Classification and Definitions

It is important to place AVMs and AVFs in the proper pathological classification given the multitude of names one may encounter in the literature.

First, a vascular malformation of the central nervous system is believed to be a dysplastic process, which should be distinguished from a neoplastic process (i.e., a hemangioma is defined as a neoplasm derived from the endothelial cells of a blood vessel). Some literature will, for example, refer to a cavernous malformation as a “cavernoma” or “cavernous angioma,” with the suffix “oma” implying a neoplastic process. In a similar manner, one may also encounter the name “venous angioma” used to describe a developmental venous anomaly. In the category of dysplastic vascular malformations, there have traditionally been four pathological entities:^1–3 developmental venous anomalies, capillary telangiectasias, cavernous malformations, and AVMs. In addition, mixed malformations have been found, though they are thought to be rare.⁴ What separates an AVM from the first three is the presence of an arteriovenous shunt, which is defined as oxygenated blood passing directly into the venous system without gas exchange occurring in a capillary bed. These shunts are characterized by high flow and high pressure, which distinguish them from other vascular malformations.

AVMs may be plexiform, fistulous, or both. A fistulous malformation may be an otherwise normal artery directly joining a vein. A plexiform malformation is defined as an artery connecting to a network of poorly differentiated, immature vessels before passing into a vein. This plexiform network can be termed a nidus (Latin term for “nest”). Figure 14.1 shows a plexiform nidus on the cortical surface. AVMs with plexiform and fistulous components can be seen in any intracranial structure. Because of their developmental nature, they can span multiple structures that are otherwise anatomically distinct. Because they can occur anywhere in the brain, the term brain AVM (BAVM) is coming into wider use and becoming more accepted.⁵ However, one may encounter multiple adjectives that attempt to describe the malformation (true, cerebral, pial, parenchymal, cisternal, ventricular, medullary) but do not necessarily imply a separate type of pathological entity. However, there is one exception: Dural AVFs (dAVFs) are a distinct pathological type in that their development is not thought to be strictly congenital but acquired. The dAVF will be treated as a separate pathological entity and will be discussed later.

FIGURE 14.1 A, Axial magnetic resonance imaging with gadolinium shows an enhancing lesion in the left parietal cortex. B, Digital subtraction angiography (DSA) of the same patient shows an arteriovenous malformation (AVM) with a middle cerebral arterial feeder and a cortical draining vein to the superior sagittal sinus. C, Intraoperative image of the same AVM shows the nidus on the cortical surface. Note the large draining vein with oxygenated blood going superiorly. Here, intraoperative cortical stimulation was attempted because of the eloquent location of the nidus. D, Postresection image.

Diagnostic Radiology

Radiological Findings

A judicious use of diagnostic imaging studies is warranted with these complex lesions. A Joint Writing Group publication, in 2001, was a multidisciplinary effort to provide guidelines in the standardized reporting of AVMs for the purposes of clinical research.⁵ A summary of the important features is provided here. However, note that when AVMs are described, certain characteristics may have more clinical relevance.

Nidus

The size of an AVM usually refers to that of the nidus itself, though the presence of adjacent dilated veins may be confounding. Generally, cross-sectional imaging will provide a more accurate assessment using the same measurement techniques as those for any intracranial mass lesion. Location of the nidus is a second characteristic to note. One is particularly concerned about its proximity to eloquent brain structures.⁸ Both size and location, though better characterized on cross-sectional imaging, can be roughly estimated as well on angiography, as shown in Figure 14.2A. Additionally, one should characterize the shape for surgical or radiosurgical planning. Unusual geometries may be obscured in angiograms. In locating the nidus, the first step in microsurgical treatment would be consideration of the needed approach for any mass lesion in that location and the potential morbidity.

