% per annum and an increased risk of serious coronary events of about 3% per annum over the following 5 years (4,5).