Pediatric vascular malformations of the central nervous system differ from those seen in adults. Their classification may be based on symptoms, pathomechanics, patient’s age, morphologic features, or presumed etiology. This review describes the different classification schemes and the endovascular management options of these rare and challenging diseases. The proposed etiologic classification of pediatric vascular malformations may add to our understanding of these diseases in general because the phenotypic expression of a given vascular malformation can shed light on the nature and timing of the causative agent, thereby potentially opening up treatment modalities in the future that are directed against the triggering event rather than against the clinical manifestations or the morphologic appearance. With current endovascular methods, most vascular diseases can be approached safely and with good clinical results.
Before treating pediatric vascular malformation, 2 basic principles have to be taken into account that may seem trivial but still have an effect on management strategies. The first principle is that the understanding of a disease should precede its treatment. In vascular malformations, little is known about their cause, pathophysiology, or natural history, and the numerous different classification schemes that should aid in the understanding of arteriovenous (AV) shunts testify to this lack of knowledge. In addition, advances in diagnostic tools for pretreatment risk assessment as well as continuously improved treatment modalities are likely to further change the way these vascular malformations are managed. The second basic principle is that children are not small adults; vascular malformations in the pediatric population differ significantly from the adult population. Therefore, classification schemes used for and derived from the experience in treating adults are not likely to be compatible with the treatment protocols in children. As a particular example, the adult-based classification of AV shunting lesions that is related to the expected surgical outcome of AV malformations is particularly inappropriate in children, in whom (1) cerebral eloquence is difficult to assess because of the remodeling potential, particularly in the first few years of life, (2) most lesions are fistulas or multifocal, (3) the drainage usually affects the entire venous system, and (4) the potential for recovery is different. In addition, the anatomic and physiologic characteristics of the neonatal and infant brain (including hydrovenous peculiarities and immaturity of myelination) create a specific group of nonhemorrhagic symptoms and therapeutic challenges that are not encountered in adults.
This article discusses different approaches to classifying pediatric vascular malformations and describes the endovascular management options. The difficulty in classifying pediatric cerebral vascular malformations is reflected by the large variety of different approaches that have been used for these rare diseases. These classifications may be based on symptoms, pathomechanisms, patient’s age, or morphologic features. Each of these classifications may have specific advantages, but the fact that no uniform classification has yet been decided on testifies to their specific drawbacks.
Pathomechanical classification
A clinical and pathomechanical classification can lead to the following subcategories: certain high-flow shunts (ie, fistulous pial AV malformations) can lead to macrocrania, hydrocephalus, and psychomotor developmental retardation as a result of hydrovenous disorders, and cardiac insufficiency caused by cardiac overload. Venous congestion that can be caused by a high input (fistulous lesions) or a reduced outflow (secondary stenosis of the outflow pattern) may lead to cognitive decline or epilepsy. Even if signs of venous congestion are not present, a long pial course of the draining vein may indicate that venous drainage restriction is present in a large area, increasing the risk of venous congestion and subsequent epilepsy. Conversely, a short vein that drains almost directly into a dural sinus is unlikely to interfere with the normal pial drainage. If epilepsy was present in a patient with this kind of angioarchitecture, the magnetic resonance imaging (MRI) should be scrutinized for signs of perinidal gliosis or hemosiderosis as the cause of the patient’s symptoms. Mass effect is a rare pathomechanism that may result from large venous ectasias or the nidus proper compressing critical structures and may lead to epilepsy, neurologic deficits, and even hydrocephalus. Arterial steal has been associated with clinical findings such as migraine and focal neurologic symptoms that most often are transitory in nature. With the advent of new imaging modalities such as functional MRI and perfusion-weighted MRI it has now become possible to visualize whether or not the symptoms of a patient can be attributed to a true steal. Hemorrhage in AV shunting lesions may be caused by angioarchitectural risk factors such as venous outlet stenoses or intranidal aneurysms ( Table 1 ). One advantage of this classification is that it may be used to guide therapies, because it relates the pathomechanism to the clinical findings. Therefore, in patients with high-flow shunts and problems that indicate venous congestion or in patients with arterial steal, treatment should be aimed to reduce the AV shunting volume, which can be achieved by endovascular techniques. In patients with epilepsy from perifocal gliosis, or in patients presenting with mass effect, endovascular treatment may be less indicated. Surgical resection or decompression with possible preoperative embolization are likely to be more beneficial in these cases.
