Continuing Education Activity

Cavernous angiomas, also referred to as cavernous malformations (CMs), cavernous hemangiomas, or cavernomas are benign intracranial vascular malformations that form during development. Vascular malformations involve every organ and are grouped into four types according to gross and histopathologic characteristics: capillary malformations, also called telangiectasias, cavernous malformations, also called cavernous angiomas or hemangiomas, venous malformations, and arteriovenous shunting malformations. This activity highlights the role of the interprofessional team in caring for patients with cavernous brain angiomas.

Objectives:

• Identify some differential diagnoses for cerebral microhemorrhage.
• Review the evaluation of new-onset seizure with the evaluation of focal neurologic deficits presumed to be due to recurrent hemorrhages.
• Explain how to proceed once a diagnosis of familial cerebral cavernous malformation has been made.
• Summarize a well-coordinated interprofessional team approach to provide effective care to patients affected by cavernous angiomas.

Introduction

Cavernous angiomas also referred to as cavernous malformations (CMs), cavernous hemangiomas, or cavernomas are a type of intracranial vascular malformation with a developmental origin. The terms 'haemangioma' and 'cavernoma' are a misnomer as the lesions are nonneoplastic.[1][2][3][4]

Vascular malformations involve invariably every organ of the body and are grouped into the following four types by their gross and histopathologic characteristics:

• Capillary malformations (or telangiectasias)
• Cavernous malformations (cavernous angiomas/hemangiomas)
• Venous malformations
• Arteriovenous shunting malformations 

All the types mentioned above involve the brain with various manifestations.

Etiology

Cavernous angiomas occur sporadically or in a familial pattern.  Serial magnetic resonance imaging (MRI) reveals de novo lesions in families with a genetic predisposition to cavernous angiomas. The de novo development of CMs after brain biopsy and after radiosurgery also provides substantial evidence for the developmental nature of these lesions. Familial cases show an autosomal dominant pattern of inheritance with incomplete penetrance. There are several reports regarding the hereditary mutations linked to three genetic loci (CCM1, CCM2, and CCM3) which are responsible for familial cerebral cavernous malformations. Approximately all familial cases of cavernous cerebral malformations among Hispanic Americans and non-Hispanic Families have been linked to a founder mutation of CCM1 localized to 7q  and CCM2 at 7p and CCM3 at 3q respectively. Furthermore, there is a belief regarding a "second hit mutation" necessary for the onset of the pathology. [5][6][7] 

Epidemiology

Cavernous angiomas of the brain and spinal cord occur at all ages, but frequently patients present symptomatically occur in the third to sixth decades life. There is no male or female genetic predisposition. Surveys suggest that cerebral cavernous malformation (CCM) is present in 0.5% of the population. However, it tends to become symptomatic in only 40% of the cases. Sporadically occurring malformations are usually solitary and tend to remain asymptomatic. Whereas familial CCMs are multiple in number and disposed to become symptomatic. The screening of family members is therefore indicated. Although the majority of CCMs are diagnosed in adults, 25% of cases have been found in children.

Familial multiple cavernous malformation syndromes are where the number of multiple lesions is typically 5 or more, and suffering individuals usually present with seizures and/or focal neurological deficits due to recurrent hemorrhages.

Pathophysiology

Grossly, cavernous malformations have a characteristic "mulberry" appearance with engorged purplish clusters of vessels. The diameter varies from 2 mm to several centimeters.

On microscopic examination, the cavernous angiomas consist of dilated, thin-walled capillaries with a simple endothelial lining and a thin, fibrous adventitia. Vessel walls lack elastic fibers and smooth muscles. The classic description of cavernous angiomas states no intervening brain tissue in between the vascular channels of the lesion. However, further studies noted intervening brain parenchyma in 70 percent of the lesions. The closely surrounding tissue is gliotic and hemosiderin-laden due to previous hemorrhages. It also contains dilated capillaries that may represent telangiectasias. Inflammation, calcification and, rarely, ossification can be found, usually in larger lesions. Developmental venous anomalies (DVAs) are also associated with cavernous malformations (10-20%) more often with lesions present in the posterior fossa than in the supratentorial compartment. A mixed vascular malformation (MVM) is a term used to describe the anomaly comprising of a developmental venous anomaly and a cavernous malformation. 

