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Contrast-enhanced ultrasound (CEUS) in normal brain and in hypoxic–ischemic injury. a Brain CEUS in a normal 1-month-old boy in the coronal plane demonstrates more avid perfusion to the central gray nuclei (CN) as compared to white matter (WM) during the wash-in phase. b Brain CEUS in a 14-day-old boy with known hypoxic–ischemic injury to the white matter. Image obtained in the coronal plane during the peak enhancement phase shows hyperenhancement of the internal capsule (IC) and corpus callosum (CC) during the reperfusion state. The degree of enhancement is like that of the central gray nuclei (CN), resulting in loss of differential perfusion between these structures. Central gray nuclei should be the most avidly enhancing structure at peak enhancement in infants. c Brain CEUS in a 10-month-old girl with known multiple hypoxic–ischemic insults to the brain. Image obtained in the coronal plane during wash-in phase shows mild ventriculomegaly (V) and avid perfusion of the cortical ribbon (dashed line), corpus callosum (CC) and central gray nuclei (CN). This finding predates the extensive laminar necrosis on follow-up MRI (not shown here)
Source publication
Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic–ischemic i...
Citations
... Lastly, this study was limited to the assessment and quantification of the diagnostic value of conventional iUS imaging based on B-mode images. Several recent studies report on the potential of more advanced iUS techniques like Doppler imaging [18], strain elastosonography [26,27], and contrast-enhanced ultrasound (CEUS) [19,[28][29][30][31][32]. Future research needs to show if more advanced iUS techniques contribute to a more optimal EoR and a minimal disruption of the surgical workflow. ...
Purpose
The aim of this study was to evaluate the diagnostic value and accuracy of navigated intraoperative ultrasound (iUS) in pediatric oncological neurosurgery as compared to intraoperative magnetic resonance imaging (iMRI).
Methods
A total of 24 pediatric patients undergoing tumor debulking surgery with iUS, iMRI, and neuronavigation were included in this study. Prospective acquisition of iUS images was done at two time points during the surgical procedure: (1) before resection for tumor visualization and (2) after resection for residual tumor assessment. Dice similarity coefficients (DSC), Hausdorff distances 95th percentiles (HD95) and volume differences, sensitivity, and specificity were calculated for iUS segmentations as compared to iMRI.
Results
A high correlation (R = 0.99) was found for volume estimation as measured on iUS and iMRI before resection. A good spatial accuracy was demonstrated with a median DSC of 0.72 (IQR 0.14) and a median HD95 percentile of 4.98 mm (IQR 2.22 mm). The assessment after resection demonstrated a sensitivity of 100% and a specificity of 84.6% for residual tumor detection with navigated iUS. A moderate accuracy was observed with a median DSC of 0.58 (IQR 0.27) and a median HD95 of 5.84 mm (IQR 4.04 mm) for residual tumor volumes.
Conclusion
We found that iUS measurements of tumor volume before resection correlate well with those obtained from preoperative MRI. The accuracy of residual tumor detection was reliable as compared to iMRI, indicating the suitability of iUS for directing the surgeon’s attention to areas suspect for residual tumor. Therefore, iUS is considered as a valuable addition to the neurosurgical armamentarium.
Trial registration number and date
PMCLAB2023.476, February 12th 2024.
... Contrast-enhanced ultrasound (CEUS) is a validated method of examining microvascular cerebral perfusion and, among many applications, clinical CEUS of the pediatric brain has been used to evaluate the neonatal hypoxic-ischemic injury, brain tumour enhancement characteristics for surgical planning, and intraoperative monitoring of brain perfusion. [17][18][19][20][21] Much of the existing literature has focused on CEUS as a sensitive modality in evaluating acute ischemia, [22][23][24] but to our knowledge, little is known about the imaging evaluation in the fetus or of the chronic hypoxic state as with CHD. ...
Background
Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD.
Methods
Fifteen fetal lambs [hypoxic animals ( n = 9) and normoxic controls ( n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained.