FIGURE 14.2 A, Use of digital subtraction angiography (DSA) in the early arterial phase lateral (I) and anteroposterior (II) projections to estimate the size and location of an arteriovenous malformation (AVM) nidus as seen on T2 axial magnetic resonance imaging (MRI) (III). Note that the conical shape of the nidus with the apex near the posterior lateral ventricle cannot be appreciated with DSA alone. Also note that the large flow void laterally on the MRI depicts a major draining vein that is not readily appreciated on this phase of the angiogram. B, An AVM with a 3-cm nidus in the parietal cortex as seen on lateral DSA vertebral injection (above) and left inferior cerebral artery (below). The arrows point to the same draining vein in order to help orient the reader to the same structures in each image. The primary arterial feeder is a middle cerebral artery branch from the carotid circulation. However, the early opacification of the same vein on the vertebral injection indicates a posterior circulation contribution as well. C, The same AVM seen on oblique views shows the posterior cerebral arterial feeders (above) are en passage arteries which likely supply normal brain tissue. The location of this nidus in a vascular border zone likely allowed the surrounding normal cerebral tissue to recruit additional arterial supply from the posterior circulation over time. During embolization or surgery, it is important to recognize the difference between these vessels to avoid a cerebral infarct.

(A from Hamm KD, Klisch J, Surber G, et al. Special aspects of diagnostic imaging for radiosurgery of arteriovenous malformations. Neurosurgery 2008;62(5):A44.)

Arterial Supply

Arteries supplying the AVM should be noted for number, size, relative contribution to the nidus, and location. They can be characterized first by noting what vascular territory they arise from. Angiography from each intracranial vessel should be performed. The detailed description of the intracerebral anatomical vasculature is beyond the scope of this chapter. However, when describing the source of a feeding vessel it would be best to describe its course from the circle of Willis. For large AVMs, when there is concern for meningeal involvement, angiograms of the external carotid arteries should be done as well. Contribution from deep perforating arteries should be clearly noted as they are particularly difficult to deal with in surgery. Finally, one should note that large AVMs or even smaller ones in the temporal or occipital lobe may lie in the vascular border zone between the anterior and posterior circulations; they could, therefore, have vascular pedicles from both. In the era before digitized images, one could simply overlay the transparent films from multiple angiographic injections to get an idea of the complete nidus along with relative locations of erratic feeders. Modern, electronic PACS (picture archiving and communication system) software does not yet seem to have a simple equivalent (Fig. 14.2B).

There are three types of arterial feeders. Direct feeders are the simplest to conceptualize: they end directly and exclusively in the nidus, and they are also known as terminal feeders. Transit arteries are normal arteries that appear on angiogram to pass near or even through the nidus while going on to supply normal tissue. These normal arteries can be easily obscured during nidus opacification. At the same time, their distal territory may never get a sufficient supply of contrast to opacify. An example may be the pericallosal artery passing adjacent to a mesial frontal lobe nidus before proceeding posteriorly. The third type of feeding artery is the indirect feeder or artery en passage. This artery combines the previous two in that as it passes near the nidus it can contribute to the shunt before continuing on to supply normal brain. AVMs within the sylvian fissure usually harbor many en passage contributions from the distal middle cerebral arteries. Rotational angiography and three-dimensional reconstruction has now replaced the old-fashioned stereoangiography, which previously provided excellent tracking of the course of feeding arteries and draining veins.

Superselective angiography of a suspected vessel can show if it contributes to the nidus or not and help distinguish a transit artery. However, superselective catheterization of an artery en passage can have variable presentation on angiography depending on the hemodynamics of the vessel. Knowledge of normal cerebrovascular anatomy can help the neurosurgeon recognize where normal vessels should be expected. Also, a common theme among many, though not all, AVM feeders is that they do not seem to follow the traditional pattern of progressive luminal narrowing as they flow distally. Arterial feeders can even exhibit pathological stenosis or even aneurysms. Embolization or surgical ligation of an unrecognized en passage artery can lead to infarcts of normal tissue. The superselective angiography also helps identify any intranidal aneurysm as well as small prenidal aneurysms.

One other point of importance is the supply to AVM coming from pial collaterals. An AVM in the parietal area, for example, may have most of its supply from the middle cerebral artery, but it also gets its contribution from the posterior cerebral branches coursing over the hemisphere essentially supplying the distal territory of middle cerebral artery beyond the AVM (Fig. 14.2C). Even though these vessels are larger than normal, they are not suitable for endovascular occlusion. This fact also needs to be taken into consideration during microsurgery so that the supply to the normal brain is not affected.