| Clinical Findings | Angiographic Sign | Additional Imaging Diagnostics | Primary Pathomechanism | Treatment Rational |
|---|---|---|---|---|
| Neurologic deficits | Perinidal high flow and associated extranidal (remote) hypoperfusion | Perfusion-weighted MRI: extranidal hypoperfusion, Functional MRI (detection of eloquent tissues) | Steal | Reduce shunt |
| Neurologic deficits | Venous ectasias/pouches close to eloquent brain | MRI: compression, focal edema?, Functional MRI: detection of eloquent tissues | Mass effect | Remove mass effect |
| Headaches | Occipital high-flow AVM | Perfusion-weighted MRI: extranidal occipital hypoperfusion | Steal | Reduce shunt |
| Headaches | Large draining veins | MRI: hydrocephalus with draining veins close to the aqueduct or interventricular foramen | Mass effect | Decrease size of draining vein |
| Headaches | Pseudophlebitic aspect in venous phase, prolonged venous phase | MRI: edema | Venous congestion | Reduce shunt |
| Epilepsy | Long-standing high-flow shunts, pseudophlebitic aspect in venous phase | CT: calcifications | Venous congestion | Reduce shunt |
| Epilepsy | Unspecific | MRI: perinidal gliosis | Gliosis | Surgically removal |
| Epilepsy | Long pial course of draining vein | Unspecific | Venous restriction | Reduce shunt |
| Cardiac insufficiency | High-flow shunts | MRI/CT: large venous pouches | Right → left shunt | Reduce shunt |
| Psychomotor developmental retardation | High-flow shunts, pseudophlebitic aspect in venous phase, reduced outflow | MRI: melting brain? CT: calcifications | Venous congestion in not fully matured brain | Reduce shunt |
| Dementia | Pseudophlebitic aspect in venous phase | MRI: edema | Venous congestion | Reduce shunt |
Age-related classification
A classification of pediatric vascular malformations according to the patient’s age is helpful in predicting what type of vascular malformations will be encountered, but does not explain why the predominance of specific vascular malformations in specific age-groups exists. However, the major advantage of this classification is the ability to predict symptoms that are specific for each pediatric age-group.
In the fetal age, prenatal MRI or ultrasound may detect high-flow fistulous lesions, vein of Galen AV malformations (VGAMs) or dural sinus malformations (DSMs). Systemic manifestations such as macrocrania with or without encephalomalacia (melting brain syndrome) and cardiac manifestations may be clinically present and point toward a bad prognosis. Similar to the fetal period, in the neonatal period, VGAMs, DSMs, and pial AV shunts are the predominant lesions; however, albeit rarer, cavernomas and arterial aneurysms have also been observed in this age-group. Systemic pathomechanisms as described earlier and hydrovenous pathomechanisms (hydrocephalus, maturation delay) are found more often in this period. Neurologic manifestations (seizures, focal deficits) point toward a hemorrhagic infarct or venous congestion. During infancy, VGAMs, pial AV shunts (more often fistulous than glomerular), DSMs, aneurysms, and cavernomas may be present. In shunting lesions, hydrodynamic disorders are the predominant pathomechanisms: the cerebrospinal fluid (CSF) reabsorption in this age-group is solely dependent on the venous (transparenchymal) drainage because the arachnoid granulations are not yet fully functional. Therefore, an increased pressure within the venous system (caused by an AV shunt) leads to retention of CSF within the ventricles with a concomitant increase in ventricular size and transependymal pressure gradient until a new equilibrium is found. Macrocrania, cognitive delay, hydrocephalus, and cerebellar tonsillar prolapse are the clinical manifestations at this stage. After 2 years of age, the classic AV malformations, cavernomas, aneurysms, and dural AV shunts may be encountered. Hydrodynamic pathomechanisms become less important, whereas symptoms related to the AV shunt and its secondary effects (secondary intranidal aneurysms and venous stenoses leading to hemorrhage, arterial steal, long-standing venous congestion with epilepsy, and focal neurologic deficits) are more often observed ( Table 2 ).
