♦ Description

Cerebral cavernous malformations (CCMs) are vascular malformations composed of intertwined clusters of abnormally dilated capillary-like channels. These vascular channels consist of a single layer of endothelial cells and lack structural elements of mature vessels, including elastin and smooth muscle. Typically, no normal parenchyma is found in between the sinusoidal vascular spaces ( Fig. 24.1 ). Unlike normal cerebral vessels, the endothelial cells are often devoid of tight junctions. Additionally, other elements of the blood-brain barrier, including astrocytic foot processes and pericytes, are also either diminished or completely missing.1 ^– 3 Consequently, cavernous malformations are “leaky,” and frequently there are microhemorrhages at and surrounding the lesion site.1 Whereas many of these bleeds remain clinically silent, they nonetheless impact the surrounding brain parenchyma over time, causing reactive gliosis as well as hemosiderin deposits that accumulate as blood is metabolized.

Macroscopically, CCMs are reddish-purple in color and variable in size, ranging from 1 mm to several centimeters in diameter. They are often multilobular and encapsulated by a variable layer of fibrous adventitia, giving them their characteristic mulberry-like appearance. Due to the recurrence of microhemorrhages and associated blood metabolism, CCM lesions are dynamic, both increasing and decreasing in size over time.

Although most common intracranially, CCMs can be found in any component of the central nervous system (CNS), including the spinal cord, cranial nerves, ventricles, and retina, and rarely in other organs, including the skin.

♦ Epidemiology

Before the advent of magnetic resonance imaging (MRI), CCMs were definitively diagnosed only at autopsy or during surgery, and were thus thought to be rare. An MRI-based study showed a 0.4% prevalence of CCMs,4 in agreement with an earlier autopsy study.5 With the improvement of diagnostic acumen, CCMs are now recognized as common lesions, affecting one in every 200 people and accounting for 8 to 15% of all vascular malformations of the CNS.6 ^, 7

Cerebral cavernous malformations occur in both sporadic and familial forms. Sporadic cases almost never involve more than two lesions, and family history is absent. On the other hand, the familial form usually manifests as multiple lesions in the setting of a strong family history of neurologic disease. Regardless of disease type, the vast majority of CCMs occur in the brain, primarily in the supratentorial compartment (63–90% of lesions)6 and the posterior fossa (7.8–35.8%), with the brainstem being the most common site infratentorially (9–35%).8 Spinal CCMs are rare, but their exact frequency is unknown, and can be extra- or intramedullary as well as extradural or intradural.

Cerebral cavernous malformations are associated with developmental venous malformations (DVMs) in up to 100% of cases,8 making CCM plus DVM the most common mixed cerebrovascular lesion ( Fig. 24.2 ).9 This co-occurrence has implications for surgical treatment (see below).

♦ Natural History

The clinical presentation and progression of CCMs vary widely among individuals, and depend on the location of the lesion and the presence and extent of hemorrhage. Although previously believed to be congenital, CCMs have been shown to develop de novo.10 Once present, lesions are dynamic,10 growing and shrinking in size as microhemorrhages occur and are resorbed, and as vessels thrombose and recanalize.11 Lesion development and sequelae therefore remain unpredictable, as host, environmental, and genetic factors combine to produce the resulting clinical manifestation.

Although CCMs are common, only 20 to 30% of individuals with lesions will ever become symptomatic.4 Those who do typically remain asymptomatic until the third to fifth decades of life, presenting with seizures, headaches, progressive neurologic defects, or cerebral hemorrhages.4 Seizures are the most common symptom, especially in patients with lesions in the frontal and temporal lobes. Simple, complex partial, and generalized seizures have been reported in patients with supratentorial CCMs.12 The median age of an individual’s first seizure is 42 ± 4 years.13 The estimated risk of suffering a seizure is 1 to 2% per year.13 Infratentorial CCMs, particularly those arising in the brainstem, tend to become symptomatic at smaller sizes, and usually manifest as progressive neurologic deficit.14