Venous Drainage

The final feature to characterize in an AVM is the draining veins. In a similar manner to the arteries, one should note the number, size, and locations of the major veins.

The draining veins may be of unusual caliber with a tortuous course, ectasias, or stenosis.⁹ Of particular importance to note is whether the veins drain superficially via the cortical surface or deeply to the vein of Galen. This is usually easy to identify with an angiogram as the first evidence of an arteriovenous shunt is early opacification of the veins by using anatomical recognition of the vein of Galen along with the major cerebral venous sinuses.

Like the transit arteries, it is important to recognize the possible existence of normal veins draining functional cerebral tissue that may be adjacent to the lesion. Again, careful study of the angiogram may show veins that opacify later than veins draining the nidus yet still in the same region. During surgical excision, it may be difficult to distinguish between them without knowing their locations relative to each other preoperatively.

Special Tests

Use of adjunctive diagnostic studies is helpful in selective cases. Functional MRI (fMRI) has helped assess the proximity of language and motor function in relation to AVM but has limitations (Fig. 14.3). Magnetic source imaging (MSI) can accurately localize sensory cortex and even visual and motor areas and the information can be overlaid on the MRI. Recently introduced, tractography should aid in assessing the relationship of deep white matter tracts to the AVM. The information derived from these studies is helpful in deciding the treatment and possibly assessing the neurological risk before intervention. Intraoperative functional mapping has limited value because one cannot do partial treatment in AVMs, in contrast to tumors.

FIGURE 14.3 A, Digital subtraction angiography (DSA) left internal carotid artery injection shows perisylvian nidus in a 31-year-old female patient. B, Functional magnetic resonance imaging (fMRI) during verb generation showed activation of speech centers away from the nidus. Immediately postoperatively, however, the patient had aphasia. Though her speech eventually recovered, it is likely the fMRI results were inaccurate.

Grading Systems

Clinicians have been attempting to classify AVMs with the goal of helping patients understand the risks by comparison to historical outcomes. An ideal classification system would have the flexibility to cover many pathological variants, the simplicity to be used in a bedside fashion, and the utility to prognosticate. The variability and rarity of AVMs, however, have made this goal difficult to achieve in practice. Several classification schemes have been proposed.^10,11 Of these, the Spetzler-Martin system (Table 14.2)¹² has the most widespread use and should be known by the practicing neurosurgeon. Grades I and II AVM patients generally tolerated resection without morbidity while grade IV and V AVMs had higher risks of postoperative deficits. Retrospective and prospective studies have shown its utility for surgical decision making.^12,13 There are several weaknesses of this system, however. First, it lacks the ability to assess risks for interventions other than exclusive microneurosurgery. Second, the studies were carried out by a highly experienced vascular team and may not necessarily be applicable to a general neurosurgeon’s ability. Third, despite its simplicity, interobserver variability can still occur.¹⁴ Finally, there is continuing concern that this system may oversimplify many AVMs. A more recent classification scheme attempts to add deep perforator supply and nidus diffuseness parameters to the Spetzler-Martin system¹⁵ as predictors of higher surgical morbidity rates. The chief drawback is the difficultly applying the diffuseness parameter based on imaging (Fig. 14.4). These factors, however, have been recognized to make microsurgical resection more challenging.

TABLE 14.2 Spetzler-Martin Scale for Grading Arteriovenous Malformations

^∗Total scores range from 0 to 5; high scores are associated with high risk of permanent neurological deficit after surgery.

FIGURE 14.4 Axial magnetic resonance imaging (MRI) with gadolinium shows a large left frontal lobe nidus with a high level of diffuseness compared to the one seen in Figure 14.1. This characteristic, though not part of the Spetzler-Martin scale, may increase treatment morbidity.

(From Du R, Keyoung HM, Dowd CF, et al. The effects of diffuseness and deep perforating artery supply on outcomes after microsurgical resection of brain arteriovenous malformations. Neurosurgery 2007;60(4):638-646; discussion 646-648.)