| Age | Clinical Presentation | Type of Vascular Malformation |
|---|---|---|
| In utero | Congestive cardiac failure (pulse>200 beats/min, ventricular extrasystoles, tricuspid insufficiency), macrocrania, ventriculomegaly, brain loss (melting brain) | Pial high-flow AVFs, VGAMs, DSMs |
| Neonate | Congestive cardiac failure, multiorgan failure, coagulopathies), intracranial hemorrhage (hematomas, venous infarct, SAH), convulsions | VGAMs, pial high-flow AVFs, DSMs |
| Infant | Hydrovenous disorders: macrocrania, hydrocephalus, convulsions, retardation, intracranial hemorrhage (hematoma, venous infarct, SAH) | VGAMs, pial AVMs (fistulous > nidal), aneurysms, cavernomas |
| Child | Intracranial hemorrhage (hematoma, venous infarct, SAH), progressive neurocognitive and neurologic deficits, convulsions, headaches | Pial AVMs (nidal > fistulous), aneurysms, cavernomas, dural AV shunts |
Age-related classification
A classification of pediatric vascular malformations according to the patient’s age is helpful in predicting what type of vascular malformations will be encountered, but does not explain why the predominance of specific vascular malformations in specific age-groups exists. However, the major advantage of this classification is the ability to predict symptoms that are specific for each pediatric age-group.
In the fetal age, prenatal MRI or ultrasound may detect high-flow fistulous lesions, vein of Galen AV malformations (VGAMs) or dural sinus malformations (DSMs). Systemic manifestations such as macrocrania with or without encephalomalacia (melting brain syndrome) and cardiac manifestations may be clinically present and point toward a bad prognosis. Similar to the fetal period, in the neonatal period, VGAMs, DSMs, and pial AV shunts are the predominant lesions; however, albeit rarer, cavernomas and arterial aneurysms have also been observed in this age-group. Systemic pathomechanisms as described earlier and hydrovenous pathomechanisms (hydrocephalus, maturation delay) are found more often in this period. Neurologic manifestations (seizures, focal deficits) point toward a hemorrhagic infarct or venous congestion. During infancy, VGAMs, pial AV shunts (more often fistulous than glomerular), DSMs, aneurysms, and cavernomas may be present. In shunting lesions, hydrodynamic disorders are the predominant pathomechanisms: the cerebrospinal fluid (CSF) reabsorption in this age-group is solely dependent on the venous (transparenchymal) drainage because the arachnoid granulations are not yet fully functional. Therefore, an increased pressure within the venous system (caused by an AV shunt) leads to retention of CSF within the ventricles with a concomitant increase in ventricular size and transependymal pressure gradient until a new equilibrium is found. Macrocrania, cognitive delay, hydrocephalus, and cerebellar tonsillar prolapse are the clinical manifestations at this stage. After 2 years of age, the classic AV malformations, cavernomas, aneurysms, and dural AV shunts may be encountered. Hydrodynamic pathomechanisms become less important, whereas symptoms related to the AV shunt and its secondary effects (secondary intranidal aneurysms and venous stenoses leading to hemorrhage, arterial steal, long-standing venous congestion with epilepsy, and focal neurologic deficits) are more often observed ( Table 2 ).
| Age | Clinical Presentation | Type of Vascular Malformation |
|---|---|---|
| In utero | Congestive cardiac failure (pulse>200 beats/min, ventricular extrasystoles, tricuspid insufficiency), macrocrania, ventriculomegaly, brain loss (melting brain) | Pial high-flow AVFs, VGAMs, DSMs |
| Neonate | Congestive cardiac failure, multiorgan failure, coagulopathies), intracranial hemorrhage (hematomas, venous infarct, SAH), convulsions | VGAMs, pial high-flow AVFs, DSMs |
| Infant | Hydrovenous disorders: macrocrania, hydrocephalus, convulsions, retardation, intracranial hemorrhage (hematoma, venous infarct, SAH) | VGAMs, pial AVMs (fistulous > nidal), aneurysms, cavernomas |
| Child | Intracranial hemorrhage (hematoma, venous infarct, SAH), progressive neurocognitive and neurologic deficits, convulsions, headaches | Pial AVMs (nidal > fistulous), aneurysms, cavernomas, dural AV shunts |
Morphologic classification
The most widely used classification of vascular malformation is based on angioarchitectural and histomorphologic features. This purely descriptional classification leads to the well-known differentiation in dural and pial AV shunting lesions, the cavernomas, capillary telangiectasias, and developmental venous anomalies (DVAs).
