Facial Venous Malformations Are Associated with Cerebral Developmental Venous Anomalies

Discussion

Our case-control study examining the prevalence of DVAs in patients with VMs and a group of control patients demonstrated a number of interesting findings. First, the prevalence of DVAs in the VM population was >2 times higher than that in the general population. Most interesting, more often than not, DVAs were located along the same metamere and/or side as the VM. These findings are important because they suggest that there may be a similar pathophysiologic or embryologic basis to both craniofacial VMs and intracranial DVAs.

Prior studies have demonstrated a possible association between DVAs and VMs. However, no case-control studies have been performed to date comparing the prevalence of DVAs in patients with VMs and in a group of patient controls without VMs. In a series of 40 patients who underwent cerebral angiography as part of the evaluation of facial venous vascular malformations, Boukobza et al⁷ identified 8 patients (20%) with complex DVAs, with most patients having multiple DVAs. Unlike Sturge-Weber Syndrome, these complex DVAs were associated with a normal superficial cortical venous system. Most DVAs were supratentorial and had large flaming venous radicles that drained into a tortuous deep venous system, and most were ipsilateral to the facial VM. One patient had a symptomatic cavernoma that required resection.⁷ Overall, the DVA prevalence rate and clinical presentation of these VM-associated DVAs are very similar to those seen in our patient population. A number of additional case reports have been published concerning patients with extensive facial venous malformations and associated ipsilateral DVAs. Such an association hardly appears to be coincidental.^{2,3,6,8⇓–10}

DVAs are thought to form in later periods of cerebral venous development as functional adaptations to thrombosis or failure of development of superficial or deep veins.¹¹ It is possible that early postnatal venous occlusion could trigger remodeling of medullary veins, thus resulting in DVA formation. Furthermore, when DVAs become symptomatic, it is invariably due to thrombosis of the collector vein or a venous radicle.¹¹ Nonetheless, the common final pathway is an error in vascular embryogenesis resulting in occlusion and maldevelopment of normal venous structures in a given part of the brain. To date, there have been no genetic mutations associated with DVA development.

Some authors have postulated that a similar error in vascular embryogenesis (ie, thrombosis resulting in occlusion and maldevelopment) affecting the craniofacial venous vasculature could result in the formation of VMs as well. Like DVAs, VMs generally do not develop de novo or proliferate and spread to other vascular beds in adult life. Most interesting, some authors have suggested that VMs are also thought to form due to a procoagulable state.^12,13 In a case-control study of patients with and without VMs, Dompmartin et al^12,13 found that 43% of patients with VMs have an elevated D-dimer level compared with just 4% of patients without VMs. Up to one-third of children with VMs have some form of prothrombotic coagulopathy.¹⁴ In another study, Dompmartin et al^12,13 found that almost 50% of patients with VMs have local intravascular coagulation, a factor thought to be responsible for VM enlargement and pain. So how can we explain the link between DVAs and extensive facial VMs in a more or less unilateral distribution in this patient population? Given that both VMs and DVAs are associated with some degree of prothrombotic state, we hypothesize that VMs and DVAs may develop due to an increased predilection for local venous thrombosis and occlusion, possibly due to a metameric disorder related to venous endothelial dysfunction.

Our study has both practical implications and implications for future research. First, on the basis of these findings, one might consider a whole-head MR imaging for patients with VMs to evaluate intracranial vascular abnormalities. Two patients had DVA-associated cavernomas, one of which developed de novo and was associated with clinical symptoms. Identification of extensive DVAs in the patient population with VMs could be used to select patients who may require closer imaging surveillance. Regarding implications for future research, the genetic and pathophysiologic mechanisms that result in the codevelopment of DVAs and VMs should be further studied. Three patients in our study had either a classic Sturge-Weber syndrome or a form fruste of Sturge-Weber. It is now well-established that Sturge-Weber is due to a somatic mutation in the GNAQ gene, which plays a role in expression of the endothelin in vascular endothelial cells.¹⁵ Meanwhile, somatic mutations in vascular endothelial cells of the PIK3CA gene are associated with the development of venous vascular malformations.¹⁶ Discovery of these genetic associations has led to promising research in targeted therapy for these diseases. It may be that patients with DVAs and head and neck VMs carry a common vascular endothelial cell somatic mutation. Further research into identifying genetic mutations in this patient population may provide insight into disease pathophysiology and targeted treatment of venous vascular malformations.