Introduction

We provide a selective overview of pediatric central nervous system (CNS) vascular malformations, encompassing both diagnosis and treatment. We include references from pertinent literature and representative cases from our institution.

Pediatric CNS vascular anomalies comprise a wide a range of lesions, including some that are only found in children, in addition to the full gamut of vascular lesions found in adults, such as arteriovenous malformation (AVM) and arteriovenous fistula (AVF). Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some lesions that occur in adults, such as AVM, have fairly distinct characteristics in children, although some of these differences have been exaggerated in the literature, as discussed below.

An important feature characterizing children with CNS vascular malformations is the frequent presence of associated broader conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia and RASA1 mutation. Many of these conditions and the associated genetic mutations have only recently been described, and thus our understanding of the underlying biology and pathophysiology is in its infancy.

Infantile hemangiomas versus vascular malformations

We begin with attention to a critical piece of nomenclature: the distinction between infantile hemangioma and vascular malformations. As first delineated by Mulliken et al. [1] in 1982, these entities have different characteristics with crucial treatment implications. Infantile hemangiomas have a striking growth phase beginning within weeks of birth, characterized by endothelial cell proliferation, followed by an involutive phase that extends from approximately 1 year of age to the early school years. Because their pathognomonic diagnostic feature is the strawberry red skin lesion, infantile hemangiomas are characterized by the tip-of-the-iceberg effect, whereby visible skin lesions often suggest only a small portion of the lesion’s full extent when seen in its depth. Infantile hemangiomas are thus true benign vascular tumors of infancy. In contrast, vascular malformations are not tumors; these are characterized by normal endothelial cell cycles, and they overwhelmingly grow commensurately with the child. Interestingly, infantile hemangiomas have a striking female predominance, while vascular malformations affect both genders equally.

Although the literature is rife with use of the term “hemangioma” to characterize nearly every type of CNS vascular malformation, this muddled terminology serves only to conflate distinct entities, and true infantile hemangioma involving the neuraxis is rare. When it does occur, extension intracranially or intraspinally seems to follow neuroforamina contiguously from an overlying visible skin infantile hemangioma [2]. In our case series, there were no examples of intracranial or intraspinal hemorrhage and no cases of symptomatic mass effect related to the infantile hemangioma. Moreover, the behavior of infantile hemangioma within the CNS space mimics the lesion’s behavior outside, both in its natural history and response to therapy. Thus a child with infantile hemangioma on the back, for example, who had invasion of the spinal column treated with corticosteroids, shows synchronous regression of both the cutaneous and extra-cutaneous infantile hemangioma (Fig. 1). A case report to the same effect showed involution of cutaneous and intraspinal infantile hemangioma in response to propranolol [3].

Fig. 1
figure 1

Imaging in a girl with infantile hemangioma involving the back and spine, before and after treatment with corticosteroids. a Clinical photograph of the cutaneous infantile hemangioma at age 4 months. b Axial T2-weighted MRI at age 4 months demonstrates intraspinal and prespinal infantile hemangioma. c Corresponding axial T1-weighted post-contrast MRI at age 4 months. d, e Axial T2 (d) and fat-suppressed post-contrast T1-weighted (e) MR images at age 4 years demonstrate interval regression of infantile hemangioma after treatment with corticosteroids

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PHACES

PHACES is a constellation of anomalies made manifest in infants who have large head and neck infantile hemangioma; the word PHACES is an acronym describing the location or type of the main clinical manifestations (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies, and sternal anomalies). Although much attention was focused initially on the posterior fossa anomalies, most commonly Dandy–Walker malformation and cerebellar dysgenesis, the arterial anomalies that are part of PHACES now receive the lion’s share of study. These include segmental stenoses or entirely hypoplastic arteries, patulous dysplastic segments, true aneurysms, and persistent fetal vessels [4]. As of now, the long-term natural history of the arterial dysplasias of patients with PHACES is not known. However, this is an area of active interest, and young children with PHACES are being followed closely as they age so the natural history of their lesions can be determined.

Adult-type central nervous system vascular malformations in children

Nearly all of the CNS vascular malformations found in adults — including brain AVM, cavernous malformation, and dural AVF — can occur in children. However, there are often subtle differences in the clinical manifestations of these similar lesions.

Consider brain AVMs as an example. Brain AVMs in children sometimes appear to have multi-focal sites of arteriovenous shunting [5], a finding that is rare in adults (Fig. 2). However it is unclear whether this is a truly unique pediatric morphological subtype of AVM or rather there is nascent AVM bridging the angiographically visible foci in the young child that can be expected to develop as the child matures. Consider a 4-year-old child with a left occipital AVM, which was resected. Follow-up imaging at age 14 years demonstrated two new foci of AVM, one along the anterior margin of the resection cavity and the other in the temporal lobe, with the suggestion of subtle nidal vessels bridging these (Fig. 3). Thus it may be that, rather than reflecting a uniquely pediatric morphological subtype of lesion, multifocality in brain AVMs in children is a manifestation of immaturity, with eventual contiguity of the lesion being the expectation.

Fig. 2
figure 2

Frontal brain arteriovenous malformation. Lateral view of a selective right internal carotid injection in a 4-month-old boy with a frontal brain arteriovenous malformation shows two separate foci (arrows) of the arteriovenous malformation nidus

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Fig. 3
figure 3

Brain arteriovenous malformation resected in a girl at age 4 years and found again at age 14. a Axial T2-weighted MRI at age 4 years demonstrates left occipital arteriovenous malformation (arrow). b A different T2-weighted axial slice from the same MRI demonstrates lack of arteriovenous malformation at the anterior margin of the cavity and lack of arteriovenous malformation in the lateral temporal lobe (arrows). c T2-weighted axial MRI at age 14 years demonstrates arteriovenous malformation in the anterior aspect of the resection cavity and in the temporal lobe (arrows). Catheter angiography suggested subtle bridging arteriovenous malformation between these areas (not shown)

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Similarly, it is well known that brain AVMs in children present far more often with hemorrhage than in adults, with up to 80% hemorrhagic presentation being reported [6]. Many have taken this to reflect an underlying biological difference, whereby AVMs in children are more aggressive lesions with a higher proclivity to hemorrhage. However, careful analysis refutes this. The single most reliable predictor of future hemorrhage for AVMs is a history of hemorrhage. If pediatric brain AVMs were truly more aggressive, then one would expect that the re-hemorrhage rate would be higher in children. However, if one studies the brain AVM cohort with hemorrhagic presentation and the cohort with non-hemorrhagic presentation and carefully generates Kaplan-Meier curves of hemorrhage-free survival for each group, comparing children to adults, hemorrhage-free survival is actually prolonged in children [7]. It is thus likely that non-hemorrhagic brain AVMs are detected in adults more commonly than in children not because of any underlying biological difference, but simply because adults have more brain imaging for unrelated reasons. A moment’s reflection reveals that this must be so; given that the overwhelming majority of AVMs are congenital lesions, those same adults with non-hemorrhagic AVMs harbored them as children, too, and they went undiagnosed because of lack of symptomaticity.

Uniquely pediatric CNS vascular malformations: vein of Galen malformation

Until the advent of endovascular treatment approaches, the diagnosis of vein of Galen malformation had borne the implication of overwhelmingly high morbidity and mortality. A 1987 series, published at the end of the era of open surgical management, reported a mortality of 55.6% overall and 37.4% for surgically treated cases; among survivors, severe morbidity was 46.3% [8]. Neonates had the poorest prognosis, with an overall mortality of 91.4%, regardless of treatment.

With the development of endovascular techniques and an overall approach to patient selection and treatment timing pioneered by Pierre Lasjaunias [9], the prognosis for patients with vein of Galen malformation has markedly improved. A 2006 series of 216 patients published by the Paris group reported a 10.6% mortality rate, with 74% of survivors having no significant neurodevelopmental morbidity [9]. Lasjaunias introduced a grading system of severity, based on cardiac, cerebral, respiratory, hepatic and renal function. Patients with the highest grade (i.e. no significant organ system morbidity in early infancy) have embolization deferred to age ~6 months. At the other extreme, for those with the poorest grade (i.e. multiple organ system failure or those with demonstrated diffuse parenchymal brain loss), abstention rather than treatment is recommended. Those with intermediate grades — most commonly neonates with overwhelming heart failure at birth but with no significant brain injury evident on imaging — undergo urgent embolization as neonates. Although Lasjaunias’ [9] original paradigm resulted in a high rate of abstention (more than 21%), during the last decade a more liberal inclusion approach has become the norm at most centers. Further, the trend has been to begin elective embolization earlier for asymptomatic vein of Galen malformation patients, in the 3–5 months range.

More recent series continue to demonstrate improved outcomes using an endovascular approach to vein of Galen malformation. A 21-year retrospective study published in 2011 showed an overall survival rate of 76.9%, with two-thirds of patients demonstrating no significant neurodevelopmental delay [10]. Another, smaller series, published in 2012, focusing specifically on the neonatal vein of Galen malformation group — those who fared particularly poorly with the open surgical approach, with a mortality rate higher than 90% — showed survival of eight of the nine patients, with five of the eight survivors achieving milestones, and two more described as having mild neurodevelopmental impairment [11].

Vein of Galen malformation manifests differently throughout development. Prenatally, manifestations include brain parenchymal loss and calcification (Fig. 4). High output heart failure, particularly medically refractory pulmonary hypertension, occurs in the neonatal phase. In the first few months of life manifestations may include hydrocephalus, facial and scalp venous prominence (Fig. 5), intracranial venous hypertension, venous sinus stenosis, and global neurocognitive decline. Children who remain undiagnosed may present in adulthood with severe headache or hemorrhage, or may remain asymptomatic throughout life. Overall, hemorrhage in vein of Galen malformation is extremely rare, because unlike brain AVM, the arteriovenous shunt in vein of Galen malformation is distinct from the venous drainage pathway being employed by the brain parenchyma.

Fig. 4
figure 4

Vein of Galen malformation in a fetus. Axial fetal MR images in two consecutive pregnancies in the same mother show (a) parenchymal loss in both hemispheres due to vein of Galen malformation in one pregnancy and (b) normal brain in a subsequent pregnancy

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Fig. 5
figure 5

Vein of Galen malformation in a girl with regression of facial venous prominence. a Photo taken at age 2 years, during the course of staged embolization, shows facial venous prominence. b Photo taken at age 4 years, after treatment was completed

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The cardiac pathophysiology for neonatal presentation of vein of Galen malformation has been described in several recent publications [12–14]. Typically the most challenging feature is refractory pulmonary hypertension, with suprasystemic pulmonary artery pressures, reversal of flow in the descending aorta demonstrated on echocardiography, and resistance to all medial therapy being the norm for neonatal cases. Patients almost always have an overlay of left-side heart failure as well, with pressor dependence.

An example of a somewhat unusual case was a baby boy from Haiti who had a delayed diagnosis. He presented with mild heart failure, oxygen dependence, inability to be discharged home from the hospital and overall failure to thrive, becoming progressively cachectic during the first few months of life. Ultrasonography of the head finally performed at ~9 months of age demonstrated a high-flow lesion, and subsequent CT showed vein of Galen malformation. After embolization of the lesion, the boy had a rapid clinical turnaround, with rapid weight gain and milestone achievement (Fig. 6).

Fig. 6
figure 6

Delayed diagnosis of vein of Galen malformation and failure to thrive in an infant boy from Haiti. a Photo at age 9 months, prior to initiation of treatment. b Photo at age 12 months, after embolization

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The embryological underpinnings of vein of Galen malformation were beautifully elucidated in a 1989 paper [15] demonstrating that the arteriovenous shunt develops specifically to the anterior, plexiform aspect of the median vein of the prosencephalon, an embryonic vein that is the precursor to the vein of Galen. The typical feeding arteries are the choroidal vessels, both posterior and anterior.

Various morphological classification schemes have been proposed for vein of Galen malformation [16], though the critical distinction is that between mural and choroidal subtypes. Mural lesions have a direct arteriovenous fistula, with a hole in the persistent median vein accepting arterial inflow. In choroidal lesions the arteriovenous connection is more complex, with small nidus-like vessels carrying arterial flow into the anterior aspect of the median vein, with an angioarchitecture somewhat evocative of brain AVMs. Again following Lasjaunias’ [9] lead, at most high-volume centers, preferred treatment is via transarterial embolization; retrograde, transvenous approaches seem to bear a higher morbidity.

An example of a mural vein of Galen malformation is shown in Fig. 7. In this case, a nest of coils was deployed to slow the inflow, and subsequently a liquid embolic agent was injected, forming a cast of the trident-like arterial feeders. Although the median vein itself was never embolized, post-treatment images demonstrated its regression. Similarly, regression of the ventricular prominence and enlarged extra-axial cerebrospinal fluid spaces seen in vein of Galen malformation is to be expected in most cases after embolization.

Fig. 7
figure 7

Mural vein of Galen malformation. a Axial T1-weighted MRI in a 5-day-old boy demonstrates single fistulous arterial inflow (arrow) into the venous pouch. b Corresponding axial T2-weighted image shows prominent extra-axial space (asterisks). c Lateral views of a left vertebral artery injection shows the fistulous flow into a hole in the collecting vein (arrow). d Lateral view of a selective injection into the arterial feeder again shows the fistulous flow into a hole in the collecting vein. e Unsubtracted angiographic image shows the nest of coils (arrow) deployed to slow flow. f Subtracted angiographic image shows microcatheter injection following coil deposition with some reflux of contrast material into the feeding artery. g Lateral view of the vertebral artery injection after liquid embolic embolization shows no further arteriovenous flow. h Axial T2-weighted MR image at age 2 years shows regression of the enlarged median vein, resolution of the increased extra-axial space, and diminution in the caliber of the ventricles

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A child with a choroidal vein of Galen malformation is shown in Fig. 8. In this case the complex cast replicates the complex, nidus-like structure of the arteriovenous communication along the wall of the median vein. As in the prior example, although the embolization did not occlude the vein, regression was seen on subsequent imaging.

Fig. 8
figure 8

Choroidal vein of Galen malformation. a Anteroposterior projection of a right internal carotid artery injection in a 4-month-old girl pre-treatment demonstrates complex arterial inflow, with a nidus-like tangle of vessels along the right anterior wall of the enlarged median vein. b Sagittal post-contrast T1-weighted MR image shows the enlarged median vein and torcular, with crowding of the posterior fossa. c Unsubtracted anteroposterior angiographic image shows the onyx cast after embolization, replicating the nidus-like morphology. d Sagittal post-contrast T1-weighted MR image in the same child 2.5 years post-treatment shows regression of the median vein, some regression in caliber of the torcular, and relief of crowding of the posterior fossa

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Given that children with vein of Galen malformation are the youngest cohort treated with neurointerventional techniques, vascular access can pose a major challenge. One approach used to avoid catheterizing and potentially traumatizing the tiny femoral arteries is the trans-umbilical artery approach, offering straightforward access to the aorta in atraumatic fashion [17]. Similarly, the development in recent years of intermediate catheters for use in adults undergoing thrombectomy for acute ischemic stroke has proved to be a boon for neurointerventions in infants [18]. Some of these catheters can be introduced into very small femoral arterial sheaths while still providing distal intracranial arterial access with a large inner diameter, allowing for use of balloons and other devices that had heretofore not been part of the pediatric neuroendovascular armamentarium.

Uniquely pediatric vascular malformations: dural sinus malformation

The term dural sinus malformation is used to denote a condition, diagnosed prenatally or in early infancy, characterized by enormous enlargement of one of the dural venous sinuses, most commonly the torcular or superior sagittal sinus. In some cases the enlargement is demonstrably the result of an arteriovenous lesion with inflow directly into the involved sinus, and in other cases thrombosis of the involved sinus may be seen; however neither of these scenarios is necessary, and dural sinus malformation with idiopathic massive enlargement of a sinus can certainly be present.

In cases where an arteriovenous lesion is present, the feeding vessels are dural arteries, most often the middle meningeal or occipital arteries. The clinical challenges facing these young infants are similar to challenges faced by infants 1–6 months old with symptomatic vein of Galen malformation, with the potential for venous outflow obstruction and global parenchymal brain volume loss. However, given the frequency of thrombosis and the possibility of reflux into pial veins, intracranial hemorrhage is likelier in dural sinus malformation than in vein of Galen malformation.

Dural sinus malformation is shown in Fig. 9, which demonstrates the potentially complex interplay between arteriovenous flow and thrombosis in children with this condition. In this case a 5-month-old girl who had a normal 3rd-trimester biophysical profile on sonography and a normal birth and development presented with several weeks of increased prominence of her scalp and face vessels. She went on to develop several days of progressively decreased oral intake, then subsequently nausea and vomiting, altered mood, and lethargy. A CT scan at an outside institution showed a prominent thrombus in an enlarged superior sagittal sinus. Magnetic resonance angiography at our institution showed marked enlargement of the external carotid and middle meningeal arteries providing inflow into an AVF to the superior sagittal sinus, resulting in dural sinus malformation. Given her acute clinical deterioration, we elected to embolize urgently (Fig. 9). Immediately while still in the angiography suite, the girl’s scalp veins began to regress, and postoperatively in the intensive care unit the girl immediately awoke with normal mood and restored appetite. Given the extensive sinus thrombosis, she was anti-coagulated with heparin and was discharged. However, 3 days after discharge the girl was re-admitted with recurrence of severe nausea and vomiting, with imaging evidence of interval progression of sinus thrombosis. The girl was given elevated doses of heparin along with aggressive hydration and responded well clinically. Repeat images 6 months later demonstrated regression of clot, resolution of the ventricular prominence, and re-elevation of the cerebellar tonsils out of the foramen magnum. The girl remained clinically well and was neurodevelopmentally intact at the time of this report (3 years).

Fig. 9
figure 9

Dural sinus malformation in a 5-month-old girl. a Sagittal non-contrast T1-weighted MR image demonstrates thrombus in an enlarged superior sagittal sinus. b Axial T2-weighted MR image demonstrates massive enlargement of the posterior aspect of the superior sagittal sinus, prominence of the intracranial flow voids, and an enlarged left orbital vein. c Anteroposterior projection of a right external carotid artery injection demonstrates enlargement of the middle meningeal arterial branches, with rapid inflow into a massively enlarged superior sagittal sinus. d Unsubtracted lateral angiographic view shows the liquid embolic cast (Onyx) of the inflow to the arteriovenous fistula

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Many series on dural sinus malformation have reported poor prognoses. For example, Barbosa et al. [19] showed an unfavorable neurological outcome in 45.8%, with death in most patients who fared poorly (11 patients in their series). Given the poor published outcomes, parents and caregivers often elect to terminate pregnancy when a diagnosis of dural sinus malformation is made at 3rd-trimester ultrasound, although more recent studies suggest that the prognosis may not be as negative as previously reported [20].

Syndromic associations

A characteristic commonly seen in children with CNS vascular malformations is a frequent association with broad vascular syndromes. For example, mutations in the RASA1 gene were shown to be associated with a condition called “capillary malformation-arteriovenous malformation” in 2003 [21]. A subsequent publication demonstrated that RASA1 mutations are associated with other arteriovenous syndromes, including Parkes–Weber syndrome and vein of Galen malformation, among others [22]. More recently, we reported an association between RASA1 mutations and spinal arteriovenous lesions [23], as well as between RASA1 mutations and pial arteriovenous fistulae [24].

As an example, an infant boy presented at birth with tachypnea, with echocardiography revealing mildly elevated cardiac output and biventricular enlargement; he was easily managed with a brief course of medication. Notably, both the child and his mother had discrete flat pink skin stains, and both tested positive for a RASA1 mutation. A posterior cranial bruit was appreciated at age 3 months, and imaging revealed massively enlarged vertebral and basilar branches (posterior inferior cerebellar and superior cerebellar arteries) feeding into the vein of Galen (and not into a preserved median prosencephalic vein); the lesion thus represented a posterior fossa pial AVF rather than a vein of Galen malformation (Fig. 10). The boy underwent staged embolization, with subsequent resolution of arteriovenous shunting, regression of the lesion and resolution of increased extravascular space.

Fig. 10
figure 10

RASA1 mutation and arteriovenous fistula to the vein of Galen in an infant boy. a Axial T2-weighted MR image at age 3 months shows a tangle of enlarged vessels in the posterior fossa. b Magnetic resonance angiography at age 3 months demonstrates arteriovenous inflow (arrow) into the region of the vein of Galen, with supply from vertebral and basilar arterial feeders. c Axial T2-weighted MR image at age 3 months shows prominence of the extra-axial spaces. d Unsubtracted anteroposterior angiographic image at age 3 months shows coils and liquid embolic deposition (Onyx) overlying the inflow regions to the arteriovenous fistula (arrows). e Magnetic resonance angiography at age 3.5 years shows normalization of the vessel caliber, with no evidence of arteriovenous flow. f Axial T2-weighted MR image at age 3.5 years shows normalization of the extra-axial spaces and ventricles

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Other syndromes associated with CNS vascular malformations, such as hereditary hemorrhagic telangiectasia, have been long known, while others, such as CLOVES (congenital lipomatous overgrowth [CLO], vascular malformation [V], epidermal nevi [E] and scoliosis and spinal deformities [S]) syndrome [25], are even more recently described than RASA1 mutation. There is little doubt that we stand at the very beginning of the era of genetic characterization of CNS vascular anomalies and the incorporation of CNS vascular lesions into the broader world of vascular biology.

Summary

Accurate description of vascular lesions is critical for understanding natural history, for guiding treatment and for scientific advances in the field. In particular, the differentiation between infantile hemangioma and vascular malformations is one that is often lost but that is particularly important. All the subtypes of CNS vascular lesions seen in adults can be manifest in children as well, albeit with some differences as to morphology and presentation. In terms of CNS vascular lesions unique to children, endovascular neurointerventions have transformed vein of Galen malformation from a fatal or devastating diagnosis to one in which most children grow up intact or with minor disability. Dural sinus malformations, another CNS vascular anomaly unique to children, may have associated morbidity lower than previously reported. RASA1 mutation is representative of a family of recently identified mutations that relate CNS vascular anomalies to the broader world of vascular biology, providing both context for this set of unusual vascular lesions and potential for new avenues for therapy.