Pathology of Vein of Galen Malformations in Children

Pathophysiology

Embryology

Raybaud et al. (7) proposed an embryological model of VOGM genesis with the following features:

• Persistence of the median prosencephalic vein: These congenital lesions are characterized by a persistent median prosencephalic vein, which normally regresses by the eleventh week of embryonic development.
• AV fistula with arterial feeders: The lesion consists of an AV fistula with multiple feeding arteries derived from branches of the anterior cerebral artery, anterior choroidal artery, posterior choroidal arteries, and thalamic perforators, among others.
• Mechanism of dilation and failed regression: Persistent arterial shunting from these feeders into the median prosencephalic vein results in its dilation rather than regression. This produces the dilated midline venous sac characteristic of VOGM.
• Abnormal venous drainage: High-flow conditions may lead to persistence of the fetal circulation pattern, which can result in the retention of the falcine sinus and other abnormal venous drainage patterns.

3D reconstruction of a VOGM with associated vasculature: A dilated sac in the midline indicates the position of the VOGM, which receives arterial feeders from branches of the PCA and pericallosal artery. The VOGM is drained via the persistent falcine sinus, which empties into the torcula.

Patterns of Organ Failure

• High-output heart failure: High flow across the AV fistula produces high-output heart failure (39,40). Increased right-sided preload augments flow across the pulmonary vasculature, leading to pulmonary hypertension. Decreased perfusion of the myocardium during diastole reduces myocardial perfusion, and myocardial ischemia may occur (41). In conjunction, these factors contribute to heart failure.
• Multiorgan damage and failure: Decreased perfusion of the periphery — due to the AV shunt and, later, high-output heart failure — can produce multiorgan damage and failure (32,33).
• Arterial steal with neurological consequences: Arterial steal in the cerebral vasculature, due to the AV fistula, can lead to brain developmental abnormalities, brain atrophy, and seizures (42).
• Venous hypertension: Venous hypertension from the high-flow shunt may also precipitate brain developmental abnormalities, brain atrophy, and seizures, or a communicating hydrocephalus (39).
• Obstructive hydrocephalus: The dilated median prosencephalic vein may also exert local mass effect and occlude the cerebral aqueduct, causing an obstructive hydrocephalus that may contribute to brain injury (43).
• Patterns of brain injury: Brain injury can manifest first as delayed development. The progressive loss of brain volume and accumulation of calcified deposits caused by VOGMs is also known as “melting brain syndrome” (44).
• Communicating hydrocephalus: High flow across the AV fistula, overwhelming the venous drainage, results in cerebral venous hypertension (39). As a result, resorption of CSF is impeded, which can cause hydrocephalus.

Molecular/Genetic Pathology

The molecular mechanisms underlying the impaired regression of the median prosencephalic vein are poorly understood. Many gene variants associated with VOGM have been reviewed (12), including:

• Mutations of RASA1: Variants of RASA1 are associated with CM-AVM syndrome. RASA1 is robustly expressed in tissues derived from the ectoderm, including the brain, although the role of RASA1 variants in the pathogenesis of VOGM is unclear (12).
• Mutations of ENG and ACVRL1: Variants of ENG and ACVRL1 are associated with HHT. ENG and ACVRL1 are expressed in human vascular endothelium and encode members of the TGF-β receptor family. Thus, disruption of TGF-β and BMP signaling in the vascular endothelium may contribute to VOGM genesis (12).
• Mutations of EPHB4: Variants of EPHB4, which have been linked to defects in cardiovascular development, have been associated with VOGM (45-47).

Histopathology

• Dilated venous sac in the midline: Biopsy of a VOGM is not routine. Postmortem studies, however, have revealed anatomical and histopathological characteristics of VOGM. The characteristic lesion of a VOGM is a dilated venous sac in the midline (7).
• Weak venous wall partially responsible for dilation: The persistent median prosencephalic vein lacks a supportive fibrous wall, allowing it to dilate considerably due to high flow across the AV fistula (39).