Definition and History
The cavernous malformation (CM), also known as the cavernous angioma or cavernoma, is a vascular anomaly characterized by the presence of sinusoid-like capillary vessels. These capillaries are adjacent to one another, with little or no intervening brain parenchyma; the feeding arteries and draining veins are most often normal in size. The blood flow in the cavernous angioma is slow; therefore, standard angiography techniques usually fail to visualize this type of lesion. Stagnation of blood is also characteristic and is frequently the cause of thrombosis and calcification.
CMs can occur anywhere in the central nervous system. Their distribution seems to reflect the relative volume of the different structures. Multiple lesions are common: in one large series of 8131 magnetic resonance (MR) scans, the incidence of CMs was 0.4 percent; the incidence of multiple lesions in this group was 18.7 percent. In patients with multiple cerebral CMs, similar lesions can be found in other organ systems. Cerebral CMs are generally sporadic; at least 6 percent of cases are familial. however.
On microscopic examination, the cerebral CM is a well-lobulated, circumscribed lesion; since it is either dark red or purple in color, often it is described as mulberry-like. An average diameter of 4.9 mm was reported in one large prospective autopsy series; clinical descriptions usually give a greater diameter. The mean lesion size in a surgical series conducted by Giombini and Morello was 3.5 cm; Yasargil reported a mean lesion size of 2.2 cm in one surgical series. There is a significant correlation between size and symptomatology.
CMs vary in consistency from soft to hard, depending on the relative proportions of blood-filled spaces, calcification, ossification, and areas of thrombosis. The surrounding brain parenchyma is typically gliotic and stained yellow by hemosiderin. This staining is the result of either frank hemorrhage or slow diffusion of pigment into the surrounding tissue following lysis of red blood cells. The presence of highly epileptogenic iron salts in the susceptible brain structures explains the high incidence of seizures in patients with CMs.
Microscopically, the CM is characterized by enlarged capillaries, which are composed of a thin collagenous wall covered by a single layer of endothelium without smooth muscle fibers or elastic fibers. Typically, CMs do not have intermingled brain parenchyma: at the periphery. however, the dilated capillaries of many CMs may be separated by normal brain. Hemosiderin-laden macrophages are invariably found secondary to previous hemorrhage or red blood cell lysis. Varying degrees of thrombosis, fibrous scarring, calcification and ossification are often present.
A comprehensive review of the literature shows that patients with symptomatic CMs have presented with seizures (39 percent), hemorrhage (32 percent), or a mass effect (29 percent). A study of the members of six families with CMs, however, confirms that these malformations are asymptomatic in a significant percentage of cases (11 percent). In one study, seizures were the most common symptom (55 percent), followed by progressive neurological deficit (15%), headache (15 percent), and hemorrhage (4 percent). Another compilation of 664 patients assembled from the literature corroborates seizures as the predominant symptom (31 percent), followed by progressive neurological deficits (25 percent), hemorrhage (13 percent), and headache (6 percent); asymptomatic cases were more common than previously reported (21 percent).
Two CM variants have been described: a cystic form and the so-called hemangioma calcificans. The cystic form tends to cause recurrent bleeding and is common in the posterior fossa, with a noticeable degree of surrounding edema. In the absence of clear histologic confirmation, the hemangioma calcificans is presumed to be a calcified CM. Commonly located in the temporal lobe, it causes seizures and usually, because of its densely calcified structure, does not bleed.
The use of magnetic resonance imaging (MRI) means that CMs are now usually diagnosed at an earlier and much smaller stage than before, and rarely is calcification seen. Two old surgical studies reported the presence of calcification on conventional skull radiographs in 8 to 10 percent of the patients. Similarly, earlier reports described angiographic abnormalities in 60 to 70 percent of cases; this result also reflects a time before the advent of MRl, when patients typically had larger, symptomatic lesions. A capillary blush and early filling of the veins without enlargement of the arteries is very rarely seen. Opacification of the cavernous spaces has been noted occasionally when using prolonged arterial injection.
CT-scan can detect cavernous malformations and the distortions produced by a mass effect. On unenhanced CT scans, cavernous malformations appear as focal areas of increased attenuation: only a few lesions appear hypodense. An increase in density is characteristic of recent hemorrhage as well as of calcification, and increased attenuation can be observed on scans following an acute hemorrhage, which is frequently accompanied by a mass effect. Areas of punctate calcification are visualized in 14 percent of cases.
