Cavernous malformations of the central nervous system: A review

Cavernous malformations (CMs) of the brain and spinal cord (also known as cavenous angiomas, cavernous haemangiomas, cavernomas, angiographically occult vascular malformations, occult vascular malformations and cryptic vascular malfomrations) are low-flow, low-pressure vascular malformations of the central nervous system (CNS). Although traditionally regarded as a separate pathological entity compared with other CNS vascular malformations, current research suggests that there may be pathogenetic links to the other types of malformation.


Introduction
Cavernous malformations (CMs) of the brain and spinal cord (also known as cavenous angiomas, cavernous haemangiomas, cavernomas, angiographically occult vascular malformations, occult vascular malformations and cryptic vascular malfomrations) are low-flow, low-pressure vascular malformations of the central nervous system (CNS). Although traditionally regarded as a separate pathological entity compared with other CNS vascular malformations, current research suggests that there may be pathogenetic links to the other types of malformation. These were based mainly upon microscopic and gross histopathologic criteria. More recently the presence of mixed/combined or intermediate forms of malformation have been described, blurring the classical classification scheme.' Further improvements in the understanding of the natural history, pathogenesis and cellular biology of CNS vascular malformations will probably eventually result in further revision of this classical pathoanatomical classification to be replaced by a more biologically based one.

Pathology
CNS vascular malformations are considered to be vascular hamartomas." Grossly cavernous malformations appear as well circumscribed multilobulated masses filled with blood with a red to purple colour resembling mulberries. They can range in size from millimetres to several centimetres. They are surrounded by a transi- 4 SA JOURNAL OF RADIOLOGY • June 2003 tion zone or 'capsule' of haemosiderin-stained gliotic brain tissue. Histologically they are composed of multiple thin-walled sinusoidal vascular channels or caverns. The walls of these channels are lined by a single layer of endothelium surrounded by a thin layer of dense fibrous tissue with complete absence of elastic fibres or smooth muscle, similar in appearance to dilated capillaries.
This has led some authors to suggest that both CMs and capillary telangiectasias may represent different variants of the same pathological entity/ There is little or no intervening normal brain tissue between the sinusoids of a CM, whereas this is present in the capillary telangiectasias. Many of the dilated channels contain stagnant blood or thrombus, and focal areas of calcification may be seen.
CMs increase in size as the result of recurrent episodes of local intralesional haemorrhage and thrombosis. They are low-flow and low-pressure lesions with the result that the haemorrhages tend to be limited and generally contained within the lesion. These repeated episodes of haemorrhage and thrombosis lead to a gradual progressive deposition of haemosiderin and other blood breakdown products in the normal brain parenchyma around the CM. Occasionally a haemorrhage within a lesion can extend beyond the capsule resulting in a parenchymal or less commonly a subarachnoid haemorrhage.
CMs can be classified as either sporadic or familial. They may also be single or multiple. In sporadic cases up to 33% have multiple lesions' whereas in familial cases multiple lesions may be seen in over 70%Y Some 20 -30% of patients with Clvls in North America may have the familial form.
An autosomal-dominant pattern of inheritance is seen in the familial form. There is a particularly high incidence of familial eMs in the American Hispanic population 10 where the abnormal gene responsible for the development of these Clvls has been identified on the long arm of the 7q chromosome." Further point mutations have been identified in other ethnic groups including two on the short arm of chromasome 7(7pIS-13) and the long arm of chromosome 3(3q 2S.2.27)(eeMS2 +3).12,13 The first of these genes, eeMl, has been identified more recently as encoding the KRITI protein which probably plays a role in intracellular signalling, particularly to endothelial cells." The importance of this is that a genetic component has now actually been identified as playing a role in the development of eNS vascular malformations, and that many of these abnormalities still remain to be defined at a molecular level." Clvls have long been presumed to be congenital lesions present at birth." A number of cases have been reported in neonates supporting a congenital origin for some lesions.":" More recently cases of spontaneous de novo eM formation in adults have been described in both the familial and sporadic forms of this condition.v?-" De novo development may occur seemingly spontaneously or may be associated with a number of associated events or abnormalities. Clvl development has been documented after brain biopsy" and both stereotactic and conventional radiation therapy.":" Other factors that may be involved include head traurna," brain surgery" and viral infections including cytomegalovirus." Infection of nude mice with the polyoma virus in laboratory experiments has been shown to induce the development of multiple Clvls in the brains of these mice.":" Finally there is the association of Clvls with other eNS vascular malformation types including telangiectasias and developmental venous anomalies (DVAs).4.27,28 Further theories suggest that eMs may develop from pre-existing telangiectasias or may develop in response to micro haemorrhages or pressure changes in telangiectasias and venous malformations." Thus even if the eMs themselves are not congenital there must be some predisposing factor or defect that is, which in turn is exposed to a trigger factor at some later stage in life thereby leading to the formation of the eM by interference with normal angiogenesis or vascular modelling or remodelling mechanisms.
Immunohistochemical studies are revealing new information concerning the biomolecular structure of the constituent elements of the walls of Clvls as well as angiogenic factors related to their development.'?" For instance, fibronectin and laminin are proteins responsible for maintaining the structural integrity of a vessel wall by anchoring endothelial cells to the underlying internal elastic membrane and smooth muscle layers. Fibronectin is found predominantly in the initial stages of angiogenesis whereas laminin is found in the maturation stages. In one study, AVM subendothelia were found to contain more laminin whereas eM subendothelia contained more fibronectin." Thus, compared with AVMs, eMs have a more angiegenically immature and fragile wall which is more prone to bleed at non-arterial pressures. Angiogenic factors such as VEGF, TGFa and bFGF have been identified in Clvls as well as in normal brain tissue adjacent to the Clvls, The expression of these growth factors suggests that angiogenic processes which are normally dormant in the adult brain may become triggered, leading to the development of these malformations as a final common pathway regardless of whether the underlying defect is genetic or acquired.