Although a sudden gross hemorrhage is the most feared CCM complication, this event is infrequent, with an estimated annual risk between 0.25% and 6%13 that varies with an individual’s presenting symptom and with several features inherent to the lesion. Patients diagnosed either incidentally on routine imaging or after presenting with seizures have the lowest bleeding risk (0.4–2%). This risk increases to 5% over the following year when an individual presents with a symptomatic hemorrhage.15 Hemorrhage risk also varies with the size and location of the lesion, as well as with patient age. Larger and deeper lesions are more likely to bleed than smaller, superficial ones, and younger patients tend to have a higher bleeding risk than older patients. Furthermore, higher rates of hemorrhage have been reported during pregnancy.4

Gross hemorrhages from CCMs usually present with focal neurologic deficits. These deficits are typically maximal at the onset of the bleed and tend to resolve gradually as the hemorrhage undergoes organization and absorption. Recurrent episodes of hemorrhage are associated with progressive worsening of neurologic deficits and an increased risk of permanent neurologic impairment.16

♦ Radiographic Findings

Magnetic resonance imaging remains the radiographic tool of choice for detecting CCMs. Lesions typically appear as a mixture of high and low T1 and T2 signals surrounded by hemoglobin degradation products such as methemoglobin, hemosiderin, and ferritin, depending on the age of the surrounding blood, and these different components give lesions their typical mulberry or popcorn appearance with a surrounding dark halo composed mostly of hemosiderin from chronic bleeds ( Fig. 24.3 ).

Based on imaging characteristics, CCMs have been categorized into four types, each associated with a pathologic correlate that explains the lesion’s radiographic findings. Type I lesions are characterized by isolated subacute hemorrhage that causes a rim of hemosiderin-stained macrophages and gliotic brain to form a capsule around the lesion, visualized as a hypointense rim on T2-weighted imaging. Type II cavernomas, which are characterized by multiple recurrent hemorrhages, typically have loculated areas of hemorrhage and thrombosis, giving them a reticulated mixed signal core on both T1- and T2-weighted imaging. In type III CCMs, a hypointensity surrounded by a hypointense rim is seen on imaging due to hemosiderin staining within and around the lesion after chronic resolved hemorrhages. These lesions are also seen as markedly hypointense on gradient echo MRI. Type IV seen as markedly hypointense on gradient echo MRI. Type IV weighted MRI. They are visible on gradient echo MRI, however, where they appear as a small, punctuate hypointense foci. This grouping system provides prognostic value, as 93% of type I and II lesions become symptomatic, whereas only 33% of type III and IV lesions have associated symptoms.17

Computed tomography (CT) is less useful as a diagnostic tool for CCMs, as the majority of findings are nonspecific. CCMs typically appear as nonenhancing heterogeneous lesions, corresponding to either hemorrhage or calcification, but can also be seen as isodense or hypodense cystic lesions, with or without a nodule. Hypodense areas can further appear surrounding the cavernoma, representing edema, hemosiderin, or even atrophy.18 Lack of specific findings on CT emphasizes the need to adapt imaging modalities to the study of CCMs.18 Nonetheless, CT remains an ideal tool when ruling out acute hemorrhages.

Angiography is also of little diagnostic help, as CCMs are usually angiographically occult. Some lesions may show a subtle blush, and larger lesions may appear as an avascular mass on angiography.12 In the context of hemorrhage, however, the presence of DVMs, which can be easily recognized on angiography, should alert the clinician to the possibility of a coexistent CCM.

♦ Genetics

Although the heritable nature of CCMs has been well recognized since its original description, the extent of the familial nature of cavernomas was greatly underappreciated until the advent of MRI. By allowing detection of asymptomatic lesions, the use of MRI helped to elucidate the prevalence of the disease within families, and thus provided insight into the genetics underlying the disorder. It is now established that the genetic mode of inheritance of familial CCM is autosomal dominant with variable expressivity and a high degree of penetrance.