The intravenous (IV) administration of a contrast agent permits a faint enhancement. The CT can outline abnormalities encroaching on the brain stem: however, an acute brain stem hemorrhage that produces subarachnoid or fourth ventricular hemorrhage is more likely to be due to a cryptic arteriovenous malformation (AVM) than to a CM.
Magnetic Resonance Imaging
MRI yields extraordinary resolution and is particularly helpful in identifying CMs. On both T1- and T2-weighted images, the CM is represented as a well-defined, usually rounded lesion. The lesion is characterized by a rim of decreased signal intensity at the periphery and a heterogeneous central signal. The hypodensity of the rim is produced by the presence of hemosiderin: the appearance of the central core is generated by blood and blood byproducts in various stages of evolution, Areas of increased signal outside the hemosiderin rim on T2-weighted images may represent edema. Smaller CMs may appear only as petechial areas of decreased signal intensity ("black dots" ). Although enlarged vessels are not characteristic of CMs, a coexisting venous angioma has been identified now and then.
It is important to recognize that these appearances are not limited to CMs and that a differential diagnosis is important to rule out the presence of a cryptic AVM or hemorrhagic neoplasm. Hemorrhagic neoplasms, even when small, are accompanied by edema, which is usually absent from small CMs. Magnetic resonance angiography (MRA) permits visualization of the CM by the time-of-flight technique but not by the phase contrast technique.
Positron Emission Tomography
Positron emission tomography (PET) uses the uptake of radioisotopes to scan the brain. Both CT and MRI provide far more structural detail, but PET scanning can differentiate a CM from a tumor, since radioisotope uptake is markedly elevated in tumors but not in CMs. One small series reported normal or decreased radioisotope uptake in CMs.
A prerequisite for the management of CMs is a knowledge of their natural history. Several prospective MRI series of patients harboring characteristic lesions have yielded a clearer understanding of the true risk of overt hemorrhage from a CM. One report estimates that the annual bleeding risk is 0.7 percent per patient. Based on the assumption of uniform risk from birth to the age at which a hemorrhage is diagnosed, the risk is calculated to be 0.25 percent per lesion per year. Although this information is useful, it is not necessarily accurate: The risk of hemorrhage may not be uniform and may depend on other factors, such as gender, age and previous hemorrhage. It also is important to compare the lower risk of bleeding from a CM to the higher risk of bleeding from an AVM, which is calculated to be approximately 4.0 percent per year. Furthermore, the consequences of a hemorrhage from a CM are rarely catastrophic, in contrast to the case with an AVM or aneurysm.
The course of a non hemorrhagic lesion seems to correlate with the initial clinical presentation. In the absence of gross hemorrhage, one study reported a poor to fair outcome for 16 percent of patients. Patients who present with seizures are very likely to become symptomatic again, and, frequently, seizure control becomes more difficult with time. The location of the lesion also may be significant: CMs in the infratentorial compartment may be associated with a more aggressive natural history.
Most lesions discovered incidentally require no therapy. Occasionally, these lesions cannot be differentiated from tumors, and a biopsy is indicated. Surgical intervention can be attempted when a CM is identified as a seizure focus in patients with refractory seizures. Several authors consider that, surgery is not indicated as a measure to decrease the risk of bleeding in a patient who has never bled.
In children, surgical intervention is indicated to treat symptoms related to mass effect, hemorrhage, or seizures. Surgery is favored more for children than for adults because of the higher risk of hemorrhage and greater epileptic potential in children.
The effect of pregnancy on CMs remains speculative. Although a statistically significant association between hemorrhage and pregnancy has yet to be established, pregnant women accounted for 86 percent of the hemorrhages (one-third in the first trimester) in one series. There also are anecdotal cases of CMs expanding and becoming symptomatic during early pregnancy. It seems that an increased risk of lesion expansion and hemorrhage exists during pregnancy.
If the mother is stable, conservative management may be appropriate, and vaginal delivery is not contraindicated. Surgical resection before conception is preferred, provided the CM is located in a favorable location. Possible risks and management options should be discussed with women who plan to become pregnant, and surgical recommendations can be made at that time.
