Hemodynamic Precision in the Management of Vein of Galen Aneurysmal Malformations

A vein of Galen aneurysmal malformation is a rare but often life-threatening condition that can present with a profoundly ill neonate shortly after birth. It is important for clinicians to recognize and diagnose the various hemodynamic phenotypes to choose therapy to stabilize these infants, plan timing of surgical, and provide optimal counseling to families.After completing this article, readers should be able to: Recognize and perform a comprehensive evaluation of a neonate with a suspected vein of Galen aneurysmal malformation (VGAM).Differentiate the 3 distinct phenotypes of VGAM, which may present with hemodynamic instability in the neonatal period.Describe treatment differences of VGAM based on specific hemodynamic phenotype.Vein of Galen aneurysmal malformations (VGAMs) are extremely rare with an estimated incidence of 1 in 10 000 to 25 000 births1 and account for 1% of all congenital anomalies and 30% of pediatric vascular malformations.2 Many VGAMs are ultimately treated with endovascular therapy; however, prior, during, and after therapy these patients can have complex and changing physiologies, which are important to identify early and correctly treat. In many centers, based on the assumption that this is a single hemodynamic phenotype, the approach to hemodynamic evaluation is imprecise and focuses almost exclusively on strategies to increase systemic blood pressure and/or treat heart failure. Recent evidence suggests that several hemodynamic phenotypes exist, which require unique and oftentimes opposite approaches to preinterventional care. Unfortunately, in most centers the care is primarily focused on the approach to endovascular therapy. Correct identification of the unique hemodynamic phenotype clarifies the optimal endovascular execution and potentially improves outcomes. Essential elements of the care of affected children include the performance of a critical volume of procedures within a given center (interventionalist expertise) and access to a hemodynamics service (neonatologists or cardiologists with additional training in echocardiographic assessment of hemodynamics and prompt access to said service). The objective of this review is to provide a summary of the varying hemodynamic phenotypes, the dynamic nature of the ambient physiology, and the importance of longitudinal echocardiography evaluation to optimize pre- and postembolization care.VGAMs form between the sixth and 11th week of embryonic life due to the drainage of arteriovenous (AV) shunts into a persistent embryonic vessel, the prosencephalic vein of Markowski (MProsV).3 The posterior portion of the MProsV is the precursor structure to the vein of Galen; however, the anterior portion of the embryonic structure usually disappears during embryogenesis.4 When the anterior portion instead persists and enlarges because of the sustained high pressure from the AV shunts, a VGAM forms5 with final anatomy represented in Figure 1.VGAMs are diagnosed both prenatally and postnatally. With advances in fetal neuroimaging, more VGAMs have been detected than previously,6,7 with more contemporary case series reporting prenatal detection ranging from 60% to 70%.8,9 Postnatal presentations occur at varying time points from the neonatal period to adolescence.Both fetal ultrasonography and magnetic resonance imaging (MRI) detect VGAMs in utero, with fetal MRI being the gold standard for diagnosis. Ultrasonography is often sensitive enough to detect VGAMs as early as the second trimester with most cases being recognized in the third trimester.10–12 With the use of color Doppler, VGAMs are identified through visualization of high-volume, turbulent blood flow through the cystic lesion.11 Fetal MRI is used to delineate the size of the lesion, number and extent of feeder vessels, and potential compression on surrounding structures.6,11,13 When prenatal diagnosis is made, fetal echocardiography should be obtained to assist with prognostication. The presence of fetal cardiac failure or tricuspid regurgitation portends a worse prognosis.14,15 Prenatal diagnosis allows for optimal planning and delivery at a center equipped to care for infants with this diagnosis.Postnatal diagnosis is made pending evaluation based on clinical presentation. If clinical findings occur in the neonatal period, most affected patients present with heart failure and significant hemodynamic compromise as the infant transitions from the in utero fetal circulation.3,16 Many patients present with acute hypoxemic respiratory failure and presumed acute pulmonary hypertension (PH). These patients may be misdiagnosed as Ebstein’s anomaly because of the presence of a wall-to-wall heart on chest radiography. Clinically, some affected neonates may not initially appear in extremis but could be detected or suspected if there is a cranial bruit with or without a systolic heart murmur.17 Some patients present later in the infantile period with hydrocephalus and/or seizures; the typical presentation later in life includes symptoms of headache or intracranial hemorrhage.2 The diagnosis is made postnatally using ultrasonography, MRI, and magnetic resonance (MR) angiography.VGAMs are most frequently categorized by the Lasjaunias classification system, which divides them into either choroidal or mural subtypes.18,19 The choroidal subtype—a network of choroidal arteries draining into the venous pouch—is the most common type and is often associated with an earlier and more severe presentation.20,21 The mural subtype consists of a direct fistula with the MProsV and often has a milder presentation.The Bicêtre score can be used for prognostication and treatment decisions for patients with a VGAM. This score evaluates nonneurological effects (cardiac, cerebral, respiratory, hepatic, and kidney function) associated with the lesion and scores the infant on a scale of 0 to 21 (Table 1).20,22 A score of less than 8 is indicative of the worst prognosis, with affected patients often demonstrating severe cardiorespiratory instability and multiorgan failure, and is used in some centers to decide to pursue palliative care. A score of 8 to 12 indicates the need for emergent endovascular treatment, whereas a score greater than 12 supports medical management of the patient until age and size are optimized for endovascular intervention, which is usually around 5 months of age. This scoring system is used less frequently in recent years, with advances in fetal detection, postnatal neonatal hemodynamics evaluation, and better postnatal imaging techniques to evaluate the extent of cerebral parenchymal effects with greater precision.There are multiple cardiopulmonary considerations in the management of VGAMs. In the fetal period, the low-resistance placental circulation balances the low-resistance systemic shunt in VGAM, which may protect the fetus from heart failure.23 Following birth, changes in the systemic and pulmonary vascular resistance (PVR) in the presence of the low-resistance preductal left-to-right systemic shunt contribute to significant hemodynamic changes early in the neonatal period.There are different cardiopulmonary phenotypes that develop in patients with VGAM and have unique physiologic characteristics. These include both flow and resistance-mediated PH, effects on right ventricular (RV) performance, and pseudocoarctation physiology.24 Targeted neonatal echocardiography (TNE) provides objective and longitudinal measures of cardiopulmonary status in this dynamic disease.25 TNE is particularly useful in managing patients with VGAM, beginning with preoperative stabilization, staged endovascular embolization repair, and postoperative optimization phases.Hallmark cardiopulmonary findings in patients with VGAM include markers of decreased perfusion (decreased postductal blood pressures, decreased urine output, acidosis, elevated lactate) and echocardiography findings with increased biventricular cardiac outputs, right-sided heart dilation, and/or dysfunction and flow reversal in the preductal aortic arch24,26 (Figure 2). There are 2 principal cardiopulmonary phenotypes to consider in patients with VGAM—the flow-mediated PH phenotype and the resistance-mediated PH phenotype; however, the relative frequency of each phenotype remains unknown because published datasets have not incorporated comprehensive TNE evaluations. Some patients present with isolated RV dysfunction. Routine echocardiography fails to distinguish these phenotypes because the presence of right heart and superior vena cava (SVC) dilation, RV dysfunction, and retrograde flow in the preductal arch are common to all. In addition, subjective evaluation of right heart dilation and RV systolic dysfunction have poor interrater reliability.27 Comprehensive hemodynamic evaluation with careful characterization of surrogate indices of pulmonary vs systemic blood flow are essential to aid the differentiation of these phenotypes and optimize therapeutic precision. The standard evaluation includes assessment of the severity of PH, right and left ventricular (LV) systolic function, and RV and LV output in addition to classic findings of VGAM physiology.The most common phenotype is flow-mediated PH phenotype secondary to a large preductal left-to-right systemic shunt across the VGAM with preferential blood flow to the AV malformation. Affected patients are born with elevated pulmonary arterial pressure secondary to a combination of high pulmonary blood flow and elevated PVR. As PVR falls or when the patent ductus arteriosus (PDA) closes, there is a risk for compromised systemic blood flow to the lower half of the body, creating a pseudocoarctation physiology. Vital organs, including the kidneys, are thereby affected by this shunt. Patients with flow-mediated phenotype do not require significant amounts of oxygen because of increased pulmonary blood flow but have signs of impaired perfusion to the lower part of the body (eg, oliguria, lactic acidosis). This phenotype is distinguished on TNE evaluation by increased RV output (>300 mls/min/kg) and LV output (>300 mls/min/kg) (Figure 3). In addition, increased flow contributes to RV dilation and RV systolic dysfunction. In patients with a PDA, the flow pattern may be exclusively right to left, bidirectional, or left to right dependent on the relative aorto-pulmonary pressure gradient (Figure 4). It is also plausible that there is impaired LV systolic function due to ventricular