Assessment by doppler ultrasound of entheseal lesions in spondyloarthritis : a longitudial study to determine structural damage and disease activity lesions

RESUMO: Enthesitis is the hallmark of spondyloarthritis (SpA), and is observed in all subtypes. Wide information on SpA abnormalities, including synovitis, tendinitis and enthesitis, can be efficiently perceived by Doppler ultrasound. Furthermore, several studies on imaging of enthesis showed that imaging techniques are better than clinical examination to detect enthesis alterations; and vascularized enthesitis detected by Doppler ultrasound appears to be a valuable diagnostic tool to confirm SpA diagnosis. However, data published until now concerning entheseal elementary alterations that characterize SpA enthesitis (enthesis inflammatory activity) or enthesopathy (permanent structural changes) reflect rather the authors’ empiric opinion than a methodological validation process. In this sense it seems crucial to identify elementary entheseal lesions associated with activity or damage, in order to improve monitoring and treatment response in SpA patients. The development of better assessment tools is today a challenge and a need in SpA. The first study of this thesis focused on the analysis of the reliability of inter-lector and inter-ultrasonography equipment of Madrid sonography enthesitis index (MASEI). Fundamental data for the remaining unrolling project validity. In the second and third studies we concerned about two entheseal elemental lesions: erosions and bursa. In literature erosions represent a permanent structural damage, being useful for monitoring joint injury, disease activity and therapeutic response in many rheumatic diseases; and to date, this concept has been mostly applied in rheumatoid arthritis (RA). Unquestionably, erosion is a tissue-related damage and a structural change. However, the hypothesis that we decided to test was if erosions represent a permanent structural change that can only grow and worsen over time, as occurs in RA, or a transitory alteration. A longitudinal study of early SpA patients was undertaken, and the Achilles enthesis was used as a model. Our results strongly suggested that previously detected erosions could disappear during the course of the disease, being consistent with the dynamic behavior of erosion over time. Based on these striking results it seems reasonable to suggest that the new-bone formation process in SpA could be associated with the resolution of cortical entheseal erosion over time. These results could also be in agreement with the apparent failure of anti-tumor necrosis factor (TNF) therapies to control bone proliferation in SpA; and with the relation of TNF-α, Dickkopf-related protein 1 (Dkk-1) and the regulatory molecule of the Wnt signaling pathway in the bone proliferation in SpA. In the same model, we then proceeded to study the enthesis bursa. Interestingly, the Outcome Measures in Rheumatology Clinical Trials (OMERACT) enthesopathy definition does not include bursa as an elementary entheseal lesion. Nonetheless, bursa was included in 46% of the enthesis studies in a recently systematic literature review, being in agreement with the concept of “synovio-entheseal complex” that includes the link between enthesitis and osteitis in SpA. It has been clarified in recent data that there is not only a close functional integration of the enthesis with the neighboring bone, but also a connection between enthesitis and synovitis. Therefore, we tried to assess the prevalence and relevance of the bursa-synovial lesion in SpA. Our findings showed a significant increase of Achilles bursa presence and thickness in SpA patients compared to controls (healthy/mechanical controls and RA controls). These results raise awareness to the need to improve the enthesopathy ultrasonographic definition. In the final work of this thesis, we have explored new perspectives, not previously reported, about construct validity of enthesis ultrasound as a possible activity outcome in SpA. We performed a longitudinal Achilles enthesis ultrasound study in patients with early SpA. Achilles ultrasound examinations were performed at baseline, six- and twelve-month time periods and compared with clinical outcome measures collected at basal visit. Our results showed that basal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are higher in patients with Doppler signal in enthesis, and even that higher basal ESR, CRP and Ankylosing Spondylitis Disease Activity Score (ASDAS) predicted a higher Doppler signal (an ultrasound alteration accepted as representative of inflammation) six months later. Patients with very high disease activity assessed by ASDAS (>3.5) at baseline had significantly higher Achilles total ultrasound score verified at the same time; and ASDAS <1.3 predicted no Doppler signal at six and twelve months. This seems to represent a connection between classical biomarkers and clinical outcomes associated with SpA activity and Doppler signal, not only at the same time, but also for the following months. Remarkably, patients with inactive disease (ASDAS < 1.3) at baseline had no Doppler signal at six and twelve months. These findings reinforce the potential use of ultrasound related techniques for disease progression assessment and prognosis purposes. Intriguingly, Ankylosing Spondylitis Disease Activity Index (BASDAI) didn’t show significant differences between different cut-offs concerning ultrasound lesions or Doppler signal, while verified with ASDAS. These results seem to indicate that ASDAS reflects better than BASDAI what happens in the enthesis. The work herein discussed clearly shows the potential utility of ultrasound in enthesis assessment in SpA patients, and can be important for the development of ultrasound activity and structural damage scores for diagnosis and monitoring purposes. Therefore, local promotion of this technique constitutes a medical intervention that is worth being tested in SpA patients for diagnosis, monitoring and prognosis purposes.

