Journal of Perinatology (2014) 34, 720–722 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Treatment of congenital pulmonary lymphangiectasia using ethiodized oil lymphangiography M Gray1,5, KZ Kovatis1,5, T Stuart1, E Enlow1, M Itkin2, MS Keller3 and HM French4 Historically, congenital pulmonary lymphangiectasia (CPL) has had poor treatment outcomes despite aggressive therapy. There are recent reports of ethiodized oil (Lipiodol) lymphangiography successfully treating lymphatic leakage in adults. In this report, we describe two infants with CPL complicated by chylothoraces successfully treated by instillation of ethiodized oil into the lymphatic system. Congenital atresia of the thoracic duct was demonstrated on the lymphangiogram in both patients before treatment. Both patients have shown good short-term outcomes without supplemental oxygen or fat restricted diets at 9 months of age. Ethiodized oil lymphangiography represents a new treatment modality for some patients with CPL. Journal of Perinatology (2014) 34, 720–722; doi:10.1038/jp.2014.71
INTRODUCTION Congenital pulmonary lymphangiectasia (CPL) is a rare disorder whose hallmarks include dilation of the pulmonary lymphatics accompanied by severe respiratory distress in the neonatal period. Though cases are usually sporadic, CPL is associated with some genetic syndromes including Turner syndrome, Noonan syndrome, Down syndrome and congenital ichthyosis.1 Its etiology remains unknown, though it has been attributed to failure of the fetal lymphatic channels to regress and congenital occlusion of the thoracic duct with subsequent dilation of the peribronchial lymphatics. Mortality for CPL approximated 100% before the 1990s.1,2 With advances in ventilator management and nutritional therapy, there are varied reports of long-term survivors.3 However, despite aggressive therapy including thoracic duct ligation, pleural and abdominal drainage, medium-chain triglyceride diet, octreotide and pleurodesis, the overall mortality rate for this disease remains high.2 Recently, reports document successes using lymphangiography in adult patients with chyle leak.4,5 In this case series, we report the successful treatment of two infants with CPL using ultrasound-guided intranodal lymphangiography to perform ethiodized oil lymphatic embolization. CASE 1 This female was born at 23 weeks gestational age. Her initial neonatal intensive care unit course included mechanical ventilation for the first 6 weeks of life, treatment with dexamethasone for chronic lung disease and hydrocortisone for airway edema. At 5 months of life, she developed slowly worsening respiratory distress and hypoxia. A right pleural effusion was noted, and subsequent thoracentesis yielded chylous fluid. Feeds were
changed from breast milk to low-fat formula. One week later, her right pleural effusion reaccumulated. Her enteral feeds and medications were discontinued, a chest tube was placed and an octreotide infusion was initiated. Six days later, she developed a left-sided effusion and was referred to our center for further management. After consultation with interventional radiology, the decision was made to attempt a bilateral inguinal lymphangiogram and, if indicated, a thoracic duct embolization. An echocardiogram was first performed to exclude a right to left patent ductus arteriosus (PDA) or intracardiac shunt. Under general anesthesia, bilateral intranodal lymphangiogram using ethiodized oil, an iodinated oilbased contrast agent, for diagnosis was performed as previously described.6 The lymphangiogram demonstrated complete occlusion of the thoracic duct at the level of the lower mediastinum with numerous bilateral peribronchial and mediastinal lymphatic collaterals that filled via the cisterna chyli and lower thoracic duct (Figure 1). Thoracic duct embolization was therefore not performed and the infant received an additional intranodal injection of ethiodized oil into her inguinal lymph nodes to occlude the leaking lymphatic channels. Post procedure, fluoroscopic images demonstrated stagnant flow within the intrapulmonary lymphatic branches and her chest tubes were removed within the first postoperative week. The infant was extubated 18 days after her procedure and off all respiratory support one week later. Skimmed breast milk was initiated 1 week post lymphangiogram with an increase of feeds occurring over 3 weeks. Once on full volume feeds, breast milk fat was increased by 25% per week until 100% full fat breast milk feeds were achieved. She was discharged home at 8 months of life in room air and full feeds via a gastrostomy tube (GT). Follow up at 10 months of life showed no significant interim illnesses or hospitalizations.
1 Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 3Division of Interventional Radiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA and 4Division of Neonatology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Correspondence: Dr HM French, Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, 2nd floor, Main Building, Philadelphia, PA 19104, USA. E-mail: [email protected] 5 These authors are co-first authors. Received 22 November 2013; revised 4 March 2014; accepted 18 March 2014
Treatment of congenital pulmonary lymphangiectasia M Gray et al
721
Figure 1. (a) Radiograph during lymphangiogram with ascent of contrast in a left prevertebral channel filling paratracheal, peribronchial and mediastinal lymphatics but not flowing directly into the venous system. (b) Predischarge chest radiograph with no pleural effusions. Residual lymphographic contrast can be seen in the lymphatic system.
