Alan R. Moody

Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct Thrombus Imaging in Patients With Cerebral Ischemia

Background Thromboembolic disease secondary to complicated carotid atherosclerotic plaque is a major cause of cerebral ischemia. Clinical management relies on the detection of significant (>70%) carotid stenosis. A large proportion of patients suffer irreversible cerebral ischemia as a result of lesser degrees of stenosis. Diagnostic techniques that can identify nonstenotic high‐risk plaque would therefore be beneficial. High‐risk plaque is defined histologically if it contains hemorrhage/thrombus. Magnetic resonance direct thrombus imaging (MRDTI) is capable of detecting methemoglobin within intraplaque hemorrhage. We assessed this as a marker of complicated plaque and compared its accuracy with histological examination of surgical endarterectomy specimens. Methods and Results Sixty‐three patients underwent successful MRDTI and endarterectomy with histological examination. Of these, 44 were histologically defined as complicated (type VI plaque). MRDTI demonstrated 3 false‐positive and 7 false‐negative results, giving a sensitivity and specificity of 84%, negative predictive value of 70%, and positive predictive value of 93%. The interobserver (κ=0.75)and intraobserver (κ=0.9) agreement for reading MRDTI scans was good. Conclusions MRDTI of the carotid vessels in patients with cerebral ischemia is an accurate means of identifying histologically confirmed complicated plaque. The high contrast generated by short T1 species within the plaque allows for ease of interpretation, making this technique highly applicable in the research and clinical setting for the investigation of carotid atherosclerotic disease. (Circulation. 2003;107:3047‐3052.)

Diagnosis of Lower-Limb Deep Venous Thrombosis: A Prospective Blinded Study of Magnetic Resonance Direct Thrombus Imaging