Renal perfusion evaluation with contrast-enhanced ultrasonography.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS: CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS: Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS: This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance.

Prevalence and clinical significance of small joint synovitis detected by ultrasonography in axial SpA

Objectives:¦The aim of this study was to estimate the prevalence of subclinical small joint synovitis detected by ultrasonography in patients with axial SpA, and to evaluate their relevance in terms of function or and disease activity.¦Methods:¦Forty axial SpA patients, 40 RA and 20 healthy subjects were evaluated by ultrasonography, using a reproducible semi-quantitative score by B-mode and Doppler, for synovitis, while disease activity and function were assessed using validated instruments (DAS28, BASDAI, BASFI, m-SACRAH and HAQ).¦Results:¦Median B-mode score were respectively 8.2 for axial SpA, 11.5 for RA and 6.0 for healthy subjects, corresponding to a prevalence of clinical significant synovitis of respectively 37.5%, 60% and 11% for a level of significance at > 8 chosen to¦classify as active > 75% of RA patient with DAS28 >2.6 and < 10% of controls. Addtionally, Doppler was positive in 8% of SpA, 30 % of RA and none of the healthy subjects. Echographic synovitis correlated with disease activity (DAS28) and function¦(HAQ, mSACRAH) in RA patients, but no correlation were found for SpA patients with disease activity (BASDAI) or function (BASFI, HAQ, mSACRAH). Cases of synovitis using classification by Doppler positivity were insufficient to allow any¦statistical analysis.¦Conclusions:¦B-mode ultrasonographic evaluation can demonstrate subclinical synovitis in almost 40% of SpA patients, but they do not appear to correlate with disease activity or function on the contrary to what is observed in RA patients, representing potentially different processes

Prediction of clinical response after renal angioplasty: respective value of renal Doppler sonography and scintigraphy.

OBJECTIVE: The goal of our study was to compare Doppler sonography and renal scintigraphy as tools for predicting the therapeutic response in patients after undergoing renal angioplasty. SUBJECTS AND METHODS. Seventy-four hypertensive patients underwent clinical examination, Doppler sonography, and renal scintigraphy before and after receiving captopril in preparation for renal revascularization. The patients were evaluated for the status of hypertension 3 months after the procedure. The predictive values of the findings of clinical examination, Doppler sonography, renal scintigraphy, and angiography were assessed. RESULTS: For prediction of a favorable therapeutic outcome, abnormal results from renal scintigraphy before and after captopril administration had a sensitivity of 58% and specificity of 57%. Findings of Doppler sonography had a sensitivity of 68% and specificity of 50% before captopril administration and a sensitivity of 81% and specificity of 32% after captopril administration. Significant predictors of a cure or reduction of hypertension after revascularization were low unilateral (p = 0.014) and bilateral resistive (p = 0.016) indexes on Doppler sonography before (p = 0.009) and after (p = 0.028) captopril administration. On multivariate analysis, the best predictors were a unilateral resistive index of less than 0.65 (odds ratio [OR] = 3.7) after captopril administration and a kidney longer than 93 mm (OR = 7.8). The two best combined criteria to predict the favorable therapeutic outcome were a bilateral resistive index of less than 0.75 before captopril administration combined with a unilateral resistive index of less than 0.70 after captopril administration (sensitivity, 76%; specificity, 58%) or a bilateral resistive index of less than 0.75 before captopril administration and a kidney measuring longer than 90 mm (sensitivity, 81%; specificity, 50%). CONCLUSION: Measurements of kidney length and unilateral and bilateral resistive indexes before and after captopril administration were useful in predicting the outcome after renal angioplasty. Renal scintigraphy had no significant predictive value.

