Familial cavernous malformations

Cavernous malformations are congenital vascular lesions affecting blood vessels of the central nervous system (CNS), and account for 20% to 25% of CNS vascular malformations in children. Histologically they consist of sinusoidal-shaped blood vessels with irregular walls that are lined by a single layer of endothelium. Grossly, cavernomas are collections of sinusoidal vascular channels with an appearance similar to a raspberry and lack intervening brain parenchyma. Cavernous malformations may occur as sporadic isolated lesions or in a familial form with an autosomal dominant inheritance pattern. In the familial form there are often multiple cavernomas that may arise throughout the CNS. Familial inheritance is a risk factor for aggressive clinical behavior. Familial cavernous malformations occur most frequently in patients of Hispanic origin, although they can be found in any ethnic group.

Based on postmortem studies and magnetic resonance imaging (MRI), cavernous malformations have been estimated to affect 0.3% to 0.7% of the general population and represent 5% to 20% of cerebrovascular malformations in all age groups. Reviews of pediatric cavernous malformations estimate that between 3.5% and 26.0% are familial. According to several single-institution reviews, the familial form is estimated to represent 75% of patients who present with multiple cavernous malformations, although this number is likely influenced by the screening selection bias of Hispanic patients.

Familial cavernous malformations are inherited in an autosomal dominant pattern with incomplete clinical penetrance. Gradient-echo MRI is quite sensitive for detecting these lesions, including small associated subclinical brain hemorrhages. Despite the incomplete clinical penetrance, with gradient-echo MRI the radiologic penetrance is nearly complete. The probability that standard T2-weighted MRI fails to detect a lesion, given that one existed on gradient-echo MRI, is estimated to be 5% ( Fig. 1 ).

Axial T2-weighted MRI ( A ) from a patient with familial cavernous malformations. The T2-STAR sequence ( B ) is much more sensitive for detection of these lesions.

Labauge and colleagues reported on the largest series of familial cavernomas in collaboration with all 28 neurosurgery centers in France. They analyzed 100 symptomatic patients and 278 at-risk relatives without symptoms from 57 indexed families across France. The mean age at clinical onset was 32.6 years (range, 5–74 years). Most patients with familial cavernous malformations had multiple lesions and there was a correlation between the number of lesions and advancing patient age. Surveillance was done using gradient-echo MRI sequences, which had a higher sensitivity for detection of small lesions. The 2 most common presenting symptoms were seizures (affecting 45 of 100 patients) and cerebral hemorrhage (affecting 41 of 100 patients). Other presenting symptoms included focal sensory and motor neurologic deficits, visual field deficits, and nonmigrainous headaches. The mean age of patients at clinical onset is lower when the initial event is hemorrhage (25.2 years) when compared with all other presenting symptoms (37.8 years).

The natural history of familial cavernous malformations and the optimal radiologic screening protocol has been a topic of debate. Zabramski and colleagues reported their results after prospectively following 59 members of 6 families by serial interviews, physical examinations, and MRI at 6- to 12-month intervals. Both symptomatic and asymptomatic patients were included in the analysis. Sixty-one percent of patients were symptomatic with seizures (39%), headaches (52%), focal neurologic deficits (10%), and visual field deficits (6%). In these patients, 128 individual cavernous malformations were identified and followed for a mean follow-up period of 2.2 years (range, 1 to 5.5 years). Surveillance MRI revealed new lesions in 29.0% of patients, whereas 10.0% of lesions showed some change in radiographic signal appearance, and 3.9% of lesions changed significantly in size. The incidence of symptomatic hemorrhage for familial cavernous malformations was 1.1% per lesion per year in that series. Labauge and colleagues prospectively reviewed the natural history of 33 asymptomatic French patients with relatives diagnosed with familial cavernous malformations. Over a mean period of 2.1 years, 2 patients became symptomatic: 1 with a brainstem hemorrhage, and 1 with a partial seizure. Surveillance MRI found lesion changes in 46% of patients (bleeding in 9.2%, appearance of new lesions in 30.3%, signal intensity changes in 3.0%, and increased lesion size in 9.1%).

Cavernous malformations in children behave differently compared with adults. Cavernous malformations in children occur at a 4 times lower incidence rate than in adults, but have a more aggressive growth pattern and clinical behavior than in adults. The incidence of a symptomatic hemorrhage from cavernous malformations in children is higher than in adults (27%–78% vs 8%–37%, respectively). In children, a history of the familial form of disease, craniospinal radiotherapy for CNS tumors, and the existence of venous anomalies predicts worse clinical behavior. The existence of multiple cavernous malformations in children is estimated at 12% of cases, whereas up to 80% of patients harboring multiple cavernous malformations exhibit the familial form of disease. The presence of cavernous malformations with venous anomalies has been reported in as many as 2.1% to 26.0% of patients undergoing surgical treatment. Overall, although much is left to be answered, it is generally agreed that the natural history of cavernous malformations is more aggressive in children than in adults, given their higher hemorrhage rate.

Familial cerebral cavernous malformations are inherited in an autosomal dominant pattern with incomplete clinical penetrance. Linkage analysis of several Hispanic families identified the CCM1 gene on chromosome 7 from q11 to q22 with mutations in KRIT1, which is responsible for familial cavernous malformations. The homogeneity at the CCM1 locus, however, did not represent the expressive phenotype of familial cavernous malformations in patients of non-Hispanic ethnicity. The CCM2 gene on chromosome 7p13-15 (with MGC4607 or malcavernin mutations) and CCM3 gene at 3q25.2-27 were found after investigation of 20 non-Hispanic white families. A fourth CCM locus (CCM4) was identified in 3q26.3-27.2, representing a mutation of PDCD10. The CCM1 protein, KRIT1, participates in regulation of cell adhesion and migration via its interaction with beta-1 integrin. This interaction may control endothelial cell behavior. The CCM3 gene (PDCD10) induces apoptosis through modulation of the cell cycle. It has therefore been proposed that aberrant apoptosis, by altering the balance between endothelial and neural crest cells within the neurovascular unit, may lead to cavernoma formation. Identification of these and other molecular defects allows clinicians to better screen at-risk families. Screening of relatives with multiple or sporadic cavernous malformations continues to be a topic of debate. This question has not yet been convincingly answered by the existing clinical data, although it is generally recommended that first-degree relatives of patients with known familial cavernous malformations have a surveillance brain MRI.

Management of familial cavernous malformations differs from sporadic malformations. Although large multicenter trials have not been performed, many single-center studies show that microsurgery can be performed without significant postsurgical complications to prevent recurrent hemorrhage and control seizure disorders in these patients. The treatment of choice for symptomatic solitary cavernous malformations is often microsurgery; however, for multiple cavernous malformations, as is the case for many patients with familial cavernous malformations, the decision to offer surgery should be entertained with greater caution.