Pathology, Pathogenesis, and Pathophysiology

AVMs are high-flow cerebrovascular lesions that consist of a tangle of abnormal blood vessels. Three morphologic features are typical of these lesions: feeding arteries, draining veins, and a dysplastic vascular nidus composed of a tangle of abnormal vessels that acts as a shunt from the arterial to the venous system.⁵ Gross pathologic features include the absence of a capillary bed and the presence of small feeding arteries composed of variable amounts of smooth muscle and elastic laminae, with single or multiple direct arteriovenous (AV) connections. The lack of a capillary bed results in low resistance and, with the AV connections, permits high-flow AV shunting. Although the feeding vessels and draining veins themselves may not be congenitally abnormal, their communication through the nidus subsequently leads to arterial dilation and venous arterialization (Fig. 383-1).

FIGURE 383-1 Axial and coronal T2-weighted (A and B) and sagittal T1-weighted (C) magnetic resonance images show multiple vascular flow voids within a left frontal arteriovenous malformation extending from the cortex down to the frontal horn of the left lateral ventricle. Left internal carotid injection (lateral projection) during cerebral angiography shows that the arterial supply is via anterior left middle cerebral artery branches (D) with early venous drainage (E). The nidus is more clearly defined with superselective angiography (F).

This chronic high-flow shunt produces secondary structural changes in the feeding and draining vessels, dilation of the feeding arteries, and dilation and thickening of the draining veins.⁵ Smooth muscle hyperplasia associated with fibroblasts and connective tissue elements known as fibromuscular cushions develops in the feeding arteries.

The nidus (Latin = nest) was described by Cushing and Bailey as a “snarl” based on its gross appearance.¹ The nidus is a conglomeration of numerous AV shunts without interposed brain tissue and no capillary bed. Microscopically, the nidus has thin collagenous walls in the venous elements with muscular elastic walls in the feeding arteries.

Aneurysms are associated with 2.3% to 16.7% of AVMs (Fig. 383-2).^6,7 The pathophysiology is not known definitively, but it is believed to be secondary to a high-flow vasculopathy.^8–10 AVM-associated aneurysms are classified by location as either flow related (85%) or unrelated (15%). The latter are located on remote vessels that bear no relationship to the supply of the AVM.^11,12 Flow-related aneurysms occur along vessels that supply the AVM and are classified as being either proximal (from arteries on the circle of Willis or the proximal feeding vessels up to a primary bifurcation) or distal (from the feeding vessel distal to its origin from the parent artery at its primary bifurcation). Intranidal aneurysms occur within the nidus of the AVM and show early filling during angiography.¹¹ They account for 5.5% of flow-related aneurysms.¹¹

FIGURE 383-2 A, An axial T2-weighted magnetic resonance image shows a left temporoparietal pial arteriovenous malformation (AVM) with a left middle cerebral artery (MCA) flow aneurysm (arrow). B, Left internal carotid injection (anteroposterior projection) of the cerebral digital subtraction angiogram shows the nidus of the AVM supplied by left MCA branches. The left MCA bifurcation aneurysm is seen less clearly than on the earlier runs (arrow in C and D).

Varix formation may be associated with AVMs, especially those with a paucity of venous drainage. The pathophysiology of this venopathy is unclear but is believed to be due to secondary angiomorphologic changes induced by high flow downstream of the AV shunt of the nidus.¹³ Valavanis and Yasargil associated this condition with an increased risk for hemorrhage.¹³

The perinidal capillary network may be a cause of recurrence of surgically resected AVMs. Dilated capillaries (10 to 25 times larger than normal capillaries) form a ring (1 to 7 mm) around the nidus. These capillaries are connected to the nidus, to the feeding arteries/draining veins, and to surrounding normal brain vessels.^14,15 Unlike CMs, intervening neural parenchyma may be present within the compact network of dysplastic vascular channels that forms the nidus. The parenchymal elements tend to be gliotic, hemosiderin stained, and nonfunctional. Vascular or interstitial calcification is frequently a feature. A type of proliferative or diffuse AVM without a focal nidus is often seen in pediatric patients and has been referred to by Lasjaunias and colleagues as cerebral proliferative angiopathy.¹⁶

Etiology

AVMs may be classified as being sporadic or syndromic in origin. Sporadic AVMs are by far the most common, with a global prevalence of 0.04% to 0.52%.^17,18 Although sporadic, there is increasing evidence that they develop as the result of upregulation or downregulation of multiple homeobox genes that are involved in angiogenesis, such as Hox D3¹⁹ and Hox B3.²⁰ Syndromic AVMs account for approximately 2% of cases. Multiple familial AVMs are seen in hereditary hemorrhagic telangiectasia (HHT).²¹ Cerebrofacial arteriovenous metameric syndromes (CAMSs) involve the face and brain.²²

Three percent to 20% of sporadic AVMs are diagnosed in children,²³ and AVMs are the most common cause of spontaneous brain hemorrhage in children (excluding the neonatal period).^24,25 AVMs are prone to apoplectic hemorrhage by rupture of nidal vessels or associated aneurysms or by obstruction to venous outflow. Bleeding is typically from rupture of a draining vein in association with dilation, kinking, and thrombosis or from rupture of flow-related aneurysms, which are more prevalent than in adults.²⁶ Large AVMs generate an arterial steal phenomenon, and older children may exhibit progressive neurological deterioration or chronic epilepsy (or both).²⁷ If sufficient AV shunting is present, they may initially be manifested as congestive cardiac failure in neonates and infants.

Staging, Grading, or Classification Criteria

The Spetzler-Martin scale classifies AVMs according to size, location in relation to functionally eloquent cortex, and type of venous drainage.²⁸ Multiple brain AVMs are typically seen as part of HHT in association with pulmonary and hepatic AVMs and cutaneous and mucosal telangiectases²¹ or CAMSs.²² A typical example is Wyburn-Mason syndrome, in which an AVM, usually of the diencephalon/optic pathway or midbrain/thalamus, occurs in conjunction with retinal vascular malformations seen on funduscopy (Fig. 383-3). Other CAMSs have been described that link facial development with embryologic brain development.²² Hence, in CAMS-1, prosencephalic AVMs affecting the hypothalamus/hypophysis are seen in association with a facial AVM of the nose. In CAMS-2, AVMs affecting the lateral prosencephalon (occipital lobe, thalamus) are seen in association with facial AVMs of the maxilla. In CAMS-3, AVMs of the rhombencephalon (cerebellum, pons) are seen with facial AVMs of the mandible.^29,30

FIGURE 383-3 A, Computed tomography (CT) of the brain of an 8-year-old boy with a sudden onset of left hemiplegia shows acute hemorrhage within the right thalamus and posterior limb of the internal capsule. B, Magnetic resonance imaging shows multiple small vascular flow voids within the thalamus and basal ganglia suggestive of an underlying arteriovenous malformation (AVM), in addition to the hematoma and surrounding edema. C, CT angiography demonstrates the nidus of the AVM supplied by branches of the right anterior cerebral artery and confirmed by the digital subtraction angiogram (D). E, Funduscopy shows multiple dilated and tortuous retinal vessels, findings confirming the diagnosis of Wyburn-Mason syndrome.

AVMs occur throughout the neuraxis, and most come to attention between the ages of 20 and 50 years because of symptoms. They are definitively identified by angiography,³¹ which shows not only the nidus of tangled vessels but also early venous filling secondary to direct arterial-to-venous shunting within the lesion. Clinically, they are primarily manifested as hemorrhage, which is seen in approximately 65% of symptomatic lesions¹⁷; 15% to 35% have seizures as the initial symptom,³² and the remainder are manifested as headache or progressive neurologic deficits. Although a hemorrhagic manifestation is also common with CMs, the extent of hemorrhage in AVMs is frequently more dramatic and disabling because of the high-flow nature of these lesions. Consequently, mortality rates associated with AVM hemorrhage are approximately 6% to 29%.^17,33,34

Pathology, Pathogenesis, and Pathophysiology

CMs are composed of sinusoidal vascular channels (or caverns) lined by a single layer of endothelium. The caverns are separated by a collagenous stroma that is devoid of elastin, smooth muscle, or other mature vascular wall elements. Lack of intervening brain parenchyma is a pathologic hallmark. Macroscopically, CMs are often referred to as having a “mulberry” appearance.^2,4 Within the cavernoma, hyalinization, thrombosis with varying degrees of organization, calcification, cyst formation, and cholesterol deposition are common. The surrounding brain parenchyma exhibits evidence of previous microhemorrhage, hemosiderin staining, and hemosiderin-laden macrophages. A surrounding parenchymal gliomatous reaction is characteristic and may form a capsule around the lesion.^38,39 Based on the magnetic resonance imaging (MRI) appearance (Figs. 383-4 and 383-5) of CMs, they have been classified into four types reflecting their dynamic nature and propensity for hemorrhage.⁴⁰

FIGURE 383-4 Axial T2-weighted (A) and contrast-enhanced T1-weighted (B) magnetic resonance images in a 25-year-old with a sudden onset of headache, diplopia, and dizziness show recent hemorrhage into a pontine cavernoma. Central hemorrhagic products are surrounded by a partial hemosiderin rim, and an associated developmental venous anomaly is also noted (arrow).

FIGURE 383-5 Magnetic resonance images in a 45-year-old woman with progressive neurological deterioration show blood products of various stages within a midbrain cavernoma, including deoxyhemoglobin or hemosiderin (gradient echo, A), and methemoglobin (increased signal on the coronal and sagittal T1-weighted images, B and C). D, A time-of-flight magnetic resonance angiogram also shows T1 shortening within the cavernoma because of hematoma.

Pathology, Pathogenesis, and Pathophysiology

The vessels of a capillary telangiectasis are enlarged or dilated, which sets them apart pathologically from normal cerebral capillaries. There is no increase in the number of capillaries in the malformation. They are usually small (<2 cm in diameter) and mostly solitary (78%) and can affect any area of the brain. Larger diameter lesions have occasionally been described. The pons is the most common location, followed by the middle cerebellar peduncle and the dentate nucleus of the cerebellum.

Blackwood in 1941 provided the first classic pathologic description.⁴⁶ On gross examination, the cut surface of the brain has small areas resembling pink or brownish petechial hemorrhages. Microscopically, they resemble small tufts of capillaries. There is no smooth muscle and an absence of elastic fibers, and there are no feeding or draining vessels. Normal brain parenchyma is present between the dilated capillaries. Mild gliosis can surround the parenchyma; however, hemosiderin and other evidence of previous hemorrhage are unusual. “Hemangioma calcificans” is a rare calcified variant of capillary telangiectasia.⁴⁷ The pathogenesis of these lesions is unknown.

Arteriovenous Malformations and Capillary Telangiectasia

Chang and coauthors reported a patient in whom capillary telangiectasia developed and became symptomatic approximately 1 month after resection of an adjacent AVM.⁴⁸ They postulated that growth of the capillary telangiectasia may have been caused by the decompressive effect or changes in hemodynamics associated with resection of the AVM or by the release of angiogenic factors after surgery. This is the only report of such an association.

Arteriovenous Malformations and Developmental Venous Anomalies

The coexistence of developmental venous anomalies (DVAs) and AVMs is well recognized despite being rare. The earliest description may have been that of Hirata and colleagues in 1986.⁴⁹ This patient did not have an AVM nidus, however, and it may have been an AVF. Awad and associates reported a series of three lesions that clearly had both AVM and DVA components.⁵⁰ The signs and symptoms in these three patients were thought to be caused by the AVM, not the DVA. These combined lesions preserve the appearance of the DVA on angiography with the exception of AV shunting during the arterial phase of the injection. Consequently, the venous lesion is identified earlier (Fig. 383-6). Frequently, it is difficult to appreciate the DVA separate from the AVM on MRI, and conventional cerebral angiography is more sensitive. Meyer and coworkers emphasized the pitfall of obliterating the DVA when approaching the AVM component in patients with symptomatic hemorrhage.⁵¹ From a pathophysiologic perspective, the association of an AVM with a DVA is perhaps the simplest of all the mixed malformations to explain. Mullan and colleagues reviewed four such patients and discussed the pathophysiology in the context of embryologic development of the cerebral venous system.⁵² They suggested that the AVM might form in a fashion similar to a DAVF: thrombosis of the star cluster would allow the DVA to become arterialized and form the basis of an AVM. Nussbaum and coauthors described the association of small AVMs with a DVA in the posterior fossa.⁵³ They observed that venous hypertension may increase directly, through erythrocyte diapedesis, or indirectly by tissue ischemia causing an increase in the levels of angiogenic factors, an explanation previously suggested by Wilson.⁵⁴ This venous hypertension may become chronic at the site of drainage of the DVA, with an acute increase reflecting a rise in intracranial venous pressure or occurring as a result of acute thrombosis. Comey and collaborators⁵⁵ cited Dillon’s unpublished series of patients in whom so-called collector vein stenosis was suggested as a further mechanism for venous hypertension. Wilson speculated that venous hypertension may force previously diminutive AV shunts open, which could then enlarge over time.⁵⁴ This supports the development of AVFs but not necessarily AVMs. In support of these theories, the literature has described areas of signal abnormality and enhancement surrounding some DVAs associated with CMs. This finding may indicate that some patients have legitimate hypertension and disruption of the blood-brain barrier,⁵⁵ which is indicated by contrast enhancement. This concept is supported by a case reported by Ciricillo and coworkers.⁵⁶ An angiographically occult AVM in association with a DVA was resected from a child in whom new angiographically occult lesions later developed that were presumed to be CMs. More recently, Im and coauthors reported a series of 15 atypical DVAs with arterialization but without a distinct nidus that behaved clinically as AVMs.⁵⁷ The most interesting question that this article raises is whether these lesions are separate types of vascular malformations or simply part of a continuum of these lesions.⁵⁸ The answer at present is unknown, and any theories will ultimately be proved or disproved by histochemical analysis.⁵⁶

FIGURE 383-6 A, Computed tomographic scan of the brain of a 50-year-old man with acute intraventricular and pontine hemorrhage. B, Digital subtraction angiography shows a posterior fossa arteriovenous malformation supplied by the left posterior inferior cerebellar artery and superior cerebellar vermian branches with rapid arteriovenous shunting into the torcular and left transverse sinus. An associated developmental venous anomaly is seen (lateral and anteroposterior projections, C and D).

Arteriovenous Malformations and Cavernous Malformations

AVMs have been described in association with CMs. Garner and coworkers reported one such patient,⁵⁹ and Awad⁵⁰ and coauthors reported three. The latter group suggested that the AVM portion of the lesion tends to be angiographically and radiographically occult, thus making preoperative diagnosis extremely difficult. With respect to pathogenesis, smooth muscle may develop in the wall of the CM as a reaction to angiogenic factors. An alternative theory suggests that microhemorrhage from an occult AVM precipitates development of the CM.

Hereditary Syndromes Featuring Cerebral Arteriovenous Malformations

HHT, also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant vascular dysplasia characterized by vascular malformations in multiple organ systems. The nasal, mucocutaneous, pulmonary, cerebral, gastrointestinal, and hepatic vascular beds are most commonly affected.⁶³ The clinical diagnosis of HHT is generally made according to the established Curaçao criteria.⁶⁴ An individual is considered to have HHT if three of the following four criteria are met: recurrent spontaneous epistaxis; mucocutaneous telangiectasia; visceral involvement such as pulmonary and cerebral/spinal AVMs, gastrointestinal bleeding, or intrahepatic shunting; and a family history of HHT. The vascular malformations affecting the brain are primarily AVMs. Symptomatic cerebral AVMs are present in up to 5% of patients with HHT.^63,65 Screening for asymptomatic lesions reveals a higher incidence of nearly 13%.^66,67 Families with this uncommon angiodysplastic disorder often have multiple cerebral AVMs, with up to a third of HHT patients harboring AVMs having multiple lesions.⁶⁵ HHT is known to have age-dependent penetrance (almost complete by 40 years of age).

HHT is a genetically and clinically heterogeneous disorder. Linkage analysis has mapped the genes underlying this syndrome to regions 9q33-q34.1^68,69 on chromosome 9 (HHT type 1 [HHT1]) and 12q11-q14^70,71 on chromosome 12 (HHT2). HHT1 (Online Mendelian Inheritance in Man [OMIM] 187300) is caused by mutations in the ENG (endoglin) gene^72,73 and is associated with a higher prevalence of pulmonary and cerebral AVMs. HHT2 (OMIM 600376) is caused by mutations in the ACVRL1 (activin receptor–like kinase 1 or ALK-1) gene⁷⁴ and is associated with a milder pattern of disease expression and later age at onset. About 20% of HHT families remain unclassified after mutation analysis of these two genes, thus suggesting that other genes may be implicated.⁷⁵ Indeed, in 2005 Cole and coworkers identified a new locus for HHT (HHT3) mapped to chromosome 5q31.3-32, although the causative gene remains unidentified.⁷⁶ Mutations affecting the two genes endoglin (HHT1) and ALK-1 (HHT2) can partially explain the phenotypic heterogeneity of HHT, such as disease severity, variation in organ involvement, and age at onset. Distinct genotype-phenotype correlations do exist; for example, HHT1 is associated with a higher incidence of pulmonary and cerebral AVMs. Distinct mutations within the ALK-1 locus itself also appear to be linked to specific phenotypic traits⁷⁷; however, the severity and type of clinical manifestations can differ even among family members carrying the same mutation,⁷⁸ which suggests that epigenetic factors, such as the environment, blood pressure, or hormonal factors, may influence the clinical manifestations. Modifier genes may act to alter expression of the clinical characteristics.⁷⁹ This is supported by murine models of HHT that show different phenotypic traits based on the background strain,⁸⁰ thus suggesting that the genetic background modifies clinical expression of the disease. A subset of patients with a combined syndrome of juvenile polyposis and HHT (OMIM 175050) harbor mutations in the MADH4 gene.⁸¹

Linkage analysis in 1994 first mapped HHT to chromosome 9q33-q34.1,^68,69 where endoglin was previously mapped in 1993.⁷³ Subsequent testing confirmed endoglin as the disease-associated gene for HHT1.⁷² Endoglin is a receptor for transforming growth factor-β (TGF-β), specifically, the type III TGF-β receptor, and endoglin is the most abundant TGF-β binding protein in endothelial cells (ECs).⁶⁰ Subsequently, mutations in another gene at the 12q locus were identified that affect ALK-1.⁷⁴ ALK-1 is a member of the type I TGF-β receptor family

The TGF-β superfamily of proteins is involved in many functions, including vasculogenesis, wound repair, and angiogenesis. TGF-β itself is a potent angiogenic factor that plays important roles in tissue repair, growth, and differentiation. Endoglin, a type III TGF-β receptor, is a membrane glycoprotein with a molecular weight of 180 kD.⁶⁰ By associating with the TGF-β type II and type I receptors (ALK-5 and ALK-1) at the cell surface, endoglin acts as a component of the type I TGF-β receptor complex, which binds TGF-β isoforms.^82,83 Its expression is limited primarily to ECs and activated monocytes. Knockout mice lacking endoglin die during gestation secondary to defective vascular development, thus suggesting that endoglin is critical for vascular development. Mutated forms of endoglin may act as a dominant negative protein.⁸⁴ However, studies of ECs and monocytes in both cerebral and pulmonary AVMs from patients with HHT1 have shown that normal endoglin dimers are still expressed at the cell surface but are reduced by 50% in comparison to normal individuals. No mutant endoglin was expressed on the cell surface but instead was found only as an intracellular homodimer.⁸⁵ Such studies suggest that the mutant form of endoglin is not secreted to form heterodimers at the cell surface and is therefore unlikely to act as a dominant negative protein. This supports a model of haploinsufficiency,⁷⁵ namely, that reduced levels of functional endoglin are the mechanism by which vascular abnormalities occur in HHT1. Because there is still some normal endoglin expression, the AVMs cannot be attributed to loss of heterozygosity and complete loss of endoglin expression.⁸⁶

Like endoglin, ALK-1, one of the type I TGF-β receptors, is expressed exclusively on ECs. Mutations of the ALK-1 gene in HHT2 patients indicate that ALK-1 also plays an important role in vascular development.⁸⁷ Mice lacking ALK-1 die during gestation, similar to endoglin knockout mice. They exhibit vascular abnormalities, including hyperdilation of vessels and abnormal fusion of capillary structures.⁸⁸ The mutations that have been identified in patients with HHT2 appear to result in disruption of the activity of translated protein or instability of mutant mRNA. ALK-1 levels are reduced in ECs from patients with HHT2.⁸⁹ Therefore, reduced expression of ALK-1 appears to be the primary defect in HHT2, as with endoglin in HHT1. In fact, most mutations of endoglin and ALK-1 identified to date in patients with HHT create null alleles that lead to reduced message or protein levels. This supports haploinsufficiency as the predominant mechanism, with inheritance of a mutation leading to reduced levels of the protein on the surface of vascular endothelium and predisposing affected individuals to the development of HHT-associated vascular lesions.⁹⁰ The precise mechanism by which endoglin and ALK-1 mutations result in vascular abnormalities is unknown, but both proteins play a role in TGF-β signaling. Binding of TGF-β to type II TGF-β receptors, which is accelerated in the presence of endoglin, results in phosphorylation of the TGF-β type I receptors ALK-I and ALK-5. Phosphorylated ALK-1 and ALK-5 activate downstream proteins, known as Smad proteins, that enter the nucleus and regulate gene transcription involved in angiogenesis.⁹¹