A thorough medical history, family history- and physical examination, and detailed neuroimaging studies are crucial to the preoperative evaluation. MRI is particularly helpful in identifying the exact preoperative location of the lesion and multiple lesions, which often are not detected by CT. For patients with a seizure disorder, electroencephalography (EEG) can confirm whether the epileptic focus is anatomically related to the CM and can localize the seizure focus when multiple CMs are present.
Standard microsurgical techniques are employed for the resection of CMs. The surgical microscope and microsurgical instrumentation have revolutionized the surgical treatment of CMs, particularly the treatment of lesions located in the brain stem or deep in the cerebral hemispheres. Some authorities have recommended the use of the CO2 laser, but it does not seem necessary for extirpation of these lesions. One useful addition to the surgical armamentarium is a stereotactic system, which can be used to precisely localize deep-seated lesions intraoperatively.
Usually, significant intraoperative bleeding does not accompany the resection of a CM. One area of notable exception is the extracerebral middle fossa CM. Significant bleeding in this area is probably due to intralesional pressures that are at once decidedly lower (38.2 ±0.5 mmHg) than mean arterial blood pressures (99.6 ±15.1 mmHg) and higher than central venous pressures (5.0±1.0 mmHg).
In Giombini's first large, personal series accompanied by a review of the literature, 33 patients were known to have undergone radical resection of the lesion. All but three (10 percent) had improved or else continued with stable deficits after a follow-up averaging several years. The two factors given as relating to surgical success were (1) the presence of a dissection plane and (2) a relatively scarce supply of blood to the CM.
Another publication reported 17 cases with an excellent outcome and 2 cases with a good outcome among 19 patients who had hemispheric lesions: on the other hand. the outcome in patients with lesions in the thalamus, pineal region or spinal cord was consistently poor. The higher surgical morbidity associated with deep-seated CMs has several distinct causes: damage to the internal capsule. injury to the lenticulostriate arteries, damage to the venous drainage, air embolism and recurrent hemorrhage from a residual angioma:
A fairly high incidence of surgical complications has chilled some of the initial enthusiasm. The report on the largest series of brain stem CMs stresses the importance of combining clinical examination findings and MRI data to determine a safe surgical corridor for approaching the lesion. The authors recommend surgical resection for symptomatic brain stem CMs because the brain stem's ability to withstand expansion is poor.
Deep CMs located in critical areas have been treated with radiosurgery. The results have not been favorable: the incidence of complications, presumably due to delayed radiation injury, is much higher than in a similar series of AVM patients. It is discouraged to perform radiosurgical treatment for CMs, as its efficacy is very difficult to evaluate. To start with, angiographic findings appear normal, even before radiosurgery and any spontaneous reduction in the size of the CM following a hemorrhage would further complicate evaluation.
Middle Cranial Fossa Cavernous Malformations
Middle cranial fossa CMs are extraparenchymal and usually extradural. Histologically. these lesions are composed of dilated cavernous channels lacking mural smooth muscle. They routinely surround the structures in the cavernous sinus. including the internal carotid artery and cranial nerves III through VI. These lesions are rare and primarily affect women.
The clinical presentation includes headaches and, more commonly. acute or subacute visual symptoms. Ocular findings include proptosis, visual loss, field cuts and diplopia. Facial numbness and pituitary dysfunction are less common. Lesion growth often erodes the bone in the area of the cavernous sinus. Angiography outlines a vascular mass without an arteriovenous shunt. These lesions are a formidable surgical problem, as they tend to cause intraoperative, life-threatening hemorrhages. After biopsy, terminating attempts to further resect the lesion will drastically reduce mortality and morbidity, as will giving a course of radiotherapy prior to definitive surgical treatment.
Retinal Cavernous Angioma
Retinal cavernous angiomas have been linked to one of four neurooculocutaneous syndromes (ophthalmic phakomatoses), characterized by disseminated hamartomas of the eye, skin and brain. On direct visualization of the retina, these lesions resemble clusters of grapes protruding from the inner retinal surface into the vitreous. The capillaries appear thin-walled and are similar to those of cerebral CMs. The arteries and veins surrounding the lesion are normal in appearance.