Despite considerable recent advances in diagnostic techniques for lower-limb deep venous thrombosis (DVT), current methods have disadvantages. Ultrasonography, the most accurate noninvasive test, is widely available and cheap. As such, it has largely replaced venography as the test of first choice for symptomatic DVT. In a recent meta-analysis, the sensitivity of ultrasonography was 89% overall for symptomatic DVT and 97% for above-knee thrombosis (1). Large outcome studies have shown that patients may be safely left untreated after a negative result on ultrasonography if they have a low clinical risk score, a low d-dimer level, or a negative result on repeated ultrasonography at 1 week (2-4). However, these strategies may be complex and still require 3% to 34% of outpatients and most inpatients to undergo repeated ultrasonography at 1 week (2-4). In practice, retesting after 1 week is inconvenient, and physicians often rely on a single test or request immediate venography (5). Other problems with ultrasonography include poor sensitivity for asymptomatic disease, difficulties in diagnosing DVT recurrence, and limited visualization in the pelvis (1, 6, 7). Impedance plethysmography is also commonly used; however, it has a lower diagnostic accuracy than ultrasonography and has similar weaknesses in the setting of recurrent thrombosis, asymptomatic DVT, and DVT below the knee or in the pelvis (1, 4, 6). Computed tomography and magnetic resonance imaging techniques can visualize DVT above the knee and in the pelvis but in general are unsuccessful below the knee (8-10). The ability of these techniques to diagnose DVT recurrence and asymptomatic disease has not been tested. Venography is the reference standard diagnostic test, but it has in large part been replaced by noninvasive tests. In clinical practice, it is the most reliable test for the diagnosis of asymptomatic thrombosis and thrombosis isolated within the calf or pelvis. However, imaging in the pelvis is inadequate in up to 24% of normal studies, and the proximal extent of thrombosis is frequently not delineated in patients with above-knee DVT (11). Underfilling of vessels and vessels overlying one another also create problems with venography below the knee. Studies have shown that interobserver variability for venography is high (10% to 16%), especially below the knee ( = 0.46 to 0.73 below the knee and 0.46 to 0.84 above the knee) (12, 13). In addition, a high proportion of studies are nondiagnostic for possible DVT recurrence (1, 6). A noninvasive test is needed that accurately diagnoses above-knee DVT and thrombus below the knee, in the pelvis, and in asymptomatic limbs. Unlike most imaging techniques, which identify thrombus as filling defects, magnetic resonance direct thrombus imaging (MRDTI) visualizes thrombus against a suppressed background (14). In an unblinded comparison with venography, we previously showed that MRDTI precisely visualizes acute deep venous thrombus (14, 15). In the current study, we sought to assess prospectively whether MRDTI is a reliable diagnostic test for suspected acute symptomatic DVT. Methods The ethics committee at our institution granted approval for the study, and all participants gave written informed consent. With the exceptions of pregnant women, patients with known contrast allergy, and those with renal failure, all patients with DVT suspected on the basis of lower limb symptoms are investigated by using venography at our institution. Participants were recruited after routine venography was done between May 1998 and September 1999. During this time, 338 consecutive patients underwent routine contrast venography. Consecutive patients with positive venograms were selected, along with one quarter of those with negative venograms, according to a predetermined random sequence. This protocol was chosen to equalize the numbers of positive and negative cases and was based on a 6-month audit of venograms in our institution that found that 22% of venograms were positive. Clinical diagnostic criteria were not used, and the decision to request investigation for suspected DVT had been made by the attending clinician; however, patients who did not have leg symptoms were not recruited. Other exclusion criteria were failed or inconclusive venography, failed or inconclusive MRDTI, contraindications to MRI, and claustrophobia (Figure 1). Individual venous segments that were nondiagnostic at venography were also excluded from analysis. Figure 1. Outline of the study. Magnetic resonance direct thrombus imaging was performed on all patients recruited within 48 hours of venography. The scans were interpreted by an experienced radiologist (reviewer A) and by a nonradiologist (reviewer B) trained to read MRDTI scans. For venograms and MRDTI scans, the reviewers noted the presence or absence of DVT; the diagnostic classification of DVT, divided into isolated calf DVT, femoropopliteal DVT, and ileofemoral DVT; and the presence of thrombus in the calf, femoropopliteal, and iliac venous segments. Venograms were obtained and initially reported by the radiologists on duty. This initial report was used to make recruitment decisions; if the results were discordant with those of MRDTI, ultrasonography was also performed. However, ultrasonography was not used in the calculations of the accuracy of MRDTI. After completion of the study, venograms were interpreted by an independent radiologist, and these results were used as the gold standard against which MRDTI was compared. Results of MRDTI and venography were reported without knowledge of the results of other tests and the other readings. The d-dimer level was measured in all patients at the time of the MRDTI scan by using the Nycocard (Nycomed Pharma AS, Asker, Norway) technique (normal level < 0.3 mg/L). Venography Venography was performed by cannulating a dorsal pedal vein with a 21-gauge needle and rapidly injecting 50 to 100 mL of iodinated contrast medium (I2, 300 mg/mL), with the patient supine and tilted 30 degrees with his or her feet downward. A tourniquet was applied above the ankle. Anteroposterior and two oblique views of the deep calf and popliteal veins were obtained. Views of the femoral and iliac veins were then obtained. The study result was considered positive if intraluminal filling defects were seen or persistent nonfilling of veins with a sharp cut-off was detected. Magnetic Resonance Imaging Magnetic resonance imaging was performed by using a 1.5-Tesla unit (Siemens Vision, Erlangen, Germany) with a T1-weighted magnetization-prepared three-dimensional gradient-echo sequence. The sequence included a water-only excitation radiofrequency pulse to abolish the fat signal, and the effective inversion time was chosen to nullify the blood signal. Imaging was performed from the ankle to the inferior vena cava in two imaging blocks with a total acquisition time of 12 minutes by using a 55-cm body coil. Both legs were imaged simultaneously. Scanning was performed by radiographers in all cases. Image assessment involved reading of coronal source data and standard image reconstruction techniques. Acute thrombus was diagnosed on the basis of its high signal against the suppressed background (Figure 2). Figure 2. Magnetic resonance direct thrombus imaging in three patients. A. arrows B. arrows C. single arrows double arrow Ultrasonography Color flow and compression ultrasonographic images of the symptomatic limb from the common femoral vein distally were obtained by using a 5-MHz linear array transducer. As much of the superficial femoral vein as possible was imaged, together with the popliteal vein and the calf veins. Augmentation of flow was used to verify patency. Examinations were performed by senior radiologists, and DVT was confirmed in all cases by noncompressibility on gray-scale images. The sonographer was unaware of the other test results, but in cases of possible isolated calf thrombosis, he or she was told to concentrate the examination below the knee to maximize accuracy in this region. Statistical Analysis Sensitivity and specificity were calculated for the overall diagnosis of DVT; diagnosis of isolated calf DVT, femoropopliteal DVT, and ileofemoral DVT; and presence of thrombus in the calf, femoropopliteal vein, and iliac vein. Exact CIs were calculated. Interobserver error was calculated for these observations by using the weighted statistic with equally spaced weights for positive, nondiagnostic, and negative studies. Confidence intervals for the statistic were calculated from asymptotic estimations of the standard error. Calculations were performed by using SPSS software (SPSS, Inc., Chicago, Illinois). Results One hundred four patients were recruited according to our protocol (Figure 1). The time between venography and MRDTI was less than 8 hours in 28 patients, 8 to 24 hours in 44 patients, and 24 to 48 hours in 32 patients. Age ranged from 20 to 95 years, and symptom onset varied from 1 to 35 days. Ninety-five patients were referred from medical specialties and 9 from surgical specialties; 47 were inpatients and 57 were outpatients. Both reviewers reported that 3 of 5 patients with ipsilateral total hip replacements had nondiagnostic MRDTI scans. Venography diagnosed femoropopliteal DVT in 1 of these patients and was negative in 2 patients. These 3 patients were excluded from further analysis, leaving 101 patients in the study. One patient could tolerate only the first scanning block from ankle to thigh level owing to claustrophobia; however, femoropopliteal DVT could still be diagnosed. All other patients tolerated MRI. Eighteen of 148 patients (12%) were excluded from the study. Fifteen patients could not undergo MRI because of contraindications (9 patients) or claustrophobia (6 patients), and 3 patients had inconclusive results on MRDTI. Venography failed (29 patients) or was inconclusive (11 patients) in 12% of patients (40 of 338). Venography was inconclusive

Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events.

BACKGROUND Carotid endarterectomy is beneficial in severe (>70%) symptomatic carotid stenosis. The risk of stroke in moderate carotid stenosis (50%-69%) is modest, and so the role of carotid endarterectomy in this group is unclear. Intraplaque hemorrhage is associated with advanced atherosclerosis and can be detected in the carotid arteries by magnetic resonance imaging. This study evaluates whether magnetic resonance imaging detected intraplaque hemorrhage (MR IPH) can identify patients with symptomatic mild to moderate carotid stenosis who are at higher risk of ipsilateral transient ischemic attack (TIA) and stroke. METHODS Prospective longitudinal cohort study of symptomatic patients with mild to moderate (30%-69%) carotid stenosis followed up for 2 years after imaging for IPH using magnetic resonance imaging. RESULTS Sixty four participants were followed up for a median of 28 months (interquartile range 26-30) after MRI of the carotid arteries. Thirty-nine (61%) ipsilateral arteries showed intraplaque hemorrhage. During follow-up, five ipsilateral strokes and a total of 14 ipsilateral ischemic events were observed. Thirteen of these ischemic events, of which five were strokes, occurred in those with ipsilateral carotid intraplaque hemorrhage (hazard ratio = 9.8, 95% confidence interval 1.3-75.1, P = .03). CONCLUSIONS MR IPH is a good predictor of ipsilateral stroke and TIA in patients with symptomatic mild to moderate (30%-69%) carotid stenosis. This technique could help in the selection of patients for carotid endarterectomy.

