Cerebral Cavernous Malformations, Developmental Venous Anomaly, and Its Coexistence: A Review

Cerebral cavernous malformations (CCM) are intracranial vascular malformations that can exist as a single or mixed vascular lesion. The most common mixed form is the coexistence of CCM with an associated developmental venous anomaly (DVA). These lesions follow a benign course as individual lesions but have a high risk of hemorrhage when they occur together. In this paper, we discuss in detail the topic of CCM, DVA, and their occurrence as a mixed vascular malformation.

Intracranial or cerebral vascular malformations are a group of vascular lesions with varying hemodynamic or structural properties (Fig. 1). Aneurysms – abnormal saccular outpouchings of the cerebral arteries [1]. Moyamoya disease – chronic occlusive cerebrovascular disease resulting in progressive stenosis of the internal carotid artery and its branches [2]. Capillary telangiectasia – dilated thin-walled capillaries due to the absence of smooth muscle or elastic fibers [3]. Arteriovenous malformations – clusters of abnormal arteries and veins with an increased risk of intracranial bleed, more common in young adults [4]. DVAs – most commonly encountered malformation involving the intracranial venous system, which are also known as venous angioma, cerebral venous medullary malformation, or cerebral venous malformation [5]. CCM – vascular spaces of varying sizes, lined by a single layer of endothelin with no distinct features of arteries or veins [6]. Mixed vascular malformation – coexistence of vascular malformations and the most commonly encountered form is a CCM that occurs in association with a DVA [7].

CCMs are also called as cavernous angioma, cavernous hemangioma, or cavernoma.

Hereditary or familial CCM – this constitute about 20% of all cavernomas in patients, has a positive family history, and it commonly occurs as multiple lesions. It occurs from autosomal dominant mutation of 3 genes CCM1, CCM2, and CCM3 [8] (Table 1). In most cases, it can be a nonsense, frameshift, or splice site mutation, resulting in a nonfunctional protein product. In some cases, there can be a deletion or duplication of multiple exons or the entire gene [9]. Sporadic CCM – sporadic cavernomas are less common and occur as single lesions. They are usually asymptomatic and may occur in association with a DVA [10].

CCMs have an incidence of <1%, an annual hemorrhage risk of up to 3%, and a rebleed risk of 4.5–23% per year [12]. They are the second most common form of intravascular malformations, after DVA. The malformations can be present in any age group, though it is found to be more common during the third decade of life [10]. A prospective imaging study done in the Mayo Clinic involving 4,721 individuals of ages between 50 and 89 years found an overall prevalence of 0.46%, with a slightly higher prevalence among men than among women [13]. The overall prevalence of familial CCM is about 1:3,300–1:3,800, and the occurrence of symptomatic hereditary mutations is approximately 1:5,400–1:6,200 [14]. There are studies that suggest a higher occurrence of familial CCMs in patients with a Hispanic ancestry of Mexican or southwest US-American descent [15, 16].

CCMs are single-layer endothelin-lined vascular spaces without intervening brain parenchymal tissue within them [17]. There is low pressure and slow flow of blood within the lesion, which results in thrombus formation, followed by its organization, and this occurs in a repetitive fashion. These features are grossly visualized as the characteristic “mulberry appearance” [18]. There is insufficiency of the tight and adherens junctions of the endothelial cells, resulting in leaking and a dysfunctional blood-brain barrier [14].

CCMs can have varied presentations depending on the location of the lesion. They can be supratentorial, which affects the cerebral cortex, and infratentorial, affecting the brainstem or the cerebellum; however, most of them are supratentorial lesions [19]. When these lesions become symptomatic, it can have a wide array of clinical presentation that includes seizures, hemorrhage, headache, and focal neurological deficits [20]. Supratentorial lesions have been found to present more commonly with seizures, whereas infratentorial malformations present with focal neurological deficits [21]. There are studies that try to explain the natural course of hemorrhage occurring in patients with CCM [22, 23]. Gross and Du [24] summarized the risk factors for hemorrhage in these patients, which included prior hemorrhage from a cerebral cavernous angioma, female sex, and brainstem location of the lesion. Cavernous angiomas are a rare cause of an isolated non-aneurysmal SAH, and very few cases have been reported [25].

CCM diagnosis is particularly challenging to the practicing physicians because they tend to be angiographically occult due to the slow blood flow through them. Due to their increased potential of recurrent bleeding, early detection and prompt management are demanded [9].

CT scans can detect lesions that are complicated by hemorrhage or calcification but lack the sensitivity and specificity to detect smaller lesions; hence, it is not the primary modality for diagnosis of these lesions [26].