CASE 2 This female, born at 36 weeks gestational age, was prenatally diagnosed with bilateral pleural effusions. At delivery, she had persistent cyanosis and increased work of breathing requiring intubation. The patient’s respiratory status continued to decline and bilateral chest tubes were placed yielding chylous fluid. The patient’s respiratory status further worsened, and she required a 10-day course of veno-arterial extracorporeal membrane oxygenation. After decannulation, the patient continued to have respiratory symptoms attributed to her pleural effusions. A chest magnetic resonance imaging at 5 weeks of life demonstrated body wall edema, bilateral pleural effusions and ascites. An echocardiogram demonstrated normal ventricular size and function with a small left to right PDA. A bilateral intranodal lymphangiogram using ethiodized oil performed 2 weeks later demonstrated excessive inguinal lymphatics, absence of the cisterna chyli and thoracic duct and abnormal flow via a large aberrant paraaortic lymphatic channel filling the distribution of the peribronchial lymphatics in both lungs, consistent with diffuse lymphangiectasia (Figure 2). An additional small volume of ethiodized oil was injected into the bilateral groin nodes to achieve relative stagnation of lung lymphatic flow. Trophic feeds with skimmed breast milk were initiated once chest tube output diminished. Feeds were gradually advanced in volume and fat content until she reached full fat breast milk feeds 5 weeks after her lymphangiogram. The patient’s chest tubes were removed 3 weeks after her lymphangiogram, and the infant was extubated within a month of her procedure. The baby was discharged home at 5 months of life in room air and 100% enteral feeds with breast milk via a GT. At 9 months of age, the infant has no respiratory morbidities.
DISCUSSION Pulmonary lymphangiectasia and other lymphangiectasias are a rare group of disorders believed to result from an abnormality in the development of the fetal central lymphatic conduction system. Historically, the diagnosis of lymphangiectasia has been based upon the clinical presentation combined with the anatomic and histologic findings of dilated lymphatics on autopsy. Recently, Clemens et al.7 has introduced the term, ‘central lymphatic conducting anomalies,’ to better characterize this group of disorders. In both infants described here, the lymphangiograms demonstrated absence of the cranial segment of the thoracic duct and lymphovenous connection at the left subclavian vein. We hypothesize that this anomaly is a result of intrauterine regression of the thoracic duct with subsequent development of the compensatory peribronchial lymphatic collaterals. © 2014 Nature America, Inc.
Figure 2. (a) Early view during bilateral inguinal lymphangiogram showing inguinal and lower pelvic lymph nodes and dilated lymphatics. Note the abnormal inferomedial flow into external genital lymphatics. (b) Contrast has ascended via several abnormal prevertebral channels, none of which is a normal thoracic duct. The largest vessel, carrying the gastrointestinal flow, fills the paratracheal, peribronchial and mediastinal lymphatics. Lipiodol was instilled via the inguinal nodes until a point of flow stagnation into the lungs occurred. (c) Predischarge chest and abdomen radiograph with no pleural effusions. Residual lymphographic contrast can be seen.
The introduction of ultrasound-guided intranodal lymphangiography has revolutionized lymphangiography, making this procedure readily and reliably available for neonatal patients.6,8 Ethiodized oil (Lipiodol, Roissy CdG Cedex, France) is an oil-based contrast agent used for lymphangiography and can be both diagnostic and therapeutic.4 Due to its high viscosity, Lipiodol results in mechanical occlusion of the lymphatic vessels. It is routinely used for arterial occlusion during chemoembolization of hepatic tumors.9 Some hypothesize that antinflammatory reaction causing progressive sclerosis of small lymphatics occurs over the ensuing weeks.10 Injection of commercially available water-soluble contrast into the lymphatic system is usually not diagnostic primarily due to diffusion of water-soluble materials out of the lymphatics before reaching the central venous system. It should be noted that a right to left cardiac shunt would be a relative contraindication for lymphangiogram due to risk of systemic emboli. In this case series, we describe favorable short-term outcomes using lymphangiogram with ethiodized oil to treat two infants with CPL. Although these infants had reduced mortality and morbidity compared with prior reports, the long-term outcomes of patients treated with ethodized oil embolization are unknown. In addition, infants who undergo this treatment often have other comorbidities that may impact long-term outcomes. Despite these concerns, ethiodized oil embolism has provided a new therapeutic option for patients with CPL that may reduce the need for aggressive medical management and should prompt further investigation. CONFLICT OF INTEREST The authors declare no conflict of interest.
