eMedicine Specialties > Radiology > Brain/Spine

Brain, Cavernous Angiomas

Author: James C Jacobsen, MD, Staff Physician, Vascular and Interventional Radiology, X-Ray Medical Group, Sharp Grossmont Hospital
Coauthor(s): L Gill Naul, MD, Professor and Head, Department of Radiology, Texas A&M University College of Medicine; Chair, Department of Radiology, Chief, Section of Magnetic Resonance Imaging, Scott and White Memorial Hospital and Clinic
Contributor Information and Disclosures

Updated: May 20, 2009

Introduction

Background

Cavernous angiomas belong to a group of intracranial vascular malformations that are developmental malformations of the vascular bed. These congenital abnormal vascular connections frequently enlarge over time. The lesions can occur on a familial basis. Patients may be asymptomatic, although they often present with headaches, seizures, or small parenchymal hemorrhages.

Frequency of vascular malformations

Generally, the relative frequency of vascular malformations as a cause of intracranial hemorrhage is approximately 5%. In particular, the risk of hemorrhage of cavernous angiomas is estimated to be less than 2% per lesion per year. As a cause of hemorrhage, cavernous angiomas are far less common than hypertension; nevertheless, as a cause of hemorrhage, they must be excluded, especially in young patients. Cavernous angiomas can also cause a variety of symptoms and neurologic findings similar to those of tumors.

Types of vascular malformations

Types of vascular malformations are differentiated from one another on the basis of their gross and histopathologic characteristics.

Traditionally, intracranial vascular malformations are grouped into 4 types, as follows:

• Capillary malformations (or telangiectasias)
• Cavernous malformations (cavernous angiomas/hemangiomas)
• Venous malformations
  • Venous angiomas
  • Vein of Galen malformations
  • Venous varix
• Arteriovenous shunting malformations
  • Parenchymal malformations
  • Dural arteriovenous shunting malformations (arteriovenous malformations [AVMs]) and arteriovenous fistulae
  • Mixed pial-dural AVMs

Newer schemes add the following 2 classifications:

• Arterial malformations (no arteriovenous shunting)
  • Congenital angiodysplasias
  • Intracranial aneurysms (berry/saccular, giant, serpentine)
• Mixed malformations
  • Venous cavernous type
  • AVM venous type
  • Cavernous AVM type

The evolution of such classification schemes has paralleled that for vascular anomalies in other organ systems. Classification based solely on descriptive terminology has given way to more precise pathoanatomic and embryologic definitions.

A vast amount of knowledge has been gained in understanding the natural history, pathophysiology, and cellular biology of CNS vascular malformations. Substantial advances in the cellular and molecular biology of the vasculogenesis, angiogenesis, and cardiovascular physiology of these anomalies and findings from detailed clinicopathologic and clinicoradiologic retrospective and prospective longitudinal studies have led to a better understanding of vascular malformations as a whole.

Pathophysiology

Grossly, cavernous angiomas are typically discrete multilobulated lesions that contain hemorrhage in various stages of evolution. Because they are lobulated and dark red to blue, the lesions grossly resemble small mulberries.

The histoarchitecture of the component vessels resembles that of capillary telangiectasias, consisting of a single layer of endothelium and differing quantities of subendothelial fibrous stroma, with distinct absence of smooth muscle and elastic fibers. The immaturity of the blood vessels within the cavernous angioma differentiates it from a venous angioma, which conversely consists of mature vessels responsible for normal venous drainage.

Cavernous angiomas are considered to be congenital vascular hamartomas composed of closely approximated endothelial-lined sinusoidal collections without significant amounts of interspersed neural tissue. The lack of intervening neural tissue is the only histopathologic characteristic that distinguishes these lesions from capillary telangiectasias. As a result, some authors have suggested that these 2 lesions actually represent a phenotypic spectrum within a single pathologic entity.

Nearly all cavernous malformations show evidence of recent and remote hemorrhage, as suggested by the presence of hemosiderin-laden macrophages, cholesterol crystals, and hemosiderin-stained parenchymal tissues. Clots and blood products of various stages of evolution within the lesion, as well as calcification and gliosis, often are seen. The lesions surround the cavernoma, creating the appearance of a pseudocapsule.

Cavernous angiomas vary from several millimeters to several centimeters (usually <3 cm) in diameter. Reendothelialization of the hemorrhagic cavities, growth of new blood vessels, and proliferation of granulation tissue may account for the apparent growth of some cavernous angiomas.

De novo pathogenesis may occur spontaneously or in association with a variety of events, such as biopsy or preexisting venous malformation. Some have proposed that persistent elevations in venous pressures, as may be seen locally within a venous malformation or telangiectasia, may promote a pathologic reactive angiogenesis or angiogenic proliferation, resulting in abnormal blood vessel growth and coalescence. Because cavernous malformations exhibit immunohistochemical characteristics of immature or new blood vessels in early studies, some have hypothesized that venous malformations may somehow promote conditions for the development and growth of cavernous angiomas.