Moderate Carotid Artery Stenosis: MR Imaging–depicted Intraplaque Hemorrhage Predicts Risk of Cerebrovascular Ischemic Events in Asymptomatic Men

PURPOSE To investigate the association between magnetic resonance (MR) imaging-depicted intraplaque hemorrhage (IPH) in the carotid artery wall and the risk of future ipsilateral cerebrovascular events in men with asymptomatic moderate carotid stenosis by using a rapid three-dimensional T1-weighted fat-suppressed spoiled gradient-echo sequence. MATERIALS AND METHODS The institutional ethics review board approved this retrospective chart review and waived the requirement for written informed consent. All patients gave informed verbal consent at follow-up telephone interviews. Ninety-one men (mean age, 74.8 years; range, 47-88 years) who attended a vascular clinic between 2003 and 2006, who had asymptomatic carotid stenosis (50%-70% at Doppler ultrasonography), and who had undergone MR imaging for IPH detection were retrospectively identified. Seventy-five men with 98 eligible carotid arteries were included in the study. Patients were followed for a minimum of 1 year (mean follow-up, 24.92 months; range, 12-43 months). Kaplan-Meier survival and univariate Cox regression analyses were conducted to compare future ipsilateral cerebrovascular event rates between carotid arteries with and those without MR-depicted IPH. RESULTS Of the 98 carotid arteries included, 36 (36.7%) had MR-depicted IPH. Six cerebrovascular events (two strokes and four transient ischemic attacks) occurred in the carotid arteries with IPH, as compared with no clinical events in the carotid arteries without IPH. Univariate Cox regression analysis confirmed that MR-depicted IPH was associated with an increased risk of cerebrovascular events (hazard ratio, 3.59; 95% confidence interval: 2.48, 4.71; P < .001). MR-depicted IPH negatively predicted outcomes (negative predictive value = 100%). CONCLUSION In this cohort with asymptomatic moderate carotid stenosis, MR-depicted IPH was associated with future ipsilateral cerebrovascular events. Conversely, patients without MR-depicted IPH remained asymptomatic during follow-up. The absence of IPH at MR imaging, therefore, may be a reassuring marker of plaque stability and of a lower risk of thromboembolism.

Venous Thromboembolism After Acute Ischemic Stroke A Prospective Study Using Magnetic Resonance Direct Thrombus Imaging

Background and Purpose— We prospectively evaluated the prevalence and clinical risk factors for venous thromboembolism (VTE) after acute ischemic stroke using magnetic resonance direct thrombus imaging, a highly accurate noninvasive technique that directly visualizes thrombus. Method— 102 unselected patients with AIS receiving standard prophylaxis with aspirin and graded compression stockings (GCS) were sequentially recruited, underwent regular clinical assessments, and were screened for VTE. Results— The prevalence of all VTE, proximal deep vein thrombosis (PDVT), and pulmonary embolism (PE) after 21 days were 40%, 18%, and 12%, increasing to 63%, 30%, and 20% in patients with Barthel indices (BI) of ≤9 2 days after stroke (BI-2≤9). Clinical deep vein thrombosis and PE occurred in 3% and 5% overall; half these events were overlooked by the attending team. The true incidence of clinical events is probably higher because the natural history of subclinical PDVT was modified by screening and anticoagulation. BI-2≤9 or nonambulatory status 2 days after stroke were the clinical factors most strongly associated with subsequent VTE on univariate analysis. Odds ratios for any VTE and PDVT for BI-2≤9 versus >9 were 8.3 (95% CI, 2.7 to 25.2) and 8.1 (95% CI, 1.7 to 38.3) on multivariable analysis. Conclusion— BI ≤9 or nonambulatory status around the time of admission identifies a subgroup of acute ischemic stroke patients at very high risk for VTE in whom the current strategy of thromboprophylaxis may be inadequate. Future thromboprophylactic studies should focus on the patients at high risk defined in this study.