interdependence. Supporting cardiac dysfunction with inotropy as well as systemic blood flow through a right-to-left ductal shunt is key in managing these patients. In patients with a restrictive and/or small PDA, the use of prostaglandins to support systemic blood flow is essential. Strategies to promote right-to-left ductal flow include the use of lower oxygenation targets and permissive hypercapnia. Selective pulmonary vasodilators, such as inhaled nitric oxide (iNO), are contraindicated because they exacerbate flow-driven physiology, thus increasing pulmonary blood flow (Figure 5). If this occurs, PH worsens and potentially reverses the obligatory right-to-left shunt needed to perfuse the lower half of the body in pseudocoarctation physiology.24The second phenotype is resistance-mediated PH phenotype. Affected patients present with severe hypoxemia and a picture that mimics classic acute PH (otherwise known as persistent PH of the newborn). This phenotype arises from the change of the pulmonary vascular bed remodeling secondary to abnormal fetal pulmonary blood flow.28 Unlike the prior phenotype, patients with the resistance-mediated low-PH phenotype have low pulmonary blood flow, impaired pulmonary venous return, and, therefore, low-cardiac (LV) output. Like the flow-driven phenotype, there is evidence of right heart dilation, impaired RV systolic function, and impaired LV systolic dysfunction secondary to ventricular interdependence. In patients with a PDA, the flow pattern is either exclusively right to left or bidirectional depending on the relative aorto-pulmonary pressure gradient. Affected patients often require treatment focused on pulmonary arterial hypertension physiology with early invasive ventilation and benefit from sedation and/or muscle relaxation. Prostaglandins may be necessary for infants with a flow-restrictive PDA and concomitant RV dysfunction. In these cases, judicious use of pulmonary vasodilators, including increased fraction of inspired oxygen and iNO, can improve pulmonary blood flow and LV preload for systemic circulation. It is important to recognize the dynamic nature of this physiology and need for serial (oftentimes daily) TNE evaluation. In patients in whom PVR falls, pulmonary blood flow and preductal cardiac output will increase, leading to a classic high-output flow state and echocardiography features of flow-driven physiology. Therefore, frequent reassessment is necessary to prevent development of significantly increased pulmonary blood flow and reversal of ductal shunts crucial for systemic perfusion.24Some patients with VGAM present with isolated RV dysfunction characterized by increased oxygenation need and decreased markers of perfusion. Echocardiographic markers show measures of decreased RV performance, including decreased tricuspid annular plane systolic excursion, fractional area change, and/or tissue Doppler indices.24 Mainstays of treatment of this phenotype include inotropy, afterload reduction, and/or maintaining ductal patency to support RV function.26,29,30Echocardiographic findings for flow vs resistance-mediated PH are shown in Table 2. A proposed management algorithm is shown in Figure 6.The cardiac dysfunction and hemodynamic changes due to VGAMs can lead to systemic hypoperfusion, which influences many other organ systems. Although cardiac failure and neurologic sequalae are the most obvious potential systemic effects, other organ systems must be considered. With high-output cardiac failure and PH as well as systemic steal through the SVC from the large AV malformation, multiorgan dysfunction is a well-reported sequalae of this condition.31,32 One prominent reported finding is myocardial ischemia secondary to coronary hypoperfusion, which results from both increased myocardial demand due to the high-output failure as well as the right-to-left shunt at the ductus diverting blood flow from the coronaries to the SVC and decreasing coronary artery perfusion pressure.26,33 Some report an incidence of myocardial ischemia as high as 30%.34Other downstream organ systems affected by hypoperfusion in patients with VGAMs include the intestines and kidneys, which should also be evaluated in significant hemodynamic collapse. Because of decreased distal perfusion from LV failure, there is significant upregulation of the renin-angiotensin-aldosterone system (RAAS), and once perfusion is restored, the upregulated RAAS system contributes to ongoing decreased perfusion to distal organ systems through persistent hypertension.35 The natural history of postintervention hypertension and its impact on heart function has been the subject of little investigation. Limited published data exist regarding potential bowel and mesenteric ischemia in patients with VGAM, but, given the known association with other etiologies of diastolic flow reversal in preterm infants (pathologic PDA), it is theorized that the bowel and other postductal end organs are also hypoperfused in this condition as well. Kidney dysfunction is used for prognostication in the Bicêtre score, with anuria being associated with the worst prognosis.22,33 With high-output failure and diastolic flow reversal in the descending aorta as well as the upregulated RAAS, the kidneys are predisposed