Clinical manifestations

Presentation and course

	• Vein of Galen malformation may be detected on ultrasound as a cystic, midline brain lesion.
	• The large amount of arteriovenous shunting that occurs in a vein of Galen malformation commonly leads to high output heart failure
	• Patients most commonly present in the neonatal period with symptoms due to high output heart failure or as infants with hydrocephalus, seizures, developmental delay, or failure to thrive.
	• Older children or very rarely young adults may present with headaches, seizures, or intracranial hemorrhage.

The presentation of vein of Galen malformations is best understood by knowing the usual presentations by patient age group and by understanding the patterns of organ system derangement. Patients may present in the antenatal, neonatal, infantile, pediatric, or, very rarely, young adult age groups.

Vein of Galen malformations may be detected on antenatal ultrasound at the earliest by 25 weeks gestation as a cystic, midline brain abnormality posterior to the third ventricle (03). Color flow doppler technique may aid further in characterizing the lesion as a vascular abnormality (27; 22). Other important features that may be evaluated on antenatal ultrasound are presence of hydrocephalus and cardiac dysfunction (12). Fetal MRI aids in assessment of cardiac dysfunction and brain atrophy, both of which have prognostic significance (09).

More often, patients are diagnosed after birth; heart failure or multiorgan system failure is a common presentation in neonates. The first 24 hours after birth are often normal. In utero, the low resistance of the placenta competes as an alternative route for blood with the vein of Galen malformation; thus, flow through it is reduced. After birth and subsequent removal of the placenta, the flow through the vein of Galen malformation greatly increases, and cerebral blood flow may constitute as much as 80% of cardiac output (16; 24). Arteriovenous shunting leads to a significant amount of blood returning to the right side of the heart, which is not prepared to receive or pump such a large volume. High output heart failure may ensue, and severe pulmonary hypertension may be an additional complication (09; 24). Lastly, large arteriovenous shunts may reduce diastolic pressure in the aorta and can lead to myocardial ischemia. Heart failure may range from failure to thrive or mild volume overload to cardiorespiratory failure requiring intubation and multiorgan system failure in severe cases. Cyanosis may prompt a search for congenital heart disease (18).

Patients presenting in infancy generally present with symptoms attributable to cerebral venous hypertension rather than serious heart failure. Macrocephaly, hydrocephalus, and seizures are most common. Patients presenting with cardiac dysfunction later than the neonatal period usually have milder dysfunction amenable to medical therapy, which allows for appropriate delay in endovascular treatment to a later time (03; 24). Venous hypertension may lead to increased head circumference due to hydrocephalus. The hydrocephalus may be obstructive due to compression of the cerebral aqueduct or communicating due to decreased resorption of CSF as a result of venous hypertension. Other indications of venous hypertension may include dilated scalp veins, proptosis, cranial bruit, or recurrent epistaxis (09). Severe cases are characterized by calcifications, developmental delay, and seizures, though endovascular treatment has been observed to lead to improvement in cerebral calcifications (02). Rarely these calcifications may be associated with movement disorders. The most severe cases show irreversible brain damage and rapid atrophy called melting brain (01; 15). Patients who have patent venous sinuses do not experience melting brain syndrome because of the absence of pial and subpial venous reflux, though calcifications and a slow and permanent insult still occurs without early treatment (19).

Older children and, very rarely, young adults may present with headaches or seizures attributable to subarachnoid or intraparenchymal hemorrhage (12; 09; 01; 24). Microaneurysms may occur in the blood vessel network supplying the vein of Galen malformation, which creates an additional risk of hemorrhage (13).

Prognosis and complications

Beginning in utero, the use of ultrasound and fetal MRI can establish those patients who have a poor prognosis. However, the mere presence of a vein of Galen malformation is not necessarily an indication for termination of the pregnancy. Patients who show antenatal heart failure have 80% mortality (25). Similarly, the observation of brain atrophy or cardiac insufficiency on fetal MRI is associated with a poor prognosis (06). The poor outcomes of these patients are not improved with successful radiologic obliteration of the lesion; thus, heart failure or severe cerebral damage observed on antenatal imaging are potential indications for termination of pregnancy or conservative treatment on birth (10; 19).

After birth, neonates who have severe heart failure have the worst prognosis, though the development of endovascular methods to treat the arteriovenous shunting in a staged manner has greatly improved these patients compared to the past (03; 24). Before the advent of endovascular embolization, mortality rates for affected patients neared 100% (13).

There remains a significant amount of mortality in patients who present with early heart failure or multiorgan failure as well as neurologic disability among survivors. Multiple sources indicate a mortality rate ranging between 10% and 30%, with neonates at greater risk. Among patients treated with endovascular methods, between 50% and 74% have good outcome and normal neurocognitive function (19; 24; 11; 20). In a study of the long-term outcomes of children with vein of Galen malformations 6 to 11 years after treatment, authors found that 37% of patients had poor outcome and 13% of patients died despite or because of treatment complications (26).

Biological basis

	• The median prosencephalic vein of Markowski drains the fetal choroid plexus and is present from 6 to 11 weeks of gestational age; it normally involutes except at its most caudal end where it receives the internal cerebral veins and persists as the great vein of Galen.
	• The vein of Galen malformation is actually a misnomer and results from the development of abnormal arteriovenous shunts into the median prosencephalic vein of Markowski, which normally involutes but instead becomes hugely dilated due to arteriovenous shunting.
	• Vein of Galen malformations may be classified as choroidal or mural according to the classification scheme by Lasjaunias, or as types I to IV by Yasargil with only types I to III as true vein of Galen malformations.

A discussion of the ultimate cause for vein of Galen malformations must start with a basic understanding of development of cerebral vasculature and, more specifically, the venous system. During fetal development of the nervous system, closure of the anterior and posterior neuropores occurs between gestational weeks 6 and 10. During this time, the telencephalon blood supply is from multiple choroidal arteries arising from the fetal choroid plexus. Venous drainage of the choroid plexus is provided by paired internal cerebral veins that terminate on the caudal portion of the median prosencephalic vein of Markowski. The median prosencephalic vein of Markowski appears at gestational week 6, and it begins to involute in a rostral to caudal manner. By gestational week 11, the median vein regresses such that only the caudal portion where the internal cerebral veins join it remains, now as the great vein of Galen (09; 24; 17). For unknown reasons, it is during this period between gestational weeks 6 and 11 that arteriovenous shunts develop (23). The high blood flow and pressure lead to progressive dilation of the median prosencephalic vein, and instead of regressing, the vein enlarges in an aneurysmal fashion. This large dilation is possible because the vessel lies unencumbered in the subarachnoid space within a cistern called the velum interposition. Thus, though the caudal portion of the median prosencephalic vein normally persists in a small portion as the vein of Galen, a vein of Galen aneurysmal formation is a misnomer because the vessel of interest is actually an abnormally dilated and persistent median prosencephalic vein.

The arterial supply to the median prosencephalic vein varies and has led to a classification scheme developed by Lasjaunias to describe the two basic types of angioarchitecture of these lesions. The first type, termed choroidal, represents a developmentally more primitive arrangement of vessels in which choroidal arteries, including the anterior choroidal, posterior choroidal, and pericallosal arteries, contribute and form a complex arterial network before connecting with the vein. The choroidal type generally leads to a more severe clinical presentation and course. The second mural type of arrangement is less severe clinically and consists of a direct arteriovenous fistulous connection of one or more arteries with the vein (09; 19). Yasargil developed a similar classification system based on arterial feeder patterns, with types I to III representing true vein of Galen malformations and type IV representing an arteriovenous malformation producing a dilated vein of Galen proper (28).

Etiology and pathogenesis

The reason for development of arteriovenous shunts into the median vein of the prosencephalon remains unknown. It is postulated that an insult to the cerebrum of the fetus occurs between gestational weeks 6 and 11, the time during which the median prosencephalic vein is present. It is during this time that the arteriovenous shunt develops and the median prosencephalic vein persists as a large, aneurysmally dilated vessel. Genetic data and rare reports indicate that the vein of Galen malformation may occur in some cases due to RASA1 or EPHB4 genes (17).

Epidemiology

The vein of Galen malformation is a rare lesion that accounts for 30% of pediatric vascular and 1% of all congenital abnormalities (24). It presents more commonly with high output heart failure and is an uncommon cause of intracranial hemorrhage in the pediatric population. Cerebral arteriovenous shunts are an uncommon cause of high output heart failure in children though this etiology should always be considered in children presenting in such a manner (10).

Differential diagnosis

The main condition that may be confused with vein of Galen malformations is a cerebral arteriovenous malformation draining into the vein of Galen, producing secondary dilation of the vein of Galen proper. This represents a distinct entity with a more substantial risk of hemorrhage (03). Another entity that may be confused with a vein of Galen malformation would be a giant arterial aneurysm, but this will be easily differentiated with MRI or CT angiography.

A vein of Galen malformation and other arteriovenous shunts should be considered in neonates presenting with high output heart failure. The differential diagnosis for high output heart failure is extensive and includes congenital heart disease, valvular disease, thiamine deficiency, and many others (14).

Diagnostic workup

	• Evaluation of a patient should include history and physical examination, laboratory tests of hepatic and renal function, transfontanellar ultrasound, transthoracic echocardiogram, and magnetic resonance imaging of the brain.
	• Catheter-based cerebral angiography should not be performed purely as a diagnostic test but only if the patient should undergo endovascular treatment.

Evaluation of the pediatric patient suspected to have a vein of Galen malformation should begin with a complete history and physical including weight and head circumference. There should be special attention to neurologic function and development along with cardiorespiratory function and any clinical signs of renal or hepatic impairment. Laboratory tests of kidney and liver function are essential to assess for evidence of end organ dysfunction. A transthoracic echocardiogram should be obtained to assess for presence of and extent of any cardiac dysfunction. A transfontanellar ultrasound should be obtained to assess for encephalomalacia and may further aid in visualizing and characterizing any vascular malformations. Magnetic resonance imaging of the brain is essential to assess for brain atrophy, status of myelination, and morphology of the lesion. Noncontrast computed tomography may detect the vein of Galen malformation as a mass; however, in younger patients, magnetic resonance imaging of the brain is preferred as it spares the patient radiation. Commuted tomography with angiography has excellent resolution for the assessment of vascular architecture but does involve radiation exposure. Catheter-based cerebral angiography is the gold standard imaging modality for evaluation of the vascular lesion. However, it should not be obtained unless it has been deemed appropriate for the patient to receive endovascular embolization for treatment.

Management

	• The decision of when and if to treat patients through endovascular embolization is complex and factors to be considered include age of the patient, the presence of established cerebral damage, cardiorespiratory function, hepatic function, and renal function.
	• If possible, endovascular treatment of neonates is delayed until at least 5 to 6 months of age. During this time, patients are treated medically for heart failure as necessary. There are cases of severe heart failure or other end organ dysfunction that necessitate early endovascular intervention.
	• Endovascular treatment may be staged and is most commonly performed via embolization with cyanoacrylate glue. Transvenous approaches may be used in combination or when an arterial route is not feasible or successful. Open neurosurgical treatment has little role in modern-day treatment aside from ventricular shunting for hydrocephalus or, rarely, evacuation of intraparenchymal hemorrhage.

Management of patients with vein of Galen malformations is complex and best suited to a multidisciplinary team in a large center familiar with the condition. The management may be divided into medical, endovascular, and surgical approaches. The specific approach and decision-making process is influenced by the patient’s age at presentation and severity of disease.

Seizures should be managed with appropriate antiseizure medications based on the patient’s age and medical comorbidities. For patients in an intensive care unit setting or in whom there is suspicion of status epilepticus or frequent seizures, continuous EEG monitoring should be used.

An important part of medical management consists of treating any heart failure. Ideally, this is done until the patient is at least 5 to 6 months of age before endovascular treatment is pursued. There is a wide spectrum of severity of symptoms of cardiac insufficiency. Mild cases may manifest with feeding difficulties, tachycardia, minimal volume overload, and changes in chest radiography. Such cases may do well on only diuretics until definitive treatment with endovascular methods can be achieved. More severe cases may manifest with failure to thrive, severe volume overload, and respiratory failure. The most severe cases manifest with respiratory failure requiring mechanical ventilation, cardiogenic shock, and multiorgan failure, which may necessitate emergent endovascular embolization to help improve cardiac function. Until such measures can be undertaken, patients may require inotropes, diuretics, vasodilators, and mechanical ventilation (08; 24). Serial ultrasound may aid in assessing response to medical therapy.

The decision-making process to pursue endovascular treatment of a vein of Galen malformation must take into account many factors. First, angiography is technically challenging and high risk in neonates and becomes easier by 5 to 6 months of age (03). The ideal management of a neonate or infant with a vein of Galen malformation is medical treatment until this age. There are cases in which patients have heart failure refractory to medical therapy who require endovascular treatment on a more emergent basis before the age of 5 to 6 months. There is a set of patients in whom the presence of established severe brain damage or severe multiorgan failure are appropriate indications for conservative management or a comfort-focused model of care. Even if such patients have successful radiographic embolization, they are destined for extremely poor neurologic outcome (09; 19). Making matters more difficult is the observation that some patients have extremely poor neurologic outcomes despite normal brain imaging before successful emergency embolization.

Such complexity led Lasjaunias and colleagues to develop a 21-point score, called the Bicetre Neonatal Evaluation Score, with 5 domains describing cerebral, cardiac, respiratory, renal, and hepatic function to guide the complex decision-making process in neonates. A score of less than 8 indicates severe multiorgan dysfunction and generally leads to a decision not to pursue endovascular treatment. A score between 8 and 12 generally leads to emergency endovascular treatment, whereas scores above 12 lead to a decision for medical management and delaying of endovascular therapy until the age of 5 to 6 months (19). It should be kept in mind that such a scoring system cannot predict outcomes perfectly and that there are exceptions to the expected course of both low and high scores. For example, a patient with initial score of 6 underwent endovascular therapy and was neurologically intact after more than 2.5 years of follow up, whereas other patients with high scores of 21 had sudden declines and death before endovascular treatment (21; 24). Thus, patient care and decisions must be individualized.

When endovascular treatment is pursued, it may be taken in a staged manner with multiple treatments over the course of several months, as complete obliteration of the lesion is not necessary for cardiac function to improve. Besides improvement of cardiac function, the goals of endovascular treatment are to prevent complications of cerebral venous hypertension and ensure normal neurologic development. Arterial access may be performed through the umbilical artery in the first 3 days of life or through a femoral approach. Treatment involves the use of a liquid embolic agent, commonly cyanoacrylate glue, to occlude one or more vessels leading to a decrease in size of the aneurysmal vein and improvement in cardiac function and venous hypertension. An arterial approach is generally preferred in review of the literature. However, a transvenous approach through femoral or jugular veins, or even direct puncture of the torcula, may be used in cases in which arterial treatment is not feasible or successful. A combination of arterial and venous treatment approaches may also be used (09; 13; 24).

When hydrocephalus is present, the need for a ventricular shunt must be reviewed extremely carefully. Hydrocephalus may be well tolerated in neonates and infants in whom the fontanelles remain open. The hydrocephalus seen in patients with vein of Galen malformations is generally a secondary phenomenon from venous hypertension induced by the primary lesion. Thus, treatment of the vein of Galen malformation will address the hydrocephalus. Furthermore, there is evidence that ventricular shunting may cause harm in the form of hemorrhage due to venous congestion and an underdeveloped venous system (19; 13; 24). Ventricular shunting may be necessary in emergency situations where patients have clinical signs of elevated intracranial pressure due to hydrocephalus. Endoscopic ventriculostomy is also a viable option in these patients.

Traditional surgery has largely been supplanted by endovascular approaches in the treatment of vein of Galen malformations. It may be necessary in cases of intraparenchymal hemorrhage and hematoma evacuation, the treatment of hydrocephalus as mentioned above, or in cases where endovascular attempts at embolization have failed (13).

Outcomes

Patients who present in the neonatal period generally have a higher mortality than those presenting later as this generally indicates a large shunt with early and severe effects on cardiac function. A good outcome is expected in patients who do not have signs of significant brain damage, and reviews have indicated normal neurologic function in approximately 50% to 74% of appropriately selected patients who underwent endovascular embolization (03; 19; 24; 11; 20). A meta-analysis of 27 studies and 578 patients found that all-cause mortality was 14% and rate of good neurologic outcome was 62%. Additional findings of interest were that neonates and patients presenting with congestive heart failure showed significantly decreased likelihood of good outcome. Lastly, studies that used the Bicetre score from Lasjaunias as a selection criteria for treatment showed greater rates of good neurologic outcome than those who did not (05).