Results
Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF ( p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami ( p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027).
Conclusion
Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes.
Impact
This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values.
These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences.
To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model.
The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.
... Contrast-enhanced ultrasound can depict perfusion changes at the tissue and microvascular level and thereby help delineate areas of ischemia, infarction, inflammation, and reperfusion injury [19,20]. Contrastenhanced ultrasound can guide the medical management of critically ill patients with abnormal organ (heart, brain, liver, kidney, intestines) perfusion for patients with shock, hypovolemia, low cardiac output states, recent solid organ transplant, hepatorenal syndrome, and potentially far more [25,28,[30][31][32][33]. ...
Background
The off-label use of contrast-enhanced ultrasound has been increasingly used for pediatric patients.
Objective
The purpose of this retrospective study is to report any observed clinical changes associated with the intravenous (IV) administration of ultrasound contrast to critically ill neonates, infants, children, and adolescents.
Materials and methods
All critically ill patients who had 1 or more contrast-enhanced ultrasound scans while being closely monitored in the neonatal, pediatric, or pediatric cardiac intensive care units were identified. Subjective and objective data concerning cardiopulmonary, neurological, and hemodynamic monitoring were extracted from the patient’s electronic medical records. Vital signs and laboratory values before, during, and after administration of ultrasound contrast were obtained. Statistical analyses were performed using JMP Pro, version 15. Results were accepted as statistically significant for P-value<0.05.
Results
Forty-seven contrast-enhanced ultrasound scans were performed on 38 critically ill patients, 2 days to 17 years old, 19 of which were female (50%), and 19 had history of prematurity (50%). At the time of the contrast-enhanced ultrasound scans, 15 patients had cardiac shunts or a patent ductus arteriosus, 25 had respiratory failure requiring invasive mechanical oxygenation and ventilation, 19 were hemodynamically unstable requiring continual vasoactive infusions, and 8 were receiving inhaled nitric oxide. In all cases, no significant respiratory, neurologic, cardiac, perfusion, or vital sign changes associated with IV ultrasound contrast were identified.
Conclusion
This study did not retrospectively identify any adverse clinical effects associated with the IV administration of ultrasound contrast to critically ill neonates, infants, children, and adolescents.
Graphical abstract
... The CEUS overcomes these limitations and allows the visualization of dynamic perfusion even in the smallest vessels in the whole brain. The CEUS also allows quantitative analysis to be performed [3]. It has already shown potential in applications to various clinical indications, such as hypoxic-ischemic injuries, stroke, intracranial hemorrhages, vascular anomalies, brain tumors, and infections. ...
... Another method for measuring tissue perfusion is the infusion-based destructionreplenishment method. This method involves destroying microbubbles in the field of imaging using a short acoustic pulse and studying the replenishment kinetics as circulating microbubbles flow back into the same region [3]. ...
... A CEUS can be helpful in establishing the diagnosis of the malformation, as the dense vascular structure of the malformation is better depicted using CEUSs in comparison to conventional USs. Additionally, after a surgical procedure or neurovascular embolization, brain CEUSs can be used to assess the residual flow within the lesion [3]. This has been more extensively researched for the other types of AVMs in the adult population [70][71][72][73]. ...
In recent years, advancements in technology have allowed the use of contrast-enhanced ultrasounds (CEUS) with high-frequency transducers, which in turn, led to new possibilities in diagnosing a variety of diseases and conditions in the field of radiology, including neonatal brain imaging. CEUSs overcome some of the limitations of conventional ultrasounds (US) and Doppler USs. It allows the visualization of dynamic perfusion even in the smallest vessels in the whole brain and allows the quantitative analysis of perfusion parameters. An increasing number of articles are published on the topic of the use of CEUSs on children each year. In the area of brain imaging, the CEUS has already proven to be useful in cases with clinical indications, such as hypoxic-ischemic injuries, stroke, intracranial hemorrhages, vascular anomalies, brain tumors, and infections. We present and discuss the basic principles of the CEUS and its safety considerations, the examination protocol for imaging the neonatal brain, and current and emerging clinical applications.