In most of the grading schemes the size measurement is taken as a linear parameter, which when taken in the context of volume, has tremendous variation within the range of dimension. As an example, the spherical volume of a 5.54-cm-diameter AVM is approximately four times greater than an AVM measuring 3.5 cm, even though both of them are assigned 2 points in the Spetzler-Martin scale. Treatment with radiosurgery is volume dependent. In addition, several series have shown that volume is a better predictor of microsurgical risk and outcomes. The approximate volume can be determined by the formula: (length × width × height)/2. These measurements can be obtained from the anteroposterior (AP) and lateral views of the angiogram corrected for magnification.

Future attempts at classification may include more parameters, thus increasing the complexity beyond a simple bedside assessment. The ubiquity of computational devices even at the bedside, however, should allow for greater access to data-mining systems that can generate more granulated prognosis based on an ever greater number of parameters. Future studies, therefore, should focus on making classification schemes accurate rather than simple.

Pathological Sequelae

Development

There has been much speculation about how arteriovenous malformations are thought to develop. Traditionally it has been thought that they are congenital lesions that develop during the embryonic stage. This reasoning stems from histological examination of AVM structures that reveal characteristics that resemble the plexuses of developing vasculature in the embryo. There is also predisposition to develop AVMs in patients with genetic disorders such as Osler-Weber-Rendu and Wyburg-Mason syndromes.²⁴

Against this theory, however, is the fact that AVMs have been known to recur after post-treatment angiographic evidence of obliteration by surgery or radiosurgery, although recurrence is very rare.²⁵ One must keep in consideration that the imaging resolution limit of an angiogram prohibits adequate visualization of the microcirculation. With this in mind, the question becomes whether these postnatal malformations arise de novo or develop into larger structures that can eventually be seen radiographically. In either case, the evidence supports the theory that AVMs are not static lesions but biologically dynamic and that they can develop and remodel over time.

The congenital theory of AVM development suggests that there is a failure of the development of a stable vascular and capillary plexus.²⁶ During embryological development of the nervous system, neuronal growth and migration help shape the vascular network that eventually will supply it. As an example, the population of neurons that develop in the germinal matrix near the ventricle and migrate radially outward toward the cortex can have vessels growing in tandem or, more commonly, migrating from the cortex inward in an antiparallel fashion.

Vascular development is believed to be a concerted mechanism that is a successive combination of three processes: vasculogenesis, angiogenesis, and arteriogenesis (Table 14.3).^26,27 Vasculogenesis is thought to occur exclusively in the embryonic period. It is defined as a process of differentiation of vascular progenitor cells into angioblastic cells which eventually form the endothelial layer of all vessels. The vasculogenesis process creates a haphazard network of immature cells that form angiocysts, which eventually fuse to form a primitive capillary plexus. The next process, angiogenesis, involves selective apoptosis along with the migration of supporting vascular smooth muscle cells to form a stable vascular bed. The interplay of these two processes during the embryonic stage requires multiple steps for cell proliferation, migration, differentiation, and programmed destruction. Any misstep during this stage could be the initiating factor in the formation of a congenital vascular malformation.

Although the interplay between vasculogenesis and angiogenesis during the embryological stage of development is thought to be the initiating factor in the formation of AVMs, arteriogenesis likely plays an important role in the later growth and remodeling of AVMs from the fetal stage onward. Both angiogenesis and arteriogenesis play a part in the maintenance and growth of AVMs into adulthood. Arteriogenesis, being mediated by vascular wall shear stress, is the likely mechanism by which an AVM with low resistance is able to recruit additional blood supply over time.

Molecular Biology and Genetics

The study of the molecular changes with AVMs has revealed the altered expression of many factors that are known to have key roles in the developmental processes noted previously. What is more interesting is that many are shared with cerebral neoplastic processes as well. This suggests that there may be a future role for targeted medical therapies based on the understanding of the abnormal molecular pathways initiated and sustained by these active lesions. Around 900 genes have been shown to have altered expression in AVMs.^26,28 Detailing the molecular factors implicated in the embryological development of cerebral vessels is beyond the scope of this chapter. However, a few of those factors that have abnormally high expression in AVMs when compared to normal brain tissue have been noted here.²⁶

VEGF (vascular endothelial growth factor) has multiple subtypes that have been seen in increased amounts not only in AVMs but in the surrounding tissue. Additionally, VEGF receptors are noted to have altered expression patterns in AVMs. Normally, VEGF variants are expressed in high levels during embryonic development. They play a key factor in angiogenesis, vascular proliferation, and capillary migration. VEGF expression is normally suppressed in adulthood but can be rapidly increased by HIF-1 (hypoxia-induced factor) in response to a low oxygen microenvironment.