Journal of Perinatology (2014), 720 – 722
Treatment of congenital pulmonary lymphangiectasia M Gray et al
722
REFERENCES 1 Esther CR Jr, Barker PM. Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr Pulmonol 2004; 38(4): 308–313. 2 Bouchard S, Di Lorenzo M, Youssef S, Simard P, Lapierre JG. Pulmonary lymphangiectasia revisited. J Pediatr Surg 2000; 35(5): 796–800. 3 Bellini C, Boccardo F, Campisi C, Toma P, Taddei G, Villa G et al. Congenital pulmonary lymphangiectasia. Orphanet J Rare Dis 2006; 1: 43. 4 Alejandre-Lafont E, Krompiec C, Rau WS, Krombach GA. Effectiveness of therapeutic lymphography on lymphatic leakage. Acta Radiol 2011; 52(3): 305–311. 5 Matsumoto T, Yamagami T, Kato T, Hirota T, Yoshimatsu R, Masunami T et al. The effectiveness of lymphangiography as a treatment method for various chyle leakages. Br J Radiol 2009; 82(976) 286–290.
Journal of Perinatology (2014), 720 – 722
6 Nadolski GJ, Itkin M. Feasibility of ultrasound-guided intranodal lymphangiogram for thoracic duct embolization. J Vasc Interv Radiol 2012; 23(5): 613–616. 7 Clemens R, Kreindel T, Lillis A, Alomari A. Characterization of central conducting lymphatic anomalies. Pediatr Radiol 2013; 43(Suppl 2) S319. 8 Rajebi MR, Chaudry G, Padua HM, Dillon B, Yilmaz S, Arnold RW et al. Intranodal lymphangiography: feasibility and preliminary experience in children. J Vasc Interv Radiol 2011; 22(9): 1300–1305. 9 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164–1171. 10 Yamagami T, Masunami T, Kato T, Tanaka O, Hirota T, Nomoto T et al. Spontaneous healing of chyle leakage after lymphangiography. Br J Radiol 2005; 78(933): 854–857.
© 2014 Nature America, Inc.
PERINATAL/NEONATAL CASE PRESENTATION
Treatment of congenital pulmonary lymphangiectasia using ethiodized oil lymphangiography M Gray1,5, KZ Kovatis1,5, T Stuart1, E Enlow1, M Itkin2, MS Keller3 and HM French4 Historically, congenital pulmonary lymphangiectasia (CPL) has had poor treatment outcomes despite aggressive therapy. There are recent reports of ethiodized oil (Lipiodol) lymphangiography successfully treating lymphatic leakage in adults. In this report, we describe two infants with CPL complicated by chylothoraces successfully treated by instillation of ethiodized oil into the lymphatic system. Congenital atresia of the thoracic duct was demonstrated on the lymphangiogram in both patients before treatment. Both patients have shown good short-term outcomes without supplemental oxygen or fat restricted diets at 9 months of age. Ethiodized oil lymphangiography represents a new treatment modality for some patients with CPL. Journal of Perinatology (2014) 34, 720–722; doi:10.1038/jp.2014.71
INTRODUCTION Congenital pulmonary lymphangiectasia (CPL) is a rare disorder whose hallmarks include dilation of the pulmonary lymphatics accompanied by severe respiratory distress in the neonatal period. Though cases are usually sporadic, CPL is associated with some genetic syndromes including Turner syndrome, Noonan syndrome, Down syndrome and congenital ichthyosis.1 Its etiology remains unknown, though it has been attributed to failure of the fetal lymphatic channels to regress and congenital occlusion of the thoracic duct with subsequent dilation of the peribronchial lymphatics. Mortality for CPL approximated 100% before the 1990s.1,2 With advances in ventilator management and nutritional therapy, there are varied reports of long-term survivors.3 However, despite aggressive therapy including thoracic duct ligation, pleural and abdominal drainage, medium-chain triglyceride diet, octreotide and pleurodesis, the overall mortality rate for this disease remains high.2 Recently, reports document successes using lymphangiography in adult patients with chyle leak.4,5 In this case series, we report the successful treatment of two infants with CPL using ultrasound-guided intranodal lymphangiography to perform ethiodized oil lymphatic embolization. CASE 1 This female was born at 23 weeks gestational age. Her initial neonatal intensive care unit course included mechanical ventilation for the first 6 weeks of life, treatment with dexamethasone for chronic lung disease and hydrocortisone for airway edema. At 5 months of life, she developed slowly worsening respiratory distress and hypoxia. A right pleural effusion was noted, and subsequent thoracentesis yielded chylous fluid. Feeds were