To differentiate these classic types, in a first step, shunting lesions have to be discerned from nonshunting lesions, the latter being cavernomas, capillary telangiectasias, and DVAs. In a second step, within the shunting lesions, those that are supplied by arteries that would normally supply the brain or the choroid plexus (pial and choroidal brain AV malformations [AVMs]) have to be differentiated from those shunts that are supplied by arteries that normally supply the dura and meninges (ie, the classic dural AV fistulae). The nonshunting lesions, on the other hand, exhibit typical neuroimaging and histologic features that in most instances allow for a further subclassification into the cavernomas, which are composed of thin-walled, dilated capillary spaces with no intervening brain tissue and blood products in varying stages of evolution, and the capillary telangiectasias, which consist of localized collections of abnormal thin-walled vascular channels interposed between normal brain parenchyma. The DVAs are nonpathologic normal variations of the venous pattern of draining the normal brain tissue distributed along transmedullary venous anastomoses ( Fig. 1 ).
This angio- and histoarchitectural classification is easy to implement routinely; it is able to predict the prognosis of the vascular malformation within an affected individual and is therefore of importance for the neuroradiologist and the treating physician. However, it does not help to further our knowledge or understanding of these diseases because no information about cause or the nature of the disease can be obtained from this classification. In this purely morphologic approach, secondary changes induced by the vascular malformation itself on the adjacent vasculature may be difficult to differentiate from the malformation proper. If the pathogenesis or cause are not completely understood, therapeutic approaches may therefore be difficult to tailor to an individual malformation. In addition, although rare, certain vascular malformations do not fit into any of the proposed categories, which may result in a therapeutic dilemma. Moreover, cases of transitional vascular malformations point toward a spectrum of overlapping vascular disease entities rather than clear-cut categories.
We therefore propose a classification of pediatric vascular malformations that is based on the cause of the vascular malformation to account for the shortcomings mentioned earlier. Although this classification will not alter therapeutic strategies for the time being, it may enhance our knowledge about the disease beyond its pure morphologic aspect.
Etiologic classification
This classification is based on the recent understanding of angio- and vasculogenesis (on the arterial and venous side) and the influence of environmental and genetic factors. To explain the concepts of this classification, we propose 3 approaches to pediatric vascular malformations: the timing, the target, and the nature of the triggering event.
The Triggering Event
The concept of the triggering event is built on the assumption that most pediatric vascular malformations can be considered as congenital malformations (ie, malformations or structural weaknesses of the vessel that have been triggered or are present before birth and that make the vessel more prone to developing, once a second hit (or second trigger) occurs, the morphologic and/or clinical vascular lesion). This concept implies that the malformations are initially quiescent and may reveal themselves only later in life, which implies a differentiation into primary (or causative) triggers and secondary (or revealing) triggers. The stages of vascular malformations based on this assumption are therefore the prepathologic stage, during which no disease exits; however, a window of exposure opens that makes the cell temporarily vulnerable for an appropriate triggering event (eg, inflammatory, infectious, radiation-induced, toxic, metabolic, or traumatic). During the genetic stage, this appropriate (or causative) trigger for the vascular target and the time produces a primary lesion (that may result in a germinal or somatic mutation or a permanent dysfunction of the vessel). If it is neither repaired nor leads to cell death, the primary local defect (although for the time being quiescent) is transmitted to later generation cells and has a clonal remote effect. At this phase, the disease is not yet morphologically apparent, but is present as a permanent structural weakness. This stage can therefore be denominated as a biologic or premorphologic stage. Later in life (in most instances postnatal), during a new window of exposure with a secondary (or revealing) trigger, a secondary mutation or an additional dysfunction allows for the phenotypic expression of the disease. This secondary trigger may appear during repeated vascular remodeling, may be related to shear stress, inflammation or trauma, or may constitute a second (somatic) mutation. At this stage, the disease manifests itself as a morphologic but not yet clinical entity (eg, incidental finding of an unruptured aneurysm). This stage is the morphologic or preclinical stage. Only after failure of biologic compensation mechanisms (intrinsic repair mechanisms), or during secondary angiopathic changes (extrinsic risk factors: hemodynamic disequilibrium, shear stresses), the already morphologically fragile disease will get symptomatic and enter the clinical, symptomatic stage ( Fig. 2 ).