Fluorescein angiography is helpful, demonstrating a significant delay in the perfusion of dye through the lesion. This is why some workers recommend angiography with a very late venous phase to cavernous heamangiomas.
Calvarial hemangiomas occur more often in females than males and present as a painless, bony swelling usually in the parietal or frontal region. The scalp moves freely over the mass and roentgenograms depict a well-defined lucent area with a trabeculated appearance. During angiography, the contrast agent pools within the lesion in the venous phase. Histologically, cavernous capillaries are separated by bony spicules.
The capillary telangiectasia (also called a capillary malformation) is a lesion characterized by the presence of capillary vessels with saccular and fusiform dilation interspersed among normal brain parenchyma. Capillary telangiectasias are punctate lesions composed of small dilated capillaries that are devoid of muscle and elastic fibers. On gross inspection, a capillary telangiectasia resembles a cluster of petechial hemorrhages. No abnormal arteries are present in the periphery of the lesion, but it may drain into an enlarged central vein. The feature that most distinguishes these lesions from CMs is the presence of normal brain parenchyma between the dilated vessels, Typically, the parenchyma does not show evidence of gliosis or hemorrhage. Most of these malformations are clinically silent and are discovered at autopsy. They occur in the same locations as CMs and like them, are frequently multiple, Observations of lesions transitional between capillary telangiectasia and cavernous malformation have been documented for years, which leads to the supposition that one lesion is the precursor of the other. Radiologic studies were not able to detect capillary telangiectasias in the past: however, MRI can detect them as punctate areas of decreased signal intensity on T2-weighted images. The hypodensity is due to the presence of small amounts of hemosiderin and most likely, previous subclinical hemorrhages or diapedesis of red blood cells through the walls of the lesion. A true massive hemorrhage is exceedingly rare and only anecdotal cases have been reported. The importance of this lesion is that it represents a possible link between different types of vascular malformations.
The venous angioma (venous malformation, medullary venous malformation) is characterized by an abnormal-looking but physiologically competent venous drainage. Venous angiomas are usually located in the deep white matter, drain an array of fine medullary veins that converge on them and drain in turn into either the superficial or deep venous system: most are located in the cerebral hemispheres or cerebellum.
Macroscopically, a tuft of fine veins converge into an enlarged central venous trunk that appears much larger than the veins joining it. Microscopically, the vein appears normal in structure, except for occasional evidence of hyalinization and thickening. No abnormal arteries are associated with the venous malformation and evidence of thrombosis, hemorrhage or calcification is rare. The intervening parenchyma appears normal.
The classic angiographic term for this lesion is caput medusae, coined because the numerous small veins appear in a radial arrangement around the enlarged central trunk: the arterial and capillary phases appear angiographically normal. By CT and MRI. the venous angioma typically appears as a linear or curvilinear structure with a nidus at the vessel origin resembling the spokes of a wheel. Clinically, venous angiomas are usually asymptomatic and their discovery is incidental: however, venous malformations located in the posterior fossa tend to be more symptomatic.
Some authorities recommend more aggressive management of posterior fossa venous angiomas when they are associated with a hemorrhage. This approach, however, carries a significant risk because the elimination of an abnormal-looking but functional draining vein, whether by surgical, endovascular, or radiosurgical techniques, can precipitate a venous infarction. The natural history of this malformation seems to be quite benign, according to some initial follow-up studies. A most interesting and clinically relevant characteristic of this lesion is its relatively common association with a cavernous malformation. This phenomenon is too common to be only coincidental. It raises several interesting questions regarding the possible genesis of cavernous malformations and the causative effect a venous angioma may have on the dilatation of the capillaries with which it is connected. Another important corollary to this previously underestimated association is that, if hemorrhage occurs, it most likely arises from the cavernous malformation rather than the venous angioma. Prior to the use of CT and MRI, a heamatoma in the vicinity of a venous malformation was thought to be due to the venous malformation: any coexisting cavernous malformation could not be detected on the angiogram. Nowadays, it is standard to look for a cavernous angioma in the vicinity of a venous angioma. If a hemorrhage occurs, the clot and cavernous angioma are removed, while the venous malformation is best left alone.