Frequency

United States

Cavernous angiomas represent approximately 1% of intracranial vascular lesions and 15% of cerebrovascular malformations. With the advent of MRI, cavernous angiomas are currently the most commonly identified brain vascular malformations. In early studies of major autopsy reports, the calculated prevalence was 0.02-0.53%. MRI of lesions with the appearance of cavernous hemangiomas provided information that led to a prevalence of 0.39-0.9%. The detection of previously unidentified asymptomatic lesions by using MRIs has recently raised the estimated overall prevalence to 0.45-0.9%.

Multiple lesions are seen in approximately 15-33% of spontaneous cases, although one series reported an incidence as high as 50%. A familial form of the disorder exists and is inherited as an autosomal dominant trait with variable expression. Multiple lesions are more common in the familial form, occurring in as many as 73% of patients.

Cavernous angiomas also appear to be the most common CNS vascular malformation subtype in patients with mixed lesions. The most common combination includes venous malformations, which are identified in approximately 10-30% of patients with cavernous angiomas.

Mortality/Morbidity

Not all cavernous angiomas are associated with symptoms, but once patients become symptomatic, 40-50% present with seizures, 20% present with focal neurologic deficits, and 10-25% present with hemorrhage. Symptoms may progress rapidly, be stable for years; or wax and wane, as in multiple sclerosis.

Patients often present with only a headache, but the reliability of headache as a presenting symptom and etiology remains controversial. Headaches are estimated to be a relevant symptom in as many as 25% of patients. Acute headaches may result from parenchymal irritation secondary to gross or repeated extralesional hemorrhage. Chronic headaches are believed to be the result of mass effect in slow-growing larger lesions as a result of repeated intralesional hemorrhage.

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. In addition, women are at a slightly higher risk for hemorrhage, especially those in the first trimester of pregnancy. The lesions do not usually produce life-threatening hemorrhages because most hemorrhages associated with the lesions are small and of low pressure. The effects usually result from the location of the lesion and, at times, their slow expansion. However, the hemorrhage may be massive and sometimes fatal, but this is an uncommon exception.

Infratentorial location and previous gross hemorrhage are associated with increased risk of subsequent and progressive neurologic disability. When large enough, the hemorrhages can cause both obstructive and nonobstructive hydrocephalus.

Race

Although most cavernous angiomas are believed to be sporadic, many familial cases have been observed over the last 2 decades. These cases exhibit an autosomal dominant pattern of inheritance and seem to affect the Hispanic population in particular. Recent research has demonstrated at least 3 separate genes related to the familial form of the disease. Two of these genes have been precisely located. Current research is ongoing to more precisely locate the third.

The first gene is called CCM1 (for cerebral cavernous malformation 1) and is located on chromosome 7 at band 7q11.2-q21. It is also known as KRIT1, for the protein created by the gene. Of familial cavernous angiomas, 40% can be linked to a protein created by the gene. Of familial cavernous angiomas, 40% can be linked to a CCM1 genetic mutation. This is the gene responsible for most of the cases of familial multiple cavernous angioma in Mexican-American families and in a number of other families. CCM1, the KRIT1 gene, is responsible for creating KRIT1 protein, or Krev interaction-trapped 1 protein. The exact function of KRIT1 protein is not known. If both copies of the CCM1 gene mutate, the KRIT1 protein cannot function and cavernous angiomas form.^1,2

The second gene is called CCM2. It is located at band 7p15-p13 and controls the production of a protein named malcavernin. Of familial cavernous angiomas, 20% can be linked to a CCM2 mutation.^1,2

The third gene (CCM3) identified as linked to familial cavernous angioma is on chromosome 3 at band 3q. Research is ongoing to further delineate the function of this gene and its relationship to cavernous angiomas. As of January 2004, clinical diagnostic testing is available only for the CCM1 (KRIT1) mutation, but testing for CCM2 should become available shortly.^3,2

Further investigation into a possible genetic component to the pathogenesis of these malformations has led several groups to independently demonstrate either a common founder mutation on chromosome arm 7q or other point mutations responsible for familial cavernous malformations.

Sex

No sex predilection is reported.

Age

Cavernous angiomas can occur at any age, but they are most likely to become clinically apparent in patients aged 20-40 years.

Anatomy

Cavernous angiomas can be found in any part of the brain because they can occur at any location along the vascular bed. Frontal and temporal lobes are the most common sites of occurrence, and 80-90% of the lesions are supratentorial. The deep cerebral white matter, corticomedullary junction, and basal ganglia are common supratentorial sites, whereas the pons and cerebellar hemispheres are common posterior fossa sites.

Intracranial extracerebral cavernous angiomas also occur, but these are less common. They typically occur in the middle cranial fossa and originate from the cavernous sinus. Cavernous angiomas also can occur in the spinal cord, where they frequently coexist with multiple brain lesions.