Target of the Trigger
Development of blood vessels from differentiating endothelial cells (EC) is called vasculogenesis, whereas sprouting of new blood vessels from the preexisting ones is termed angiogenesis. Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are the most critical drivers of embryonic vessel formation. During vasculogenesis lateral and posterior mesodermal cells migrate toward the yolk sac. During their migration, the precursors aggregate to clusters, termed hemangioblastic aggregates. The peripheral cells of these aggregates flatten to differentiate into EC, whereas the centrally located cells differentiate to hematopoietic cells of the blood islands. Following this differentiation, EC surrounding these blood islands anastomose to form a capillary meshwork, which serves as a scaffold for the beginnings of circulation, before the heart starts beating. It is only after the onset of heartbeat and of blood flow that the yolk sac capillary plexus is remodeled into arteries and veins in the now ongoing process of angiogenesis. Historically, it was believed that the EC of the primary capillary plexus constituted a homogenous group of cells and that further differentiation into arteries and veins occurred because of hemodynamic forces. However, in recent years, several signaling molecules were discovered, which labeled arterial or venous EC from early developmental stages onward, before the assembly of a vascular wall. Arterial EC selectively express ephrin-B2, neuropilin-1, and members of the Notch pathway, whereas other molecules are specifically expressed in the venous system only; some molecules (such as the neuropilin-2 receptor) are expressed in early stages by veins and, at later developmental stages, become restricted to lymphatic vessels. These observations led to the hypothesis that the embryonic vascular system could be predetermined to an arterial, venous, or lymphatic fate from early developmental stages onward (ie, before angiogenesis and after vasculogenesis). Arteries, veins, and lymphatic vessels are therefore different, molecularly defined targets. It can therefore be easily envisioned that triggering events are specific for either the arterial or the venous site. Diseases that strike only on the arterial site (aneurysms, dissections) can therefore be differentiated from diseases that are targeted against the capillary, venous, or lymphatic vessels.
Timing of the Trigger
The endothelium and the media of blood vessels are derived from the mesoderm and the neural crest, respectively, with the exception of the mesencephalic region and the spinal levels, both of which originate from mesoderm. These neural crest or para-axial mesoderm cells are migrating groups of cells starting from the segmented regions. They course along predetermined paths in which daughter cells are seeded. When a defect in this migrating cell is present, the defect is transmitted to the daughter cells along its migrating path. The effect, size, area, and severity of the defect produced by the causative trigger are therefore related to the timing of the event in relation to the migration; the earlier the hit, the larger the effect on the vessels with a more widespread and severe vascular lesion. Vice versa, the later the hit, the more focal the effect and the more confined the vascular lesion. Although a germinal mutation is present in all cells, an early somatic mutation may lead to various stages of metamerically arranged defects, whereas a postnatal mutation affects only a small cluster of cells. Although congenital, some of these mutations may be revealed only later in life (such as in a failed remodeling during vascular renewal).
In the early embryonic vessel configuration (ie, during the early stages of angiogenesis and after the heart started beating) not all capillaries are integrated into the primitive circulation. In this period, the primitive circulation consists of direct transitions of arteries into veins; arterial and venous blood can flow through the same vascular channel. This embryonic circulation is therefore different from the adult situation (in which blood flows through arteries into arterioles, a capillary bed, and through successively larger veins back to the heart). If this embryonic arterial-venous vessel configuration persists, large arterial-venous shunts will develop (which may be the case in certain fistulous malformations of the brain and spine). With further development of the vasculature (ie, in later embryonic and fetal stages), the area of the shunt may become more confined, again revealing the importance of the timing of the triggering event in relation to the size and effect of the vascular malformation.
Nature of the Trigger
Depending on the type of trigger, purely genetic diseases (such as hereditary hemorrhagic telangiectasia [HHT] ) can be differentiated from purely extrinsic diseases (such as vascular traumatic lesions). In between these extremes, however, triggering events with varying roles of genetic and environmental triggers can be identified.
This concept leads to the classification shown in Table 3 , in which focal, segmental, and metameric lesions (which depend on the timing of the triggering event) are tabulated against the location of the lesion along the arteriocapillary-venous tree (as the specific target hit by the triggering event) and the nature of the trigger (ie, genetic vs nongenetic). Thus, the following classification of pediatric vascular malformations is proposed, keeping in mind that this classification has to be regarded as a spectrum of diseases and that the subclassifications presented constitute arbitrary boundaries.
Related posts:
Normal and Abnormal Embryology and Development of the Intracranial Vascular System
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Stereotactic Radiosurgery for Pediatric Arteriovenous Malformations
Spinal Cord Vascular Malformations in Children
Cerebral Venous Sinus (Sinovenous) Thrombosis in Children
Traumatic Intracranial and Extracranial Vascular Injuries in Children
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