Cavernous angioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD

Cavernous angioma, also known as cerebral cavernous malformation (CCM) or cavernoma, is a rare disease that involves the capillaries of the central nervous system. CCMs have dilated endothelial-lined sinusoidal capillaries which lack intervening neural tissue. This is the only characteristic that can distinguish these lesions from capillary telangiectasia.

CCMs can be classified as sporadic or familial, which has an autosomal dominant form of inheritance. The majority of CCMs are recent and remote hemorrhages. These lesions range in size from millimeters to almost less than 3 centimeters in diameter.

Cavernous angioma, also known as cavernous hemangioma, cavernoma, and cerebral cavernous malformation, is a vascular malformation with still an unclear history of its first clinical discovery.

Developmental venous anomaly (DVA) can cause a chronic increase in intracranial pressure which can form microhemorrhages around DVA, leading to the development and growth of cavernous angioma. There are two patterns of cavernous angioma, the sporadic and the familial pattern.

There are no established causes for cavernous angioma.

Cavernous angioma appears very similar on magnetic resonance with calcified neoplastic and hemorrhagic lesions, most especially renal cell carcinoma, melanoma, pleomorphic xanthoastrocytomas, and oligodendrogliomas.

Cavernous angioma is the second most common form of intravascular malformation next to the developmental venous anomaly (DVA). The incidence in the general population is between 0.1–0.5%, and symptoms usually manifest in the third to fifth decade of life. Once thought to be strictly congenital, these vascular lesions have been found to occur de novo.

Family history increases the risk of having cavernous angioma. Genetic testing is recommended for the pathogenic variants of cavernous angioma (KRIT1, MGC4607, and PDCD10).

Cavernous angioma is usually a benign course since it is a low-flow and low-pressure lesion. Patients with cavernous angioma have variable signs and symptoms, with seizure as the most predominant symptom, followed by hemorrhage and focal neurologic deficit.

CCMs have varying presentations and these can be in the form of hemorrhagic stroke, focal neurological deficits, recurrent headaches, and seizures. Howevever, CCMs can be asymptomatic sometimes.

Cavernous angioma, also known as cavernous hemangioma, can affect several organs. Diagnosing this condition should be correlated with imaging findings.

CT scan is not usually used as a primary modality to diagnose cavernous angiomas due to the inability to detect smaller lesions despite the ability to detect lesions complicated by calcification or hemorrhage.

Diagnosis can be made through incidental findings from magnetic resonance imaging (MRI) screening. A gradient-echo sequence should be utilized to unmask punctate lesions which can go undetected. These lesions are more visible on FLAIR imaging than on T2 weighing. As compared to T2 weighing, FLAIR imaging has more suppression of free-flowing fluid signals.

A cerebral angiogram or magnetic resonance angiogram (MRA) is usually requested as lesions can go undetected in MRI. If a lesion is discernible via angiogram in the same location as in the MRI, then an arteriovenous malformation (AVM) becomes the primary concern.

There are no other imaging findings associated with cavernous angioma.

Diagnostic biomarkers can be utilized too in conjunction with imaging tools to identify cavernous angioma.

Surgery is the mainstay treatment for cavernous angioma. Complete surgical resection should be done to prevent seizures and hemorrhage due to remnant tissue.

Since cavernous angioma can be treated via medical or surgical option, therapy for this condition is relatively cost-effective.

Several insights on development of cavernous angioma exist. Some drugs have been identified to be able to reduce risk of hemorrhage, and possible development of new lesions. Advances in biomarkers are now being studied more.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD

Cavernous angioma, also known as cavernous hemangioma, cavernoma, and cerebral cavernous malformation, is a vascular malformation with still an unclear history of its first clinical discovery.

• Recognition of the first discovery of cerebrovascular angioma is still unknown. ^[1]
• In 1934, Walter Dandy performed the first successful surgical removal of cavernous angioma.^[2]
• Virchow was the first person to classify cerebrovascular malformations. Subsequent studies regarding the classification of this pathology were conducted mostly in Germany.^[1]
• The advent of cerebral angiography paved the way for a better understanding of the context of “cryptic” or occult vascular malformations. ^[1]
• McCormick clarified the current pathological features of cavernous angiomas, which are now being correlated with magnetic resonance imaging (MRI) findings. ^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D, M.D.

Developmental venous anomaly (DVA) can cause a chronic increase in intracranial pressure which can form microhemorrhages around DVA, leading to the development and growth of cavernous angioma. There are two patterns of cavernous angioma, the sporadic and the familial pattern.

In up to 30% of cases, there is a coincidence of cerebral cavernous malformation (CCM0 with a venous angioma, also known as a developmental venous anomaly or DVA). These lesions appear either as enhancing linear blood vessels or caput medusae, a radial orientation of small vessels that resemble the hair of Medusa from Greek mythology. These lesions are thought to represent developmental anomalies of normal venous drainage. These lesions should not be removed, as reports of venous infarcts have been reported. When found in association with a CCM that needs resection, great care should be taken not to disrupt the angioma.

Left Orbital Cavernous Hemangioma

Frontal and temporal lobes are the most common sites of occurrence, and 80-90% of the lesions are supratentorial.