RV contractility and exercise-induced pulmonary hypertension in chronic mountain sickness: a stress echocardiographic and tissue Doppler imaging study.

OBJECTIVES: The aim of this study was to evaluate right ventricular (RV) and left ventricular function and pulmonary circulation in chronic mountain sickness (CMS) patients with rest and stress echocardiography compared with healthy high-altitude (HA) dwellers. BACKGROUND: CMS or Monge's disease is defined by excessive erythrocytosis (hemoglobin >21 g/dl in males, 19 g/dl in females) and severe hypoxemia. In some cases, a moderate or severe increase in pulmonary pressure is present, suggesting a similar pathogenesis of pulmonary hypertension. METHODS: In La Paz (Bolivia, 3,600 m sea level), 46 CMS patients and 40 HA dwellers of similar age were evaluated at rest and during semisupine bicycle exercise. Pulmonary artery pressure (PAP), pulmonary vascular resistance, and cardiac function were estimated by Doppler echocardiography. RESULTS: Compared with HA dwellers, CMS patients showed RV dilation at rest (RV mid diameter: 36 ± 5 mm vs. 32 ± 4 mm, CMS vs. HA, p = 0.001) and reduced RV fractional area change both at rest (35 ± 9% vs. 43 ± 9%, p = 0.002) and during exercise (36 ± 9% vs. 43 ± 8%, CMS vs. HA, p = 0.005). The RV systolic longitudinal function (RV-S') decreased in CMS patients, whereas it increased in the control patients (p < 0.0001) at peak stress. The RV end-systolic pressure-area relationship, a load independent surrogate of RV contractility, was similar in CMS patients and HA dwellers with a significant increase in systolic PAP and pulmonary vascular resistance in CMS patients (systolic PAP: 50 ± 12 mm Hg vs. 38 ± 8 mm Hg, CMS vs. HA, p < 0.0001; pulmonary vascular resistance: 2.9 ± 1 mm Hg/min/l vs. 2.2 ± 1 mm Hg/min/l, p = 0.03). Both groups showed comparable systolic and diastolic left ventricular function both at rest and during stress. CONCLUSIONS: Comparable RV contractile reserve in CMS and HA suggests that the lower resting values of RV function in CMS may represent a physiological adaptation to chronic hypoxic conditions rather than impaired RV function. (Chronic Mountain Sickness, Systemic Vascular Function [CMS]; NCT01182792).

Reduced atrial emptying after orthotopic heart transplantation masquerading as restrictive transmitral Doppler flow pattern?

BACKGROUND: An elevated early (E) to late (A) diastolic filling velocities ratio, typically seen in advanced diastolic dysfunction, has also been observed after cardioversion of atrial fibrillation as a consequence of the depressed left atrial (LA) contractility. We hypothesized that the impaired LA contractile function demonstrated after orthotopic cardiac transplantation (OCT) could also lead to this "pseudorestrictive" pattern. METHOD: E/A ratio related to the tissue Doppler early mitral annular velocity (Ea) as preload-independent index of LV relaxation was evaluated in all consecutive OCT patients between 2005 and 2007. RESULTS: The study population comprised 48 patients 97 ± 77 months after OCT. Thirty-two patients (67%) had an E/A ratio > 2. LV systolic function and myocardial relaxation assessed by the Ea velocity were similar compared to patients with normal ratio (61 ± 6% vs. 60 ± 12%, P = 0.854 and 15 ± 4 cm/s vs. 14 ± 3 cm/s, r = 0.15, P = 0.323, respectively). On the other hand, the proportion of the recipient and donor LA cuffs as estimated by the recipient/global LA area ratio and the LA emptying fraction significantly correlated with the E/A ratio (r = 0.40, P = 0.005 and r =-0.33, P = 0.022, respectively). CONCLUSION: Our study shows that there is a high prevalence of elevated E/A ratio after standard OCT which seems mainly related to reduced LA contractility. Recognition of this "pseudorestrictive" pattern may avoid misdiagnosis of diastolic dysfunction.