... However, the development of microbubble contrast agents has led to the emergence of contrast-enhanced ultrasound (CEUS), which improves the contrast of ultrasound images and enhanced the visualization of lesions [9]. This technique captures more information about the microvasculature and margins of SLNs, improving the accuracy of SLN metastasis assessment [10]. Since the lymph nodes have both lymphatic and blood circulation, percutaneous or intravenous injection of contrast agents can rapidly reach lymphatic vessels and SLNs, without radiation exposure [11,12]. ...
Purpose
The status of sentinel lymph nodes (SLN) is an important factor in determining the stage of breast cancer (BC) and the surgical procedure, and also a biomarker of the BC prognosis. This meta-analysis was performed to investigate the diagnostic value of contrast-enhanced ultrasound (CEUS) for SLN metastasis.
Methods
A systematic search was conducted for relevant articles published in the PubMed, Embase, Web of Science, OVID databases, and Cochrane Library from inception to March 2023. We calculated the sensitivity, specificity, positive and negative likelihood ratio (PLR; NLR), diagnostic odds ratio (DOR), and summary receiver operator characteristic (SROC) curve to evaluate the diagnostic efficacy of CEUS in SLN metastasis. Subgroup analysis was also performed to investigate potential sources of heterogeneity.
Results
A total of 12 studies with 1525 patients were included in this meta-analysis. The overall pooled sensitivity and specificity of CEUS in the diagnosis of SLN metastasis were 0.91 (95% CI: 0.84–0.95) and 0.86 (95% CI: 0.78–0.92). The PLR, NLR, and DOR were 6.51 (95% CI: 4.09–10.36), 0.11 (95% CI: 0.07–0.18), and 59.43 (95% CI: 33.27–106.17), respectively, and the area under the SROC curve was determined to be 0.95 (95%CI: 0.92–0.96), all showing excellent diagnostic value. In the subgroup analysis, percutaneous CEUS was more sensitive than intravenous CEUS in the diagnosis of SLN metastases (0.92 versus 0.82, p < 0.05).
Conclusion
CEUS, especially percutaneous CEUS, is a reliable imaging technique for diagnosing SLN metastasis and providing important information in the stage management of breast cancer.
... In recent years, CEUS of the brain has been increasingly performed, especially in critically ill infants in the neonatal intensive care unit and intraoperatively, as the performance of MRI in these settings is logistically challenging. Several off-label applications of brain CEUS are under investigation [46]. ...
... MRI has traditionally been used for assessing acute stroke in children, although it can be impractical in critically ill children. In patients with an open anterior fontanelle, CEUS has the potential to evaluate brain perfusion and detect perfusion defects (Fig. 6) [46]. Brain death is characterized by the complete and irreversible loss of brain function. ...
... CEUS allows spatiotemporal assessment of tissue perfusion in real time, complementing conventional ultrasound, without the need for transportation, sedation, or radiation. Dynamic perfusion kinetics are quantified using the standardized time-intensity curve, wherein signal intensity in a region of interest is quantified over time [124]. CEUS uses a low mechanical index, typically less than 0.2, to avoid microbubble destruction. ...
... In stroke, hyperacute hypoperfusion or reperfusion response can be assessed. In fact, much of the CEUS studies in stroke have been in children and adults with closed fontanelles [124,126]. In using the temporal bone as the acoustic window, it is important to recognize that the acoustic-bone impedance can lead to decreased signal on the contralateral side [127]. ...
... As such, spatial changes in cerebral microvascular flow can serve as a valuable biomarker of disease and help guide therapy in the future if further validated. Beyond hydrocephalus, the potential utility of CEUS has been described in a wide range of neurologic diseases, including brain tumors and vascular malformations [124]. ...