to acute injury and hypoxia, which has both short-term and long-term effects, including increased risk of developing chronic kidney disease later in life.36 Given the wide-reaching influence on this dynamic condition, close monitoring and precision-based hemodynamic care as well as follow-up are essential for improved outcomes. The lifelong repercussions to vital organs remain unknown.The mainstay of VGAM treatment is endovascular embolization via a transvenous, transarterial, or combined transvenous and transarterial approach to embolize feeder vessels to the malformation.37–39 This can be done in a staged fashion because of changes in the hemodynamic stability of the patient with embolization and because of the restraints of contrast administration given the small patient sizes. Clinicians must recognize the need for close postinterventional cardiorespiratory instability, similar to the features of postligation cardiac syndrome.40 Similar to patients undergoing interventional closure of the PDA, embolization leads to an increase in cerebral (hence systemic) vascular resistance. This phenomenon is likely to be exaggerated by the number of feeding vessels embolized. The resultant augmentation in LV afterload in the setting of systemic hypertension, compounded by upregulation of the RAAS system, leads to impaired LV systolic performance. Left untreated, these patients can develop a low–cardiac output state and respiratory failure secondary to pulmonary venous hypertension. Early postinterventional TNE is advisable to guide use of systemic vasodilators, such as intravenous milrinone. Sometimes this procedure is accompanied by ventricular shunt placement to relieve concurrent hydrocephalus secondary to the malformation.39 The timing of treatment is often based on the clinical stability of patients—with a goal to treat closer to 5 months of age if possible. For neonates with hemodynamic distress, treatment is targeted to a time of relative stability if possible.There are ongoing efforts to evaluate whether an in utero embolization approach may lead to better outcomes. One case report of this approach demonstrated in utero improvement of cardiomegaly, and a subsequent fetal MRI demonstrated normal brain architecture.41 The infant did well initially and was discharged home 3 days after birth but presented to hospital at 3 months of age with cardiac failure; a brain MRI at that time identified interval development of encephalomalacia. after which the family decided to transition to palliative care.41 Fetal therapy will likely continue to be studied with close follow-up outpatient for patients who receive fetal intervention.Given the complexity and rareness of this condition, patients with VGAMs should preferably be managed at experienced centers with high volume of this lesion and essential specialists to provide optimal care. The establishment of vascular anomaly teams to provide oversight of fetal, neonatal, and childhood care will enhance the standardization of the care of these patients. Antenatal counseling should be comprehensive and include the expertise of maternal–fetal medicine, neuro-interventional, neurocritical care, neonatology, and neonatal hemodynamics specialists. At this stage, there are limited data to inform practice related to fetal intervention. After birth, shared decision-making, which includes all members of the interprofessional team, is advisable to determine the optimal timing of intervention and approach to postintervention care and overall prognosis.With the adoption of endovascular techniques vs open repairs, morbidity and mortality have decreased significantly in the neonatal population, with previous mortality reported to be as high as 100%.5,42 Mortality and outcome rates reported in the literature vary widely from institution and clinical circumstances, with a range of 50% to 90% survival.43–45 Neurologic outcomes continue to be worse in patients who present as neonates compared with infants, with a recent meta-analysis reporting good neurologic outcomes in 48% of neonates vs 77% of infants.46 Mortality is also higher in neonates compared with infants, with a mortality rate of 27% in the neonate group and 1% in the infant group.46 Longer-term outcomes between the ages of 1 to 11 years old, have been reported and indicate that neuropsychiatric problems are increased in the population of survivors, which includes requiring special schooling and language issues.9In conclusion, VGAM is a rare but life-threatening condition that is best treated in the setting of prenatal diagnosis and plans for delivery at experienced centers with the hemodynamic expertise to perform advanced monitoring and ultimately endovascular treatment. Continued measures should be taken to refine precision in prenatal diagnosis as well as prompt recognition of this potential pathology in the postnatal setting. Early TNE determination of the predominant hemodynamic phenotype and recognition that phenotypes can change allow for tailored therapy to optimize outcomes. Because of the potential for multiorgan involvement, subspecialists should be with early A should to identify the timing for of the of heart failure and PH in the the presence of and vascular of the the physiology of the