CCM can also be subdivided into two categories, according to its pattern of occurrence: ^[1]

• Familial or Hereditary CCM
  • Constitutes 20% of all cavernous angioma cases
  • Occurs as multiple lesions
  • Can have frameshift, nonsense or splice-site mutations
  • Can also have deletions or duplication of exons ^[1]

• Sporadic CCM
  • Occurs as single lesions ^[2]

Genes involved in the pathogenesis of cavernous angioma include: ^[3][4][5]

• Cavernous angioma is diagnosed using clinical imaging.

• Key feature: Absence of muscular layer in the vessel wall.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

There are no established causes for cavernous angioma.

• The exact etiology of cavernous angioma is still unknown.

• However, it is believed that cavernous angioma usually arises as a result of aplasia, hypoplasia or occlusion of newly formed veins at an early stage of development.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D, M.D.

Cavernous angioma appears very similar on magnetic resonance imaging (MRI) with calcified neoplastic and hemorrhagic lesions, most especially renal cell carcinoma, melanoma, pleomorphic xanthoastrocytomas, and oligodendrogliomas.

Cavernous angioma can have a similar appearance in neuroimaging with other pathologies such as: ^[1]

• Hemorrhagic lesion
• Calcified neoplastic lesions
• Renal cell carcinoma
• Melanoma
• Pleomorphic xanthoastrocytoma
• Oligodendroglioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

Cavernous angioma is the second most common form of intravascular malformation next to the developmental venous anomaly (DVA). The incidence in the general population is between 0.1–0.5%, and symptoms usually manifest in the third to fifth decade of life. Once thought to be strictly congenital, these vascular lesions have been found to occur de novo.

• Cavernous angioma is the second most common form of intravascular malformation next to the developmental venous anomaly (DVA).^[1]
• The incidence in the general population is between 0.1–0.5%.^[1]

• With the advent of magnetic resonance imaging (MRI), cerebral cavernous malformations are currently the most commonly identified brain vascular malformations.

• These lesions are observed in 15-33% of spontaneous cases and can be seen mostly in familial or inherited forms which have a autosomal dominant pattern with variable expression. ^[2]

• Cavernous malformations can occur at any age, but they are most likely to become clinically apparent in patients around 37 years old.^[1][2]

• Although there is not enough evidence regarding the distribution of cavernous angioma among various races, there is a greater prevalence of cavernous angioma among Hispanic populations and Southwest US-American descent .^[3][4][5]

• Cavernous angioma is more commonly observed in men than in women. ^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

Family history increases the risk of having cavernous angioma. Genetic testing is recommended for the pathogenic variants of cavernous angioma (KRIT1, MGC4607, and PDCD10).

• There are three known genetic loci for cavernous angioma. These are CCM1, CCM2, and CCM3.
• CCM1 encodes for krev interaction trapped 1 (KRIT1) which binds to integrin cytoplasmic domain associated protein alpha (ICAP1-alpha), a beta-1 integrin associated protein. ^[1]
• CCM2 encodes for MGC4607. ^[1] The exact nature of CCM2 is still unclear. However, it has been proven that there is a macromolecularcomplex formed by CCM1 and CCM2 proteins and ICAP1 alpha inside the cell. Also, the CCM2 protein can serve as a scaffolding protein for enzymes like MAP kinases which is essential in p38 activation, responsible for regulation of osmotic stress including MEKK3 and MKK3. It also attaches to Rac and actin. Because of these, the CCM2 protein is oftentimes called osmo-sensing scaffold (OSM) for MEKK3.
• CCM3 gene is the most recently identified CCM gene. It was originally known as programmed cell death 10 (PDCD10) , which was thought to be responsible for upregulation of apoptosis (cell death) in TF-1, a human myeloid cell line. As of now, the specific role of the PDCD10 protein and its association with the CCM3 gene is not yet established.^[1]

• The mutations in the CCM1, CCM2, and CCM3 genes account for almost 70 to 80 percent of all cases of cerebral cavernous malformations. The rest has yet to be identified.

• A three-generation family history should be obtained at the time of diagnosis. More focus should be given to symptoms such as headache, stroke, any abnormal magnetic resonance (MRI) scan findings, or other neurological findings.
• In the setting of cavernous angioma, without an association of developmental venous anomalies, brain radiation history, or a family history of cavernous angioma, CCM 1-3 genes by Sanger or NextGen sequencing followed by duplication/deletion analysis should be considered.
• Counseling for the patient and family about autosomal dominant inheritance should be done when there is a positive proband.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

Cavernous angioma is usually a benign course since it is a low-flow and low-pressure lesion. Patients with cavernous angioma have variable signs and symptoms, with seizure as the most predominant symptom, followed by hemorrhage and focal neurologic deficit.

Once patients become symptomatic, 40-50% present with seizures, 20% present with focal neurologic deficits, and 10-25% present with intracerebral parenchymal hemorrhage.^[1]

• The risk of hemorrhage is not well established, but it is estimated to be 0.2-2% per lesion per year.
• This risk is increased in patients with established prior hemorrhage.
• The clinical consequences of hemorrhage vary such that location becomes important.
• Small hemorrhages in critical locations can have more severe effects, and thus, they are more likely to produce symptoms (e.g. brainstem involvement).
• Progressive neurologic deficits are more often associated with cavernous malformations in the infratentorial space and with lesions that demonstrate slow enlargement because of rebleeding episodes.

• The lesions do not usually produce life-threatening hemorrhages because most hemorrhages associated with the lesions are small and of low pressure. ^[1]
• Cavernous malformations can occur at any age, but they are most likely to become clinically apparent in patients aged 20-40 years.