Timely detection and monitoring of acute brain injury in children is essential to mitigate causes of injury and prevent secondary insults. Increasing survival in critically ill children has emphasized the importance of neuroprotective management strategies for long-term quality of life. In emergent and critical care settings, traditional neuroimaging modalities, such as computed tomography and magnetic resonance imaging (MRI), remain frontline diagnostic techniques to detect acute brain injury. Although detection of structural and anatomical abnormalities remains crucial, advanced MRI sequences assessing functional alterations in cerebral physiology provide unique diagnostic utility. Head ultrasound has emerged as a portable neuroimaging modality for point-of-care diagnosis via assessments of anatomical and perfusion abnormalities. Application of electroencephalography and near-infrared spectroscopy provides the opportunity for real-time detection and goal-directed management of neurological abnormalities at the bedside. In this review, we describe recent technological advancements in these neurodiagnostic modalities and elaborate on their current and potential utility in the detection and management of acute brain injury.
... The US scanner detects circulating microbubbles as strong echoes moving within the vessels in real-time, providing micro-and macrovascular information used to assess vascular perfusion of the whole brain [8,9]. Therefore, CEUS allows better visualisation of the cerebral vasculature in comparison to Doppler US and the evaluation of cerebral perfusion [7,10,11]. Studies in adult populations have shown that the rate of nonconclusive Doppler US examinations for determining cerebral circulatory arrest significantly reduces if CEUS is performed [6,12]. Herein, we present a case of a 1-year-old polytraumatised patient in whom CEUS was used as an ancillary imaging test for confirmation of brain death. ...
... In recent years, CEUS has established itself as a beneficial and widely used diagnostic imaging method in many different areas, such as echocardiography, for the evaluation of vesicoureteral reflux and characterisation of liver neoplasms [10]. Due to a lack of clinical reports and safety studies, the use of CEUS for the assessment of brain pathology in children is, for now, still considered off-label [11,13]. Nevertheless, there has been an increasing number of reports on the use of CEUS in children for the assessment of hypoxic-ischemic injury, acute ischemic stroke, brain tumours, paediatric neurovascular diseases, epilepsy, and the confirmation of brain death [5,11,14,15]. ...
... Due to a lack of clinical reports and safety studies, the use of CEUS for the assessment of brain pathology in children is, for now, still considered off-label [11,13]. Nevertheless, there has been an increasing number of reports on the use of CEUS in children for the assessment of hypoxic-ischemic injury, acute ischemic stroke, brain tumours, paediatric neurovascular diseases, epilepsy, and the confirmation of brain death [5,11,14,15]. These reports validate CEUS as a great method for the evaluation of the brain in children, especially the brain vasculature and vascular pathologic processes. ...
The practices for determining brain death are based on clinical criteria and vary immensely across countries. Cerebral angiography and perfusion scintigraphy are the most commonly used ancillary imaging tests for brain death confirmation in children; however, they both share similar shortcomings. Hence, contrast-enhanced ultrasound (CEUS) as a relatively inexpensive, easily accessible, and easy-to-perform technique has been proposed as an ancillary imaging test for brain death confirmation. CEUS has established itself as a favourable and widely used diagnostic imaging method in many different areas, but its application in delineating brain pathologies still necessities further validation. Herein, we present a case report of a 1-year-old polytraumatised patient in whom CEUS was applied as an ancillary imaging test for confirmation of brain death. As CEUS has not been validated as an ancillary test for brain death confirmation, the diagnosis was additionally confirmed with cerebral perfusion scintigraphy.
... Brain CEUS allows the qualitative and quantitative evaluation of cerebral perfusion, especially the slow flow dynamics of small vessels that are not readily evaluable with Doppler US [4,5]. Parenchymal perfusion can be assessed by analyzing the changes in microbubble intensity (i.e., perfusion kinetics) over time in the whole brain or within a specific region of interest (ROI). ...
... This process is depicted in what is commonly referred to as a time-intensity curve (TIC). Several CEUS quantitative measures can be extracted from the TIC such as time-to-peak, wash-in slope, peak intensity, wash-in area under the curve, wash-out area under the curve, and wash-out slope [4]. Since its first application in infants in 2014, multiple brain CEUS studies have been conducted to evaluate pathological neurovascular conditions in the pediatric population, such as hypoxic-ischemic encephalopathy and arteriovenous malformations [6,7]. ...
... We have reported the sonographic parameters used for each patient, including vendor, transducer type, and machine settings ( Table 2). Gain and depth field were adjusted before contrast administration to provide the ideal tissue background signal to maintain the imaging plane; the studies did not exceed mechanical index of 0.3 [4]. ...
AimTo evaluate the use of transtemporal brain contrast-enhanced ultrasound (CEUS) to assess cerebral blood perfusion in a cohort of children without neurological disorders.Methods
We included pediatric patients who were undergoing a clinically-indicated CEUS study. Brain scans were performed with a Siemens Sequoia scanner and a 4V1 transducer, that was placed on the left transtemporal bone. Brain scans were performed simultaneously with the images of the clinically-indicated organ of interest. Qualitative and quantitative analysis was performed to evaluate the hemispherical blood flow at the level of the midbrain during the wash-in and wash-out phases of the time-intensity curve. Clinical charts were reviewed to evaluate post-CEUS adverse events.ResultsFive patients were evaluated (mean age 5.8 ± 5.1 years). Qualitatively, more avid enhancement in the midbrain than the cortex was observed. Structures depicted ranged between the centrum semiovale at the level of the lateral ventricles and the midbrain. A quantitative analysis conducted on four patients demonstrated less avid perfusion on the contralateral (i.e. right) side, with a mean left/right ratio ranging between 1.51 and 4.07. In general, there was a steep positive wash-in slope starting at approximately 10 s after contrast injection, reaching a peak intensity around 15–26 s on the left side, and 17–29 s on the right side. No adverse events were reported.Conclusion
Transtemporal brain CEUS is feasible and safe in the pediatric population and allows qualitative and quantitative assessment of cerebral perfusion.
... The temporal bone has served as the standard acoustic window for brain US in children whose fontanelles have closed [12] (Fig. 1). The field of view is typically more restricted than that seen with brain ultrasound through open fontanelles in neonates [1,13]. ...
... The transducer selection for transtemporal CEUS relies on the optimal frequency range for visualization of microbubble signal through the bone, the morphology of the temporal bone, as well as the consideration of sound beam attenuation/absorption by the bone. Microbubble oscillation and signal detection through the temporal bone are most optimal at transducer frequency ranges of 2-4 MHz [12,15]. Higher transducer frequency ranges as seen with linear probes typically result in lower contrast signal due to the mismatch of insonation frequency and microbubble oscillation frequency, nor is depth penetration sufficient for transcranial imaging. ...
... The optimization process consists of ensuring the visualization of brain parenchyma via adjustment of acoustic power (mechanical index) and time gain compensation. The mechanical index should be equal to or lower than 0.3 either for grayscale or CEUS imaging [12]. The maintenance of a low mechanical index is desired due to concerns of microbubble destruction at a high mechanical index (> 0.8) [16]. ...
Brain contrast-enhanced ultrasound offers insights into the brain beyond the anatomic information offered by conventional grayscale ultrasound. In infants, the open fontanelles serve as acoustic windows. In children, whose fontanelles are closed, the temporal bone serves as the ideal acoustic window due to its relatively smaller thickness than the other skull bones. Diagnosis of common neurologic diseases such as stroke, hemorrhage, and hydrocephalus has been performed using the technique. Transtemporal ultrasound and contrast-enhanced ultrasound, however, are rarely used in children due to the prevalent notion that the limited acoustic penetrance degrades diagnostic quality. This review seeks to provide guidelines for the use of transtemporal brain contrast-enhanced ultrasound in children.