MRI has been found to show a higher specificity to detect both symptomatic and asymptomatic lesions as well as cavernomas located in the posterior cranial fossa or the brainstem [27, 28]. Based on the MRI images, cavernous angiomas can be classified into 4 types (Table 2). The MRI findings of cavernomas can also be seen in other disease conditions like hemorrhagic neoplasms or metastasis, calcification of neoplasms, cryptic vascular malformations, oligodendrogliomas, and pleomorphic xanthoastrocytomas [29].

Gradient recall echo (GRE) MRI is used for the accurate detection of CCM due to the characteristic hypointensity produced due to detection of hemosiderin-filled brain parenchyma [31]. Microhemorrhages seen on GRE MRI sequences are also a finding in elderly patients with hypertension and cerebral amyloid angiopathy [32].

Susceptibility-weighted (SW) MRI is more precise in detecting vascular malformations due to its high sensitivity to deoxyhemoglobin and iron content [33]. This is the only imaging method that can detect capillary telangiectasias and cavernomas that are nonhemorrhagic [34]. A study in 2008 has shown that the detection rate of familial CCMs by SW MRI was 1.7 times higher than that by T2/GRE MRI [35]. Though it can detect multifocal familial CCMs, it has not been proven superior to T2/GRE MRI. SW MRI is also not sensitive in detecting sporadic or solitary CCMs and CCM lesion associated with DVA and differentiating small venous structures from microhemorrhage and thrombosis [36].

Diffusion tensor MRI and functional MRI are used to visualize the lesions and surrounding brain tissue intraoperatively to improve the outcome of the surgery. Diffusion tensor MRI helps identify and avoid resection of areas like the white matter tracts, helping reduce the surgery-associated morbidity. Functional MRI helps assess cerebral blood flow to parts of the brain in association with activity, which helps assess the essential areas, thus aiding surgical resection of CCM [30].

Familial CCM patients should undergo a direct genetic sequencing of CCM1–3, followed by a deletion or duplication analysis. This has shown a detection rate of approximately 75% of all cases with multiple lesions [9].

One study has described an algorithm summarizing the treatment options for cavernous angioma when it is diagnosed on a brain MRI: If the lesion was diagnosed incidentally and has no clinical manifestations, it only requires conservative management irrespective of the location and yearly MRIs to assess the growth of the lesions. If the lesion has a severe clinical presentation, surgical management with either microsurgical resection or stereotactic radiosurgery was suggested [31].

Depending on the location of the CCM and the age of the patient, asymptomatic lesions can be treated by regular follow-up [37]. This is also preferred if the patient has increased risk associated with surgery. There are no set guidelines currently available for determining the frequency of imaging for follow-up [38].

Surgical resection is the most preferred form of intervention for CCM. Selection of a procedure depends on the location and severity at the presentation, which includes intractable seizures, progressive neurological deterioration, one severe hemorrhage in a non-eloquent region of the brain, or at least 2 severe hemorrhages in eloquent regions of the brain [31]. A complete resection of the lesion is mandatory due to the increased risk of hemorrhage and seizures due to remnant tissue [38]. The procedure can also be complicated by occurrence of gliosis, calcification, and hyaline degeneration following resection of the lesion [39]. The removal of hemosiderin ring should be done in patients who undergo seizure surgery. Due to an increased risk of hemorrhage from remnants, an MRI is recommended within 72 h post-surgery [40]. Microsurgical resection that is done more using intraoperative imaging helps reduce the risk of surgical complications, making it a preferred modality for the treatment of cavernous angiomas [41].

When cavernous angioma is inoperable or carries with it a higher surgical risk, stereotactic radiosurgery may be used as an option for treating the lesion, though there is controversy about its effectiveness and concern about complications like radiation-induced genesis of new cavernomas [42]. Niranjan and Lunsford [43] proposed a guideline to select patients for stereotactic radiosurgery. It includes factors like age of the individual, location of the lesion, the risk of hemorrhage, the risk associated with surgery, and the history of previous hemorrhages.

There are no medications currently useful for treating CCM. The medications used are for treatment of clinical symptoms like seizures. Rosenow et al. [44] proposed a guideline for diagnostic evaluation and therapy for patients with seizures that occur in association with CCM (Table 3). Conservative management is preferred over surgery in these patients due to the low risk of seizure occurrence in patients with cavernomas. Headache is the most common symptom of CCMs. Standard migraine therapy is considered for those patients who meet the criteria for migraine [9]. Though some studies have shown a likely safety of antiplatelet and antithrombotic medications in lowering the bleeding risk in preexisting CCM, these studies have limitations [45, 46].

DVAs are the most frequently encountered intracranial malformations on imaging.