The difference in the number of lesions seen in sporadic and familial cases suggests that the underlying molecular pathophysiology follows Knudson’s two-hit hypothesis. In this model, the first hit (mutation) is inherited, whereas the second hit is acquired, thus leading to earlier onset of more severe disease in familial forms.

Genetic linkage analyses identified three loci at which mutations have been found to cause CCM development: chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3). 19 Subsequent positional cloning experiments led to the identification of Krev1 interaction trapped protein-1 (KRIT1), as the CCM1 gene, MGC4607 (or malcavernin) as the CCM2 gene, and Programmed Cell Death-10 (PDCD10) as the CCM3 gene. It should be kept in mind, however, that mutations in these three genes account for 96% of all familial forms of the disease, leaving the possibility of a fourth disease-causing gene yet to be discovered.20

KRIT1 was the first of the CCM genes to be discovered on chromosome 7q21 and contains 16 exons that encode the 736 amino acid protein KRIT1. KRIT1 has several domains implicated in protein-protein interactions, including three ankyrin, one FERM, and three NPXY domains that are thought to participate in binding to microtubules, integrins, and other cell signaling molecules.12 Over 90 distinct frameshift or nonsense mutations have been detected to date, causing premature insertion of a termination codon, and suggesting loss of KRIT1 protein function as the underlying genetic mechanism. KRIT1 is expressed in neurons and astrocytes in the brain as well as in the endothelium of arteries and capillaries of various organs,21 and in vivo studies suggest that CCM1 plays an essential role in vascular development. Ccm1^−/− mice have vascular abnormalities that are incompatible with life and result in embryonic lethality associated with defects of arterial morphogenesis.22 Although Ccm1^+/− mice appear normal, in a background lacking p53 function, approximately half of the heterozygotes develop vascular lesions of the brain resembling cavernous malformations or capillary telangiectasias.23

The CCM2 gene is MGC4607, or malcavernin. MGC4607 is a 10-exon gene located on chromosome 7p13 and encoding the CCM2 protein. Like CCM1, most CCM2 mutations result in premature termination of protein translation, again suggesting loss of function as the underlying genetic mechanism. The expression pattern of CCM2 is similar to that of CCM1, localizing to neurons, astrocytes, and the arterial endothelium. Although its function is not completely known, CCM2 has significant homology to OSM, a protein in rodents that is responsible for osmo- and mechanosensing of the extracellular matrix. In humans, at least in certain settings, CCM2 appears to play a role as a scaffolding protein, using p38 signaling to convey information about environmental stress.24 In addition, in vivo studies predict that CCM2 has a major angiogenic role because Ccm2 knockout mice, similar to the Ccm1 mutants, die during embryogenesis. In addition, approximately 10% of Ccm2 heterozygotes develop vascular lesions.25 In conditional Ccm2 mutants, cardiovascular pathology results when Ccm2 is inactivated in the endothelium but not when it is inactivated in either neural or smooth muscles cells,26 further supporting the hypothesis that CCM is primarily a disease of the endothelium. These studies suggest that CCM2 acts autonomously in the endothelium, potentially affecting cell junctions with subsequent effects on vessel formation and integrity.26

Finally, PDCD10 was identified as being the causative gene in CCM3 families. This seven-exon gene is located on 3q26 and encodes a 212 amino acid protein. Similar to CCM1 and CCM2, all variants in CCM3 identified to date are nonsense mutations. Interestingly, the expression pattern of CCM3 parallels that of CCM1 and CCM2, being present in the arterial endothelium as well as in neurons and astrocytes.27 In vitro studies of CCM3 suggest that it is pro-apoptotic.28 Recent in vivo studies using zebrafish show that CCM3 plays a role in vascular development, as CCM3 knockout animals developed the same cardiovascular dilations seen in CCM1 and CCM2 knockout animals.29

The identification of the three CCM genes and the elucidation of the function of their encoded proteins have provided unprecedented insight into CCM pathophysiology and has begun to define the molecular pathways underlying these lesions. Further mechanistic insight into CCM signaling will have significant implications for CCM patients, potentially leading to new medical treatment algorithms in the future.