Presentation

Patients with cavernous angiomas may remain asymptomatic, but they most often present with headache or neurologic symptoms after a hemorrhage or repeated hemorrhage.⁴ Clinically evident hemorrhage is the most worrisome consequence of cavernous angiomas. Like other sequelae, the highest incidence of hemorrhage occurs in patients in the second or third decade of life. Because of the extruded blood products and the fact that some angiomas can grow slowly, the lesions may also produce seizures and a variety of neurologic findings similar to those expected of tumors.

Any hemorrhage found on CT scans in a relatively young patient should be characterized further, and cavernous angioma must be considered a possible etiology. In the workup of a patient with a seizure disorder, cavernous angioma must be considered the underlying etiology, especially if the patient is aged 20-40 years.

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 (eg, brainstem involvement). Progressive neurologic deficits are more often associated with cavernomas in the infratentorial space and with lesions that demonstrate slow enlargement because of rebleeding episodes.

Although most cavernous hemangiomas can simply be followed up over time, surgical removal is an option in lesions causing significant morbidity. Because cavernomas are well circumscribed and surrounded by a gliotic rim, surgical removal is relatively simple. Control of hemorrhage is relatively easier because of the flow of blood through the lesions is slower than that expected in more highly vascularized lesions with higher flow rates.

Hauck et al analyzed the natural history of symptomatic brainstem cavernomas and outcome after surgical resection in 44 patients who presented with symptomatic brainstem cavernomas between 1995 and 2007. They found that after a first neurologic event, the median event-free interval was 2 years, with an annual event rate of 42%; after a second neurologic event, the median event-free interval was only 5 months, with a monthly event rate of 8%. In 95% of the patients, surgery prevented further events over a median follow-up of 11 months; the postoperative event rate was 5% per year in the first 2 years and 0% thereafter. The authors therefore suggested surgical resection for symptomatic brainstem cavernomas to prevent patients' functional decline owing to recurrent events.⁴

Preferred Examination

Although cavernous angiomas may be apparent and although they can be diagnosed by using CT scans, CT is not the imaging modality of choice. CT findings are compatible not only with cavernous angiomas but also with low-grade tumors, among other entities.

The sensitivity of MRI to flowing blood and blood products of varying ages, as well as the greater contrast resolution of MRIs, greatly increases the specificity of MRI compared with that of CT. Combining multiple MRI sequences has largely eliminated misdiagnosis of cavernous angiomas, because they have relatively specific signal characteristics. Additionally, gradient-echo imaging, with its increased sensitivity to susceptibility artifact, is useful in the detection of smaller and concomitant lesions, which may not be detected with traditional sequences.

CT and MRI can both be used in the follow-up monitoring of patients with known cavernous angiomas, particularly when hemorrhagic events are suspected. Although the MRI appearance of cavernous angiomas is not helpful in predicting future bleeds, MRI is the method of choice for the long-term follow-up of patients with cavernous angiomas and for the assessment of family members in whom similar lesions are suspected. In addition, MRI is extremely helpful in presurgical planning to assess the extent of the lesion, define borders, and plan the surgical approach and exposure.

Most cavernous malformations are angiographically occult, and when they are evident on angiograms, the findings are nonspecific. When the lesions occur in combination with other vascular malformations, as they do in as many as 30% of patients with venous malformations, MRI characteristics become more complicated and less specific. In these patients, angiography can be helpful in further defining the lesions.

Limitations of Techniques

CT has only a limited role in the diagnosis of cavernous angiomas, largely because of its relative lack of specificity. CT findings are compatible with low-grade gliomas, hematomas, granulomas, and inflammatory conditions such as tuberculomas and sarcoidomas. When calcified and located near the dura, cavernous angiomas can even resemble meningiomas. CT images also cause small lesions to be missed altogether, and cavernomas, when they present as acute intracerebral hematomas, may not be detected by using nonenhanced CT.

MRI may cause small lesions to be missed if T2-weighted pulse sequences, such as T2-weighted fast spin-echo sequences, are used because these can be less sensitive to chronic hemorrhage. Additionally, even standard T1- and T2-weighted images can fail to depict minute concomitant lesions. Therefore, T2-weighted gradient-echo sequences, with their increased magnetic susceptibility effects, always should be performed during an evaluation for smaller or multiple lesions that may not be visible on standard spin-echo images.

Differential Diagnoses

Other Problems to Be Considered

Cavernous malformations detected by using CT

Other occult vascular malformation (thrombosed AVM, capillary telangiectasia)
Glioma (low-grade astrocytoma or oligodendroglioma)
Metastatic melanoma

Cavernous malformations detected by using MRI

Other occult vascular malformation (thrombosed AVM/aneurysm, capillary telangiectasia)
Hemorrhagic primary or secondary neoplasm (metastatic melanoma, thyroid, renal cell, choriocarcinoma)
Amyloid angiopathy
Treated or prior infection (toxoplasmosis, cysticercosis)
Multiple hemorrhages associated with blood dyscrasia (disseminated intravascular coagulopathy, leukemia)
Sequelae of diffuse axonal injury

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