In Vivo 3D High-Spatial-Resolution MR Imaging of Intraplaque Hemorrhage

PURPOSE To apply magnetic resonance (MR) imaging of intraplaque hemorrhage (IPH), as compared with histologic analysis as the reference standard, to detect T1 hyperintense intraplaque signal and to test the hypothesis that T1 hyperintense material represents blood products (methemoglobin). MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. Eleven patients undergoing carotid endarterectomy were examined with MR imaging of IPH, and MR images were assessed for T1 hyperintense intraplaque signal. A total of 160 images per patient were available for coregistration with corresponding histologic slices. Because of endarterectomy specimen size and degradation and processing artifacts, only 97 images were coregistered to corresponding histologic slices. A grid that consisted of 16 segments was overlaid on images for correlation of MR images and histologic slices. Only one of 16 segments was chosen randomly per slide and used in the analysis. Agreement between MR images and histologic slices was measured with the Cohen kappa statistic. RESULTS Strong agreement was seen between MR images and histologic slices, with T1-weighted high signal intensity corresponding to hemorrhagic material (kappa = 0.7-0.8). There was a low 2% false-negative rate for the detection of hemorrhage on the basis of T1-weighted hyperintensity (two of 97 measured segments). The results of diagnostic tests for T1 hyperintense detection of hemorrhage were as follows: sensitivity of 100%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 100% for reader 1 and sensitivity of 94%, specificity of 88%, positive predictive value of 78%, and negative predictive value of 97% for reader 2. CONCLUSION With its high spatial resolution, MR imaging of IPH permits detection of plaque hemorrhage location, resulting in strong agreement between imaging and histologic findings.

Direct magnetic resonance imaging of carotid artery thrombus in acute stroke

Stroke remains a common cause of morbidity and mortality and affects over 100 000 people per year in the UK. Thromboembolism complicating atheromatous disease within the carotid arteries is the major predisposing cause. Management of patients will be assisted if strokes that arise in this way can be distinguished reliably from those caused by emboli of cardiac origin or as a result of intracranial small vessel disease. Early diagnosis is commonly hampered because in any individual patient several potential causes of stroke may co-exist. The effective targeting of new treatments is dependent on the likely natural history of the condition. The ability to identify acute thrombus in association with underlying carotid disease would offer the possibility of identifying symptomatic carotid atheroma. The presumed pathological mechanism of stroke in carotid disease is embolisation of debris from an area of ruptured atheromatous endothelium, a process that is invariably associated with acute thrombus formation. The ability to identify acute carotid thrombus in this clinical setting therefore allows accurate identification of a symptomatic artery. Magnetic resonance imaging (MRI) has already been employed to detect thrombus in patients with acute deep-vein thrombosis. The high signal, short T1, material detected by MRI is likely to represent methaemaglobin, an intermediate breakdown product of haemoglobin that occurs during clot maturation. The MRI protocol comprised diffusion-weighted images, contrast-enhanced carotid angiography, and a novel direct thombus imaging technique. The latter is a T1 weighted 3-D technique that suppresses the signal from fat and nulls that from blood (TR 10·3, TE 4·0, FA 15, TI 20, FOV 3503300, matrix 2563160, 150 partitions, one acquisition, bandwidth 195 Hz/pixel) allowing ease of identification of short T1 species. A diagnosis of carotid territory acute ischaemic stroke was made on the diffusion-weighted images in 20 patients. Contrast-enhanced MR angiography of the carotid arteries demonstrated stenosis or occlusion in 16 patients on the side appropriate to the acute stroke, and in two patients on the contralateral side. Of the 16 patients, 11 had high signal intensity material on the direct thrombus imaging sequence outlining the lumen of the internal Reconstructed transverse section through the neck demonstrating a rim of high signal material within the left internal carotid artery causing a less than 50% narrowing of the vessel This paper is funded by the Italian Ministry of University and Scientific Research

The diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging

Deep vein thrombosis (DVT) has an annual incidence of between 48 and 182 per 100 000 (Coon et al, 1973; Anderson et al, 1991; Nordstrom et al, 1992; Hansson et al, 1997; Silverstein et al, 1998), so the oft quoted figure of 1 per 1000 is a reasonable estimate. Estimates of the case fatality rate range from 1% to 5% (Anderson et al, 1991). However, the incidence and the case fatality rate are very age dependent (Coon et al, 1973; Anderson et al, 1991; Nordstrom et al, 1992; Silverstein et al, 1998). There is also associated morbidity. Post-thrombotic syndrome, characterized by chronic pain, swelling and occasional ulceration of the skin of the leg occurs in up to one-third of patients who have had a DVT (Prandoni et al, 1996, 1999). The post-thrombotic syndrome can occur early or have a latency of up to 10 years, the cumulative frequency has been estimated as 23% at 2 years and 28% at 5 years (Prandoni et al, 1996). In patients who use elastic compression stockings for at least 2 years, the incidence of post-thrombotic leg can be halved (Brandjes et al, 1997). Increased awareness of DVT and its consequences has resulted in an increased number of patients being referred for assessment. Many of these patients are at low risk and this is reflected by the fall in the percentage of positive diagnoses of DVT in reported series. The objective diagnosis of DVT depends on imaging using compression ultrasound or ascending venography. However, because of the cost of these modalities, the increasing number of negative tests which are being requested and the resultant, frequently incurred delays in access to them, alternative approaches to diagnosis and decision making in suspected cases of DVT have been adopted. These rely on the use of information from clinical history and examination and assays to detect D-dimers. The main emphasis of these methods is on the safe exclusion of a diagnosis of DVT, thus reducing the use of imaging techniques and speeding up the diagnostic process. While clinical examination cannot be relied upon in isolation to make a diagnosis of DVT, in combination with appropriate history taking, it can provide useful information (Wells et al, 1995, 1997). Recently, sensitive D-dimer assays that can help to exclude the diagnosis have been developed. This guideline describes the use of these methods alone and in combination with each other to develop strategies that safely exclude the diagnosis in patients presenting with suspected DVT, without resorting to the use of diagnostic imaging. An understanding of the natural history of calf vein thrombosis, and the risk of extension and embolization is also important in designing a diagnostic strategy.

Magnetic resonance direct thrombus imaging.

Summary.  As blood clots it goes through predictable stages that reflect the oxygenation state of hemoglobin within the red cells. One of these stages results in the formation of methemoglobin. This substance acts an endogenous contrast agent when imaged using a T1‐weighted magnetic resonance sequence (Magnetic Resonance Direct Thrombus Imaging, MRDTI) – appearing as high signal. MRDTI can therefore be used to detect subacute thrombosis. This technique has been applied in a number of clinical settings arising as a result of thrombosis. Deep vein thrombosis and pulmonary embolism are both readily detected using MRDTI, providing a single imaging modality for the detection of venous thromboembolic disease. The technique is also effective in the peripheral arterial tree. Furthermore, thrombosis within vessel wall atherosclerosis is a marker of vulnerable plaque likely to produce symptoms. The MRDTI technique has thus proved useful in identifying complicated plaque in the carotid arteries in the setting of transient and permanent cerebral ischemia. MRDTI therefore holds promise as a technique that is capable of detecting high risk vessel wall disease prior to significant or permanent end organ damage. Because of the non‐invasive nature of magnetic resonance imaging (MRI), application of MRDTI in the research setting for the monitoring of therapeutic interventions in a wide number of settings within vascular disease is very appealing.

MR tagging of human lungs using hyperpolarized 3He gas

To evaluate the use of spin‐tagging in conjunction with hyperpolarized gas imaging for monitoring lung ventilation and gas diffusion.