Mixed malformations
The presence of multiple malformation types in the same patient has been well documented generally involving some combination of Clvls, capillary telangiectasias, venous malformations and arteriovenous malforrnations.v-" One report even describes the juxtaposition of a capillary telangiectasia, eM and DVA in the brainstem of the same patient." The presence of mixed malformations suggests a possible common pathogenesis resulting in transitional forms of vascular malformation in the same anatomical location. One theory suggests that elevation of venous pressure in a DVA leads to ectasia in an acquired capillary telangiectasia then leading to the development of a eM. 29  Other reported frequencies of this coexistence vary from 2% to 29%.

Incidence
CMs have an estimated prevalence of between 0.45% and 0.9% of the population based on MR studies," and 0.5% -0.7% based on autopsy studies." Most CMs (75%) are supratentorial.":" Within the posterior fossa the commonest location is the pons." Spinal lesions are rare « 5%). Size can range from 3 mm to 80 mm,"  43 Kupersmith et al:" in their review of 37 patients with brainstem eMs described a bleeding rate of 2.46% per year, a rebleeding rate of 5.1% per year and an overall clinical event rate of 3.4% per year. They found a higher risk of bleeding with brainstem cavernomas of at least 10 mm in diameter. These reported figures are considerably lower than those quoted by Porter et al:" with a 5% annual risk of bleeding and 30% risk of rebleeding, and Fritschi et al" with an annual bleeding rate of 21 %. Extralesional bleeding episodes were noted in 8.1% of the total number of cases, with an extralesional haemorrhage rate of 0.44% but an extralesional rebleed rate of 14.2% per year. Their conclusion that rebleeding is not more common among patients who first present with bleeding and often has little effect on the neurological status of patients with significant morbidity occurring in only 8% of patients during the mean follow-up period of 4.9 years drew sharp criticism from several sources who ones. Also of importance in these two studies was the reported rates of change in the size and signal characteristics of individual lesions (14% and 10% of lesions respectively) indicating the dynamic nature of this disease process.

Imaging characteristics
Due to the low-flow nature of eMs they are usually not visualised at angiography, hence the previous term 'angiographically-occult vascular malformation'. Angiography may be completely negative or may show an avascular mass or region or a faint blush in the capillary phase or contrast pooling in the venous phase in larger lesions.":" With unenhanced computed tomography (CT) a rounded isodense to moderately hyperdense focal lesion may be seen (Figs la, lb, 4a, 4b).54 Calcification is common and is usually seen peripherally. Ossification is occasionally seen." MR imaging is the most sensitive and specific imaging modality. The characteristic MR appearance is described as a rounded lesion with a central heterogeneous core consisting of Tl and T2 hyperintense areas in a pattern often described as 'popcorn-like' (Figs le-g, 3a-c). The different signal intensities are due to the presence of blood products at different stages of alteration in different areas of the lesion (Figs Sa,b). A rim of low signal surrounds the  entire lesion which is of variable thickness and appears most hypointense on T2 images, particularly gradient echo T2 sequences (Figs Ie, 3b). This peripheral low signal represents haemosiderin and ferritin deposited at the interface with the adjacent brain parenchy-   core on T'l-weighted images and either a hyperintense or hypointense appearance to the care with a hypointense rