Pathology of Cerebral Arteriovenous Malformations in Children

Pathophysiology

• Unclear pathogenesis: There is much debate regarding whether AVMs are congenital, develop after birth, or perhaps both (45). Dysregulation of BMP/TGFβ and VEGF/VEGFR signaling appears to contribute to the pathogenesis of cerebral AVMs (46). Abnormal patterns of angiogenesis and inflammation suggest these lesions may form due to dysregulated “response-to-injury” mechanisms (47).
• Mechanisms of enlargement: Expansion of AVMs may be due to mechanical dilatation secondary to increased blood flow through poorly differentiated vessels and recruitment of arterial feeders, or through VEGF-mediated angiogenic mechanisms (48,49).
• Pathophysiology of AVMs: These vascular malformations are characterized by AV shunting between feeding arteries and draining veins connected through a complex nidus of abnormal vessels that lacks a network of intervening capillaries (50).
• Intracranial hemorrhage: AVMs are thought to have weakened blood vessels that are prone to rupture, leading to ICH (51). Intracerebral hemorrhage is the most common subtype of ICH caused by AVMs, followed by subarachnoid and intraventricular hemorrhage (52).
• Seizures: Seizures may be caused by AVMs, particularly larger ones, due to altered hemodynamics, irritation of brain parenchyma, mass effect, or hemorrhage (53,54,55).
• Vascular steal phenomenon: Although controversial, it has been proposed that steal phenomenon from high-flow AV shunting may reduce cerebral perfusion pressure, leading to focal neurological deficits in patients with AVMs (56).
• Headaches: Migraine-like headaches at presentation may be due to increased intracranial pressure, cerebral steal phenomenon and ischemia, or cortical spreading depression (57).

Molecular/Genetic Pathology

• Dysregulated BMP/TGFβ and VEGF/VEGFR signaling: Dysregulated BMP/TGFβ and VEGF/VEGFR signaling may contribute to abnormal angiogenesis (46). Expression of VEGF is elevated in cerebral AVMs and may contribute to the formation of dysplastic vessels (58).
• Insights from CM-AVM: RASA1 mutations in CM-AVM are associated with the development of AVMs. This gene encodes for a regulator of the Ras/MAPK signaling pathway, suggesting that aberrant Ras/MAPK signaling (which affects cellular differentiation and proliferation) may lead to abnormal angiogenesis in AVMs (59).
• Insights from HHT: HHT type 1 is associated with ENG mutations and is the HHT subtype most associated with cerebral AVMs. ENG encodes for endoglin, which affects BMP/TGFβ and VEGF/VEGFR signaling and is important for robust vascular patterning (60,61). This further supports the notion that dysregulation of BMP/TGFβ and VEGF/VEGFR signaling is involved in the pathogenesis of AVMs. Furthermore, brain AVMs are observed to both develop and spontaneously resolve in patients with HHT (122).
• Vascular instability: Matrix metalloproteinases are proteolytic enzymes that catalyze the degradation of extracellular matrix proteins. Matrix metalloproteinase-9 has been found at increased levels in cerebral AVMs, which may contribute to vascular instability (ultimately leading to rupture) within these lesions (51).
• Sporadic AVMs: A large whole-genome sequencing study identified involvement of the KRAS gene in sporadic AVMs: specifically, somatic mutation of the KRAS gene in endothelial cells may be associated with AVM formation (41,62).

Histopathology

• Direct AV connections without capillaries: These lesions consist of direct arterial-to-venous connections without an intervening capillary bed and can occur in the cerebral hemispheres, brainstem, and spinal cord (49). Functional neural tissue is absent within the lesion (49).
• Abnormal vessels: Lack of intervening capillaries leads to high flow through the nidal vessels, which may contribute to vessel remodeling (63). This produces widened vessels, venous ectasias, intranidal aneurysms, and aneurysms of arterial feeders (63).
• Microscopic findings: Dilated nidal vessels lacking smooth muscle, microhemorrhages, inflammatory infiltration, and hemosiderin deposition may be observed (63,64).