History and Physical

As earlier mentioned the majority of lesions remain asymptomatic throughout life while others present with a headache, seizure or focal neurological deficit due to hemorrhage. The risk of hemorrhage is more for familial versus sporadic cases. The bleeding tendency is also documented more with CMs that are associated with DVAs or atypical venous drainage. The presentation of cavernous malformations CMs is dependent on their location.

• Supratentorial CMs frequently present with hemorrhage, seizures, and focal neurological deficits. Several studies state annual bleeding rates of 0.25 to 1.1 percent. Mass effect, secondary compromise of the microcirculation, and/or microhemorrhages causing hemosiderin deposition irritating cortical or subcortical tissue are the possible underlying mechanisms.
• Infratentorial CMs usually present with recurrent hemorrhages and progressive neurological deficits. Lesions in the brain stem present with cranial neuropathies due to the presence of cranial nerve nuclei and their fiber tracts in the brain stem. The annual bleeding rate for brainstem lesions is 2 to 3 %, and recurrent hemorrhage rate is  17 to 21 percent. 70-90% of lesions occur in the cerebrum which is the most common location with the rolandic and temporal areas as most disposed sites. Posterior fossa lesions comprise approximately 25% total cranial cavernous malformation with the majority involving the pons and cerebellar hemispheres.

Evaluation

Radiological studies play a pivotal role in diagnosing cerebral cavernous angiomas with MRI as the modality of choice.[8][9][10]

Computed tomogram (CT) scanning plays only a limited role largely because of its relative lack of specificity. On nonenhanced, CT scan cavernomas may or may not be apparent. If visualized, they usually appear as focal oval or nodular lesions with mild-to-moderate increased attenuation. Lack of mass effect on the surrounding brain parenchyma is common unless a recent hemorrhage is present. CT scan demonstrates calcification in 33% of cavernomas. Surrounding mantle of edema is usually apparent if there is hemorrhage. Older lesions can contain central hypoattenuating non-enhancing areas or cystic cavities from reabsorbed old hematomas. Contrast enhancement can vary from minimal to prominent. Some studies report 70-94% of cavernous angiomas to demonstrate mild-to-moderate post-contrast enhancement which usually has a mottled or heterogeneous appearance. The peripheral rim of decreased attenuation is because of the pseudo capsule of gliotic tissue. Hemorrhagic events particularly those found in relatively young patients ought to be characterized further, and cavernous angioma should be considered among the possible etiologies.  Also because of their propensity to act as an epileptogenic focus CMs should always be considered in the workup of a patient with a seizure disorder, especially if the patient is aged 20-40 years.

MRI establishes the diagnosis. It demonstrates typical, smoothly circumscribed lesions with popcorn-like, mulberry like the pattern of variable signal intensities which are consistent with hemorrhage in various stages of evolution. The heterogeneous core typically is surrounded completely by a low-signal-intensity hemosiderin rim which is most apparent, or blooms, on T2-weighted and gradient-recalled images. Smaller cavernous angiomas are usually not apparent on conventional spin-echo sequences, and these smaller lesions are best-depicted Gradient echo or T2* sequences, or other susceptibility-weighted images (SWI). SWI imaging also plays an important role in identifying the number of lesions in patients with familial or multiple cavernous angiomas. SWI also has high sensitivity in detecting calcification.

If a recent bleed has occurred then surrounding edema or mass effect may be present. The lesions show a variable pattern of enhancement. Contrast-enhanced images help delineate any potential associated developmental venous anomalies. This is critical for preoperative surgical planning as the un-deliberate resection of DVAs may compromise normal cortical venous drainage and thus lead to brain venous infarction. Angiographically these lesions are occult and usually show nonspecific findings like capillary blush or early draining vein.