ANGs (angiopoetins) regulate the recruitment of smooth muscle cells and pericytes to endothelial cells are thought to promote vascular stabilization during angiogenesis.

FGFs (fibroblast growth factors) are thought to help differentiate progenitor cells to angioblasts during vasculogenesis. The differentiation of fibroblasts to smooth muscle cells is thought to be regulated by bFGF (basic fibroblast growth factor); it may participate in the arterialization of AVM veins.

The congenital theory of development can imply that an AVM begins as a response to some environmental abnormality during development or that a genetic alteration was initially responsible. In the case of the latter, genetic alterations may be sporadic or familial. Several genetic disease syndromes have been associated with an increased predisposition to harbor AVMs such as Wyburn-Mason syndrome, Sturge-Weber disease, and ataxia-telangiectasia.^24,26

Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia, is an autosomal dominant disorder with variable penetrance. Genetic analysis has isolated two sources for mutation: HHT1 is found on chromosome 9q and HHT2 is found on chromosome 12q. Incidence for AVM in HHT1 mutations is approximately 10 times higher than that for HHT2, which shows that different genetic mutations alter the risk of developing AVMs based on the function each encoded protein has during development.²⁹ In addition to known hereditary disorders, there have been AVM cases among families, suggesting a multifactorial genetic patterning to formation.

Physiology

The physiology of AVMs can be generally categorized into those of the malformation itself and those of the surrounding brain structures. Understanding the hemodynamics of arteriovenous shunts is a key concept.

Intracranial hemorrhage from an AVM is thought to occur when a vessel within the circuit ruptures. Typically this vessel is thought to be within the nidus or a draining vein, though an arterial feeder bleed may be possible. It is difficult to localize the exact source of hemorrhage within an AVM using current imaging modalities. Hemorrhage will occur when the stress exhibited within a vessel wall exceeds the limit for structural integrity. This may occur from either a decrease in the structural integrity limit of the wall or an increase in the stress delivered. The structural integrity limit of the wall depends on the material of the wall itself. The stress delivered depends on the pressure within the vessel along with the radius and the thickness of the vessel. Changes to the vessel shape and material composition can occur chronically over time as a result of biological processes, and pressure changes can vary relatively quickly. Aneurysms, for example, are biological processes that are known to increase the risk of rupture within an AVM by changing the structure and material composition of the vessel wall itself.

The hemodynamics of AVMs is a subject of continuing study. It is difficult to model an AVM using fluid dynamic models given their individual variability. Some electrical network analogies have been described in the literature in order to help conceptualize individual elements within a complex system.^30,31 For the scope of this chapter, it may be simpler to reduce the concept into flow rates and pressures through three structures—the feeding artery, the nidus, and the draining vein—of an AVM with one of each. In this model, for conservation of mass, any flow increase to one structure will be the same to all. Flow increase may be achieved, however, through increased feeding arterial pressure, decreased draining pressure, or decrease in the vascular resistance of the AVM by enlargement of the nidus. A nidus can enlarge by increasing the diameter of existing vessels or generating new ones. Note that if a nidus increase can bring about decreased vascular resistance, the feeding artery’s pressure can either drop or its flow rate can increase until a new equilibrium is reached. For pressure to increase in a nidus, flow can be increased by increasing pressure in the feeding artery or flow can be decreased by increasing pressure (indirectly by increasing distal resistance) in the draining vein. This model neglects the fact that many AVMs are not so simple. Also, there is the possibility of capacitance, that is, the ability of the nidus to increase flow without necessarily increasing vascular resistance or, therefore, pressure.

With these concepts in mind, some general hemodynamic considerations in AVM therapies are as follows: (1) Decreasing flow is best effected by obstructing feeding arteries, and (2) decreasing flow by obstructing veins will increase intranidal pressures and, therefore, bleeding risk (Fig. 14.5).

FIGURE 14.5

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