Lymphatic abnormalities in patients with single ventricle physiology can lead to early Fontan failure and severe Fontan complications, such as protein-losing enteropathy (PLE), plastic bronchitis ...(PB), chylothorax, and edema. Recent developments in lymphatic imaging and interventions have shed new light on the lymphatic dysfunction in this patient population and the role of the lymphatic circulation in PLE, PB, and chylothorax. In this study, we reviewed some of the latest developments in this field and discuss new treatment options for these patients.
With the expanding horizon of microsurgical techniques, novel treatment strategies for lymphatic abnormalities are increasingly reported. Described in this article is the first reported use of ...lymphovenous anastomosis surgery to manage recalcitrant chylothoraces in infants. Chylothorax is an increasingly common postoperative complication after pediatric cardiac surgery, with a reported incidence of up to 9.2 percent in infants. Although conservative nutritional therapy has a reported 70 percent success rate in this patient population, failed conservative management leading to persistent chylothorax is associated with a significant risk of multisystem complications and mortality. Once conservative medical strategies are deemed unsuccessful, surgical or radiologic interventions, such as percutaneous thoracic duct embolization or ligation, are often attempted. However, these procedures lack high-level evidence in the infant population and remain a challenge, given the small size of the lymphatic vessels. As such, we report our experience with performing lymphovenous anastomoses in two infants who had developed refractory chylothoraces secondary to thoracic duct injury following cardiac surgery for congenital cardiac anomalies. In addition, this article reviews the relevant pathophysiology of chylothoraces, current treatment algorithm following failed conservative management, and potential role of the microsurgeon in the multidisciplinary management of this life-threatening problem. As part of the evolving microsurgery frontier, physiologic operations, such as lymphovenous anastomosis, may have a considerable role in the management of refractory pediatric chylothoraces. In our experience, lymphovenous anastomosis can restore normal lymphatic circulation within 1 to 2 weeks, liberate patients from mechanical ventilation, and enable expeditious return to enteral feeding.
Therapeutic, V.
Lymphatic flow disorders include a broad spectrum of abnormalities that can originate in the lymphatic or the venous system. The development of these disorders is multifactorial and is most commonly ...associated with congenital heart diseases and palliative surgeries that these patients undergo. Central lymphatic disorders might be secondary to traumatic leaks, lymphatic overproduction, conduction abnormalities or lymphedema, and they can progress to perfusion anomalies. Several imaging modalities have been used to visualize the lymphatic system. However, the imaging of central lymphatic flow has always been challenging. Dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) allows for visualization of central lymphatic flow disorders and has been recently applied for the assessment of plastic bronchitis, protein-losing enteropathy, chylothorax and chylopericardium, among other lymphatic disorders. The hepatic and mesenteric accesses are innovative and promising techniques for better identification and understanding of these abnormalities. The main objectives of this review are to discuss the physiology and anatomy of the lymphatic system and review the current uses of DCMRL in the diagnosis and management of lymphatic flow disorders.
Abstract
Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction ...affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.
Etiology and new treatment options for patients with plastic bronchitis Dori, Yoav, MD PhD; Itkin, Maxim, MD
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
08/2016, Letnik:
152, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Plastic bronchitis in patients after single ventricle palliation has a lymphatic etiology and responds to lymphatic based treatments.
Background In the palliative pathway of single-ventricle physiology, lymphatic abnormalities on T2-weighted magnetic resonance imaging have been shown after the Glenn operation. It is believed that ...postsurgical hemodynamic changes contribute to the lymphatic changes.However, little is known about how early these abnormalities occur. Our purpose was to determine if lymphatic abnormalities occur as early as before the Glenn operation. Methods and Results We retrospectively reviewed patients with single-ventricle physiology and a T2-weighted magnetic resonance imaging scan before their Glenn operation (superior cavopulmonary connection) at The Children's Hospital of Philadelphia from 2012 to 2022. Lymphatic perfusion patterns on T2-magnetic resonance imaging were categorized from type 1 (no supraclavicular T2-signal) to type 4 (supraclavicular, mediastinal, lung parenchymal T2-signal). Types 1 and 2 were considered normal variants. Distribution of lymphatic abnormalities were tabulated, as well as secondary outcomes including chylothorax and mortality. Comparison was done using analysis of variance, Kruskal-Wallis test, and Fisher's exact test. Seventy-one children were included: 30 with hypoplastic left heart syndrome and 41 with nonhypoplastic left heart syndrome. Lymphatic abnormalities were present before Glenn operation in 21% (type 3) and 20% (type 4), and normal lymphatic perfusion patterns (type 1-2) were seen in 59% of patients. Chylothorax was present in 17% (only types 3 and 4). Pre-Glenn mortality and mortality at any time was significantly increased when having a type 4 lymphatic abnormality compared with types 1 and 2 (
=0.04). Conclusions Lymphatic abnormalities can be found on T2-weighted magnetic resonance imaging in children with single-ventricle physiology before their Glenn operation. Mortality and chylothorax were more prevalent with advancing grade of lymphatic abnormality.
The investigators recently validated a method of quantifying systemic–to–pulmonary arterial collateral flow using phase-contrast magnetic resonance imaging velocity mapping. Cross-sectional data ...suggest decreased collateral flow in patients with total cavopulmonary connections (TCPCs) compared with those with superior cavopulmonary connections (SCPCs). However, no studies have examined serial changes in collateral flow from SCPCs to TCPCs in the same patients. The aim of this study was to examine differences in collateral flow between patients with SCPCs and those with TCPCs. Collateral flow was quantified by 2 independent measures from 250 single-ventricle studies in 219 different patients (115 SCPC and 135 TCPC studies, 31 patients with both) and 18 controls, during routine studies using through-plane phase-contrast magnetic resonance imaging. Collateral flow was indexed to body surface area, aortic flow, and pulmonary venous flow. Regardless of indexing method, SCPC patients had significantly higher collateral flow than TCPC patients (1.64 ± 0.8 vs 1.03 ± 0.8 L/min/m2 , p <0.001). In 31 patients who underwent serial examinations, collateral flow as a fraction of aortic flow increased early after TCPC completion. In TCPC patients, indexed collateral flow demonstrated a significant negative correlation with time from TCPC. In conclusion, SCPC and TCPC patients demonstrate substantial collateral flow, with SCPC patients having higher collateral flow than TCPC patients overall. On the basis of the paired subset analysis, collateral flow does not decrease in the short term after TCPC completion and trends toward an increase. In the long term, however, collateral flow decreases over time after TCPC completion.
Background
Children with Noonan syndrome are known to have increased risk for lymphatic disorders, the extent and nature of which are poorly understood.
Objective
Our objective was to describe the ...imaging findings of the central lymphatic abnormalities in children with Noonan syndrome who underwent central lymphatic imaging.
Materials and methods
We conducted a single-center retrospective review of all children with a confirmed history of Noonan syndrome who presented for lymphatic imaging over a 5-year period. Imaging evaluation was performed on unenhanced T2-weighted (T2-W) imaging, dynamic-contrast MR lymphangiography or conventional lymphangiography. Two readers evaluated the imaging in consensus for the distribution of fluid on T2-W imaging and for lymphatic flow of intranodal contrast agent and thoracic duct abnormalities on dynamic-contrast MR lymphangiography and conventional lymphangiography. We performed a chart review for clinical history and outcomes.
Results
We identified a total of 10 children, all but one of whom had congenital heart disease. Presenting symptoms included chylothorax (
n
=9) and ascites (
n
=1). Nine had T2-W imaging, seven had dynamic-contrast MR lymphangiography, and seven had conventional lymphangiography. All with T2-W imaging had pleural effusions. On both dynamic-contrast MR lymphangiography and conventional lymphangiography, perfusion to the lung was seen (
n
=6), with intercostal flow also seen on dynamic-contrast MR lymphangiography (
n
=6). The thoracic duct was not present in three children and the central thoracic duct was not present in three. A double thoracic duct was seen in two children.
Conclusion
Children with Noonan syndrome and clinical evidence of lymphatic dysfunction have central lymphatic abnormalities characterized by retrograde intercostal flow, pulmonary lymphatic perfusion, and thoracic duct abnormalities.
The Fontan operation, although part of a life-saving surgical strategy, manifests a variety of end-organ complications and unique morbidities that are being recognised with increasing frequency as ...patients survive into their second and third decades of life and beyond. Liver fibrosis, protein-losing enteropathy and plastic bronchitis are consequences of a complex physiology involving circulatory insufficiency, inflammation and lymphatic derangement. These conditions are manifest in a chronic, indolent state. Management strategies are emerging, which shed some light on the origins of these complications. A better characterisation of the end-organ consequences of the Fontan circulation is necessary, which can then allow for development of specific methods for treatment. Ideally, the goal is to establish systematic strategies that might reduce or eliminate the development of these potentially life-threatening challenges.
Purpose
To assess the feasibility of direct intra-lymphatic administration of diluted ferumoxytol as a T1-positive contrast agent for dynamic contrast-enhanced MR lymphangiography (DCMRL) imaging of ...the central lymphatics in children with renal disease.
Methods
In vitro scan of dilute ferumoxytol was initially performed using time-resolved and high-resolution 3D gradient echo (GRE) sequences with short TE values (1 to 1.5 ms). A ferumoxytol concentration of 0.25 to 0.40 mg/mL was found to retain high signal in the T1-weighted sequences. DCMRL was then performed in 4 children with renal disease with the same 3D GRE sequences administrating diluted ferumoxytol via intra-mesenteric (IM), intra-hepatic (IH), and intra-nodal (IN) routes (6 to 9 mL to each site; average total dose of 0.75 mg/kg) by slow hand injection (0.5 to 1.0 mL/min). The signal-to-noise ratio (SNR) of the lymphatics was measured for quantitative evaluation.
Results
Ferumoxytol-enhanced DCMRL was technically successful in all patients. Contrast conspicuity within the lymphatics was sufficient without subtraction. The mean SNR was significantly higher than the muscle (50.1 ± 12.2 vs 13.2 ± 2.8;
t
= 15.9;
p
< .001). There were no short-term complications attributed to the administration of ferumoxytol in any of the four patients.
Conclusion
Magnetic resonance lymphangiography using ferumoxytol via IN, IH, and IM access is a new method to directly visualize the central lymphatic system and can be applied safely in patients with renal failure based on our preliminary report of four cases. Ferumoxytol-enhanced DCMRL shows diagnostic image quality by using 3D GRE sequences with short TE values and appropriate dilution of ferumoxytol.
Key Points
•
MR lymphangiography using ferumoxytol
via
intra-nodal, intra-hepatic, and intra-mesenteric access is a new method to directly visualize the central lymphatic system from the groin to the venous angle.
•
FDCMRL can be applied safely in patients with renal failure based on our preliminary report of four cases.
•
FDCMRL shows diagnostic image quality by using 3D GRE sequences with short TE values and appropriate dilution of the ferumoxytol.
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