DVAs have an incidence rate of >2% based on both autopsy and imaging studies [47]. The hemorrhagic risk of DVA is considered <0.7% and has been seen more in patients having lesions in the posterior fossa or in pregnant patients [48].

The exact etiology of DVA is not known and is thought to develop as a compensation to the absence of normal vessels resulting from hypoplasia, aplasia, or an early occlusion of the developing veins [49].

DVAs are radial clusters of dilated centripetally draining medullary veins, typically called the “caput medusa” that converge into a common collecting vein, which drains the normal brain parenchyma [50].

DVAs were thought to be very rare lesions in the past, and with diagnostic MRI being used more, the number of cases that are diagnosed has also increased. DVAs are benign and asymptomatic in most scenarios. Acute thrombosis of the collecting vein may result in venous infarction of the surrounding brain parenchyma [51, 52]. The pathophysiological mechanisms underlying symptomatic DVA are explained in Table 4.

DVAs can be diagnosed with a CT or an MRI and digital subtraction angiography, which is the gold standard for diagnosis as it helps study the flow of blood through the various channels of a DVA [50]. Regardless of the imaging modality that is used, DVA diagnosis depends on identifying the area of caput medusa that drains into a common collecting vein. In a CT without contrast, the collecting vein appears isodense and the acute thrombosis becomes hyperdense. It also helps in detecting calcifications, white matter lesions, atrophy, and hemorrhage associated with DVA [50]. Non-contrast MRI may show phase-shift artifact and flow voids caused by the larger radical venous branches and the collecting vein [54]. Contrast-enhanced CT or gadolinium administration with MRI has been found to demonstrate DVAs by showing marked enhancement of the radial veins and the main collecting vessel [55]. GRE or SW MRI helps in detecting any acute parenchymal bleed or intravascular thrombosis [51].

DVAs that are asymptomatic or found incidentally are not treated. Though no large-scale controlled studies exist to support use of anticoagulants, it has been recommended in symptomatic, thrombosed venous angioma after extensive evaluation of affected patients for additional hemorrhagic risks [48]. Surgical excision of a DVA can result in venous congestion, leading to severe venous infarction thus favoring conservative management. Surgery is indicated in patients who present with a massive intracerebral hematoma and since they drain normal brain tissue radiosurgery is contraindicated [56].

The coexistence of CCM and DVA is the most common form of mixed intracranial vascular malformation.

A retrospective study of parenchymal abnormalities associated with DVA showed that approximately 13% of patients who had a cavernoma had an associated venous anomaly [57]. Hemorrhagic complications that occur in cases with a coexisting cavernoma with DVA is higher than an isolated cavernoma [58]. Mixed vascular malformations are currently being diagnosed at a higher rate, and there are reports on literature that suggest a causal relationship between a CCM and a DVA [59, 60].

DVAs are considered to play the evolutional role in the development and growth of CCM. The probable pathogenesis of this development is explained in Figure 2.

The use of contrast-enhanced MRI has shown to increase the detection of cavernous angiomas with coexistent DVAs, and the use of T2-weighted gradient echo MRI or SW images may help to identify these combined lesions [63, 64].

Surgical excision is a commonly accepted treatment option for patients with symptomatic cavernous angioma, and when associated with a DVA, the venous anomaly should be spared due to the potential danger of devastating venous infarction. Treatment of these lesions should be decided by gauging risks versus benefit of surgery over the natural course of these lesions [65].

CCMs and DVAs are intracranial vascular malformations whose natural history is still not well understood. Individually, these lesions have a benign natural course; however, when they coexist in the same individual, the hemorrhagic risk is increased, which prompts for rapid diagnosis and treatment. An MRI is helpful in the detection of individual and mixed vascular malformations. Conservative management for asymptomatic lesions and surgery for clinically symptomatic lesions appear to be a satisfying approach for the treatment of these CCM. Surgery is avoided in DVA patients due to the risk of thrombosis and infarction. In mixed lesions, if indicated, only the cavernoma is surgically resected and the DVA is left untouched.

Further studies are also necessary to understand more about the following: The natural course of CCMs, DVAs, and mixed malformations. Assessment and screening of patients presenting with hemorrhage from single or multiple lesions. Guidelines to follow for the diagnosis of individual and mixed vascular malformations as well as the imaging modalities that can be used for rapid detection of such lesions. Comparison studies to assess the efficacy of the different imaging options that are available. Determine the efficacy of medical treatment options in place of surgery.

The authors declare that they have no conflicts of interests.

All authors have been involved in the preparation of the manuscript. All authors have read and approved the manuscript. The corresponding author has full access to data and has the right to publish this paper.