Treatment / Management

A conservative approach is observed for asymptomatic CMs, irrespective of location. Serial routine MRIs are carried out to monitor the changes in the lesion. The conservative approach is continued for as long as the lesion appears stable, with no additional symptoms or evidence of hemorrhage.[11][12][13]

Most cavernomas are supratentorial, and indications for resection include a progressive neurological deficit, intractable epilepsy, or a single hemorrhage in CMs when located in a noneloquent area. Surgical resection of symptomatic CM lesions is considered in the case of multiple hemorrhages in eloquent areas that are associated with deteriorating neurological deficits. Other indications include severe symptoms, such as cardiac or respiratory instability, and the presence of a CM lesion within 2 mm from the pial surface. Several studies report excellent surgical outcomes (70-97 percent) for cerebral and cerebellar cavernous angiomas. Furthermore, the use of stereotaxy and intraoperative functional MR imaging combined with surgical microdissection has significantly reduced the risk of complications for most supratentorial CM lesions.

Brain stem cavernomas pose particular problems to the surgical approach due to the tightly-packed nuclei and nerve fibers. Therefore, any additional mass or introduction of fluid, such as blood products from a bleed, can compress or crush important nerve fibers that control basic, involuntary functions like respiration or heartbeat. Surgical removal may be considered in any of the below-mentioned cases:

• The lesion abuts the surface of the brain stem.
• Recurrent  hemorrhages result in progressive deficits
• Blood from the hemorrhage is entering brain tissue surrounding the cavernous angioma.
• Cavernous angioma growth is causing visible compression of surrounding tissue.
• Patients are treated with steroids for 1 to 2 preoperatively to limit the edema. In the case of  DVA associated with the CM lesion, its resection is avoided because of the high risk of venous infarction in case DVA resection.
• Complete removal of the lesion including hemosiderin ring is required to avoid further recurring hemorrhagic events and complete seizure control. The procedure is usually followed by postoperative MRI within 72 hrs for any rebleeding event in which case surgical intervention is warranted. 
• Another series identified a long preoperative seizure history and poorer preoperative seizure control as unfavorable prognostic indicators.
• Stereotactic radiosurgery is a potential alternative to conservative therapy in patients with such surgically inaccessible lesions. However, studies have reported associated high risk of complications like a recurrence of hemorrhage, permanent neurological deficits, and radiation-induced adverse effects.

Differential Diagnosis

• Cerebral amyloid angiopathy

• Chronic hypertensive encephalopathy

• Diffuse axonal injury (DAI)

• Cerebral vasculitis

• Radiation-induced vasculopathy

• Hemorrhagic metastases

• Hemorrhagic primary brain tumours

• Parry-Romberg syndrome

Pearls and Other Issues

Cavernous angioma may not be diagnosed when it presents as acute intracerebral hematoma on nonenhanced CT or MRI images. Post-contrast enhancement scan reveals cavernous angiomas as areas of nodular enhancement adjacent to the hematoma. Elliptical rather than round shape and loss of brain volume are evidence supporting pure intracerebral hematoma from the underlying cavernoma. 

The differential, when cavernous venous malformations are numerous, is that of other causes of cerebral microhemorrhages:

• Cerebral amyloid angiopathy: older adults, usually numerous small foci located in brain periphery 
• Chronic hypertensive encephalopathy: hemorrhagic foci  more common in the basal ganglia
• Diffuse axonal injury (DAI): a history of trauma, unconsciousness
• Cerebral vasculitis
• Radiation-induced vasculopathy
• Hemorrhagic metastases: metastatic melanoma, thyroid, renal cell, choriocarcinoma
• Multiple hemorrhages associated with blood dyscrasia (disseminated intravascular coagulopathy, leukemia)
• Occult vascular malformation (thrombosed AVM/aneurysm, capillary telangiectasia)
• Hemorrhagic primary neoplasm

Enhancing Healthcare Team Outcomes

The diagnosis and management of brain cavernous hemangioma are not always simple and is best done with an interprofessional team that includes a radiologist, neurologist, neurosurgeon, and a pathologist. The patient may first present to the primary care provider or nurse practitioner with CNS symptoms, depending on the location. The management of these lesions is best left to the neurosurgeon. Asymptomatic lesions can be observed but symptomatic lesions need some type of surgery. Depending on their location, complications from surgery are not uncommon. The prognosis for symptomatic patients who undergo surgery is guarded as a number of them are left with permanent neurological deficits. [2][14] (Level V)