Use of duplex ultrasonography in the treatment of thromboangiitis obliterans with iloprost.

We present a 34-year-old patient with digital necrosis due to thromboangiitis obliterans. He was successfully treated with iloprost, a prostaglandin analogue. Duplex ultrasonography was performed during the perfusion of iloprost to optimize the doses and the treatment duration. A complete revascularization was observed after 10 days. Iloprost perfusions were stopped, and a slow regression of the necroses was observed in the subsequent days. With the use of duplex ultrasonography, unnecessary high doses of iloprost and long periods of treatment can be avoided reducing side effects and treatment costs.

Intérêt de l'échographie du diamètre de l'enveloppe du nerf optique pour la détection non invasive de l'hypertension intracrânienne [Interest of optic nerve sheath diameter ultrasonography in dectecting non-invasively raised intracranial pressure].

Intracranial hypertension is an emergency suspected from clinical symptoms, imaging data and ophthalomologic signs. Intracranial hypertension is confirmed by invasive intracranial monitoring, which is the gold standard technique to measure intracranial pressure (ICP). Because of complications, hemorrhage or infection, non-invasive methods have been developed such as neuroimaging, transcranial Doppler sonography and optic nerve sheath diameter (ONSD) ultrasonography. We have reviewed ONSD technique that detects intracranial hypertension related volume variations of subarachnoid space along the retro bulbar segment of the optic nerve. Technique, indications and prospects are discussed.

Transcranial Doppler ultrasound in the acute phase of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Angiographic studies suggest that acute vasospasm within 48 h of aneurysmal subarachnoid hemorrhage (SAH) predicts symptomatic vasospasm. However, the value of transcranial Doppler within 48 h of SAH is unknown. METHODS: We analyzed 199 patients who had at least 1 middle cerebral artery (MCA) transcranial Doppler examination within 48 h of SAH onset. Abnormal MCA mean blood flow velocity (mBFV) was defined as >90 cm/s. Delayed cerebral ischemia (DCI) was defined as clinical deterioration or radiological evidence of infarction due to vasospasm. RESULTS: Seventy-six patients (38%) had an elevation of MCA mBFV >90 cm/s within 48 h of SAH onset. The predictors of elevated mBFV included younger age (OR = 0.97 per year of age, p = 0.002), admission angiographic vasospasm (OR = 5.4, p = 0.009) and elevated white blood cell count (OR = 1.1 per 1,000 white blood cells, p = 0.003). Patients with elevated mBFV were more likely to experience a 10 cm/s fall in velocity at the first follow-up than those with normal baseline velocities (24 vs. 10%, p < 0.01), suggestive of resolving spasm. DCI developed in 19% of the patients. An elevated admission mBFV >90 cm/s during the first 48 h (adjusted OR = 2.7, p = 0.007) and a poor clinical grade (Hunt-Hess score 4 or 5, OR = 3.2, p = 0.002) were associated with a significant increase in the risk of DCI. CONCLUSION: Early elevations of mBFV correlate with acute angiographic vasospasm and are associated with a significantly increased risk of DCI. Transcranial Doppler ultrasound may be an early useful tool to identify patients at higher risk to develop DCI after SAH.

Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVE: Transcranial Doppler (TCD) is widely used to monitor the temporal course of vasospasm after subarachnoid hemorrhage (SAH), but its ability to predict clinical deterioration or infarction from delayed cerebral ischemia (DCI) remains controversial. We sought to determine the prognostic utility of serial TCD examination after SAH. METHODS: We analyzed 1877 TCD examinations in 441 aneurysmal SAH patients within 14 days of onset. The highest mean blood flow velocity (mBFV) value in any vessel before DCI onset was recorded. DCI was defined as clinical deterioration or computed tomographic evidence of infarction caused by vasospasm, with adjudication by consensus of the study team. Logistic regression was used to calculate adjusted odds ratios for DCI risk after controlling for other risk factors. RESULTS: DCI occurred in 21% of patients (n = 92). Multivariate predictors of DCI included modified Fisher computed tomographic score (P = 0.001), poor clinical grade (P = 0.04), and female sex (P = 0.008). After controlling for these variables, all TCD mBFV thresholds between 120 and 180 cm/s added a modest degree of incremental predictive value for DCI at nearly all time points, with maximal sensitivity by SAH day 8. However, the sensitivity of any mBFV more than 120 cm/s for subsequent DCI was only 63%, with a positive predictive value of 22% among patients with Hunt and Hess grades I to III and 36% in patients with Hunt and Hess grades IV and V. Positive predictive value was only slightly higher if mBFV exceeded 180 cm/s. CONCLUSION: Increased TCD flow velocities imply only a mild incremental risk of DCI after SAH, with maximal sensitivity by day 8. Nearly 40% of patients with DCI never attained an mBFV more than 120 cm/s during the course of monitoring. Given the poor overall sensitivity of TCD, improved methods for identifying patients at high risk for DCI after SAH are needed.

Reference range of uterine artery Doppler parameters between the 11th and 14th pregnancy weeks in a population sample from Northeast Brazil

PURPOSE: To establish reference values for the first trimester uterine artery resistance index (UtA-RI) and pulsatility index (UtA-PI) in healthy singleton pregnant women from Northeast Brazil. METHODS: A prospective observational cohort study including 409 consecutive singleton pregnancies undergoing routine early ultrasound screening at 11 - 14 weeks of gestation was performed. The patients responded to a questionnaire to assess maternal epidemiological characteristics. The left and right UtA-PI and UtA-RI were examined by color and pulsed Doppler by transabdominal technique and the mean UtA-PI, mean UtA-RI and the presence of bilateral protodiastolic notching were recorded. Quartile regression was used to estimate reference values. RESULTS: The mean±standard deviation UtA-RI and UtA-PI were 0.7±0.1 and 1.5±0.5, respectively. When segregated for gestation age, mean UtA-PI was 1.6±0.5 at 11 weeks, 1.5±0.6 at 12 weeks, 1.4±0.4 at 13 weeks and 1.3±0.4 at 14 weeks' gestation and mean UtA-RI was 0.7±0.1 at 11 weeks, 0.7±0.1 at 12 weeks, 0.6±0.1 at 13 weeks and 0.6±0.1 at 14 weeks' gestation. Uterine artery bilateral notch was present in 261 (63.8%) patients. We observed that the 5th and 95th percentiles of the UtA-PI and UtA-RI uterine arteries were 0.7 and 2.3 and, 0.5 and 0.8, respectively. CONCLUSION: Normal reference range of uterine artery Doppler in healthy singleton pregnancies from Northeast Brazil was established. The 95th percentile of UtA-PI and UtA-RI values may serve as a cut-off for future prediction of pregnancy complications studies (i.e., pre-eclampsia) in Northeast Brazil.

Triplex Doppler evaluation of the testes in dogs of different sizes

This study aimed to assess whether there are differences in Doppler velocimetry parameters between different sizes. Twenty dogs were equally divided into small and large groups used in this study. The dogs were evaluated using Triplex ultrasound. Testicular artery was located by Colour Doppler in the spermatic cord, marginal to the testes and intratesticular segments and then, spectral Doppler were used to calculate: peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI) and pulsatility index (PI). The mean testicular volume in the left side was significantly higher than the right side, in both groups. Doppler examination showed higher velocities (EDV) at spermatic cord in large dogs; marginal to the testes was observed higher velocities in small dogs; intratesticular region no differences were observed (P < 0.05) and within the groups differences between segments of the artery were also observed for each parameter. The results showed that there are differences in Doppler velocimetry parameters between different sizes.

Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study

AZEVEDO, George Dantas de et al. Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study. Maturitas, Amsterdam, v.47, n.3, p.195-200, 2004

Early embryonic death in mares: clinical and hormonal aspects

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)