changed from breast milk to low-fat formula. One week later, her right pleural effusion reaccumulated. Her enteral feeds and medications were discontinued, a chest tube was placed and an octreotide infusion was initiated. Six days later, she developed a left-sided effusion and was referred to our center for further management. After consultation with interventional radiology, the decision was made to attempt a bilateral inguinal lymphangiogram and, if indicated, a thoracic duct embolization. An echocardiogram was first performed to exclude a right to left patent ductus arteriosus (PDA) or intracardiac shunt. Under general anesthesia, bilateral intranodal lymphangiogram using ethiodized oil, an iodinated oilbased contrast agent, for diagnosis was performed as previously described.6 The lymphangiogram demonstrated complete occlusion of the thoracic duct at the level of the lower mediastinum with numerous bilateral peribronchial and mediastinal lymphatic collaterals that filled via the cisterna chyli and lower thoracic duct (Figure 1). Thoracic duct embolization was therefore not performed and the infant received an additional intranodal injection of ethiodized oil into her inguinal lymph nodes to occlude the leaking lymphatic channels. Post procedure, fluoroscopic images demonstrated stagnant flow within the intrapulmonary lymphatic branches and her chest tubes were removed within the first postoperative week. The infant was extubated 18 days after her procedure and off all respiratory support one week later. Skimmed breast milk was initiated 1 week post lymphangiogram with an increase of feeds occurring over 3 weeks. Once on full volume feeds, breast milk fat was increased by 25% per week until 100% full fat breast milk feeds were achieved. She was discharged home at 8 months of life in room air and full feeds via a gastrostomy tube (GT). Follow up at 10 months of life showed no significant interim illnesses or hospitalizations.
1 Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 2Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 3Division of Interventional Radiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA and 4Division of Neonatology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Correspondence: Dr HM French, Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, 2nd floor, Main Building, Philadelphia, PA 19104, USA. E-mail: [email protected] 5 These authors are co-first authors. Received 22 November 2013; revised 4 March 2014; accepted 18 March 2014
Treatment of congenital pulmonary lymphangiectasia M Gray et al
721
Figure 1. (a) Radiograph during lymphangiogram with ascent of contrast in a left prevertebral channel filling paratracheal, peribronchial and mediastinal lymphatics but not flowing directly into the venous system. (b) Predischarge chest radiograph with no pleural effusions. Residual lymphographic contrast can be seen in the lymphatic system.
CASE 2 This female, born at 36 weeks gestational age, was prenatally diagnosed with bilateral pleural effusions. At delivery, she had persistent cyanosis and increased work of breathing requiring intubation. The patient’s respiratory status continued to decline and bilateral chest tubes were placed yielding chylous fluid. The patient’s respiratory status further worsened, and she required a 10-day course of veno-arterial extracorporeal membrane oxygenation. After decannulation, the patient continued to have respiratory symptoms attributed to her pleural effusions. A chest magnetic resonance imaging at 5 weeks of life demonstrated body wall edema, bilateral pleural effusions and ascites. An echocardiogram demonstrated normal ventricular size and function with a small left to right PDA. A bilateral intranodal lymphangiogram using ethiodized oil performed 2 weeks later demonstrated excessive inguinal lymphatics, absence of the cisterna chyli and thoracic duct and abnormal flow via a large aberrant paraaortic lymphatic channel filling the distribution of the peribronchial lymphatics in both lungs, consistent with diffuse lymphangiectasia (Figure 2). An additional small volume of ethiodized oil was injected into the bilateral groin nodes to achieve relative stagnation of lung lymphatic flow. Trophic feeds with skimmed breast milk were initiated once chest tube output diminished. Feeds were gradually advanced in volume and fat content until she reached full fat breast milk feeds 5 weeks after her lymphangiogram. The patient’s chest tubes were removed 3 weeks after her lymphangiogram, and the infant was extubated within a month of her procedure. The baby was discharged home at 5 months of life in room air and 100% enteral feeds with breast milk via a GT. At 9 months of age, the infant has no respiratory morbidities.
DISCUSSION Pulmonary lymphangiectasia and other lymphangiectasias are a rare group of disorders believed to result from an abnormality in the development of the fetal central lymphatic conduction system. Historically, the diagnosis of lymphangiectasia has been based upon the clinical presentation combined with the anatomic and histologic findings of dilated lymphatics on autopsy. Recently, Clemens et al.7 has introduced the term, ‘central lymphatic conducting anomalies,’ to better characterize this group of disorders. In both infants described here, the lymphangiograms demonstrated absence of the cranial segment of the thoracic duct and lymphovenous connection at the left subclavian vein. We hypothesize that this anomaly is a result of intrauterine regression of the thoracic duct with subsequent development of the compensatory peribronchial lymphatic collaterals. © 2014 Nature America, Inc.
Figure 2. (a) Early view during bilateral inguinal lymphangiogram showing inguinal and lower pelvic lymph nodes and dilated lymphatics. Note the abnormal inferomedial flow into external genital lymphatics. (b) Contrast has ascended via several abnormal prevertebral channels, none of which is a normal thoracic duct. The largest vessel, carrying the gastrointestinal flow, fills the paratracheal, peribronchial and mediastinal lymphatics. Lipiodol was instilled via the inguinal nodes until a point of flow stagnation into the lungs occurred. (c) Predischarge chest and abdomen radiograph with no pleural effusions. Residual lymphographic contrast can be seen.
The introduction of ultrasound-guided intranodal lymphangiography has revolutionized lymphangiography, making this procedure readily and reliably available for neonatal patients.6,8 Ethiodized oil (Lipiodol, Roissy CdG Cedex, France) is an oil-based contrast agent used for lymphangiography and can be both diagnostic and therapeutic.4 Due to its high viscosity, Lipiodol results in mechanical occlusion of the lymphatic vessels. It is routinely used for arterial occlusion during chemoembolization of hepatic tumors.9 Some hypothesize that antinflammatory reaction causing progressive sclerosis of small lymphatics occurs over the ensuing weeks.10 Injection of commercially available water-soluble contrast into the lymphatic system is usually not diagnostic primarily due to diffusion of water-soluble materials out of the lymphatics before reaching the central venous system. It should be noted that a right to left cardiac shunt would be a relative contraindication for lymphangiogram due to risk of systemic emboli. In this case series, we describe favorable short-term outcomes using lymphangiogram with ethiodized oil to treat two infants with CPL. Although these infants had reduced mortality and morbidity compared with prior reports, the long-term outcomes of patients treated with ethodized oil embolization are unknown. In addition, infants who undergo this treatment often have other comorbidities that may impact long-term outcomes. Despite these concerns, ethiodized oil embolism has provided a new therapeutic option for patients with CPL that may reduce the need for aggressive medical management and should prompt further investigation. CONFLICT OF INTEREST The authors declare no conflict of interest.
Journal of Perinatology (2014), 720 – 722
Treatment of congenital pulmonary lymphangiectasia M Gray et al
722
REFERENCES 1 Esther CR Jr, Barker PM. Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr Pulmonol 2004; 38(4): 308–313. 2 Bouchard S, Di Lorenzo M, Youssef S, Simard P, Lapierre JG. Pulmonary lymphangiectasia revisited. J Pediatr Surg 2000; 35(5): 796–800. 3 Bellini C, Boccardo F, Campisi C, Toma P, Taddei G, Villa G et al. Congenital pulmonary lymphangiectasia. Orphanet J Rare Dis 2006; 1: 43. 4 Alejandre-Lafont E, Krompiec C, Rau WS, Krombach GA. Effectiveness of therapeutic lymphography on lymphatic leakage. Acta Radiol 2011; 52(3): 305–311. 5 Matsumoto T, Yamagami T, Kato T, Hirota T, Yoshimatsu R, Masunami T et al. The effectiveness of lymphangiography as a treatment method for various chyle leakages. Br J Radiol 2009; 82(976) 286–290.
Journal of Perinatology (2014), 720 – 722
6 Nadolski GJ, Itkin M. Feasibility of ultrasound-guided intranodal lymphangiogram for thoracic duct embolization. J Vasc Interv Radiol 2012; 23(5): 613–616. 7 Clemens R, Kreindel T, Lillis A, Alomari A. Characterization of central conducting lymphatic anomalies. Pediatr Radiol 2013; 43(Suppl 2) S319. 8 Rajebi MR, Chaudry G, Padua HM, Dillon B, Yilmaz S, Arnold RW et al. Intranodal lymphangiography: feasibility and preliminary experience in children. J Vasc Interv Radiol 2011; 22(9): 1300–1305. 9 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164–1171. 10 Yamagami T, Masunami T, Kato T, Tanaka O, Hirota T, Nomoto T et al. Spontaneous healing of chyle leakage after lymphangiography. Br J Radiol 2005; 78(933): 854–857.
© 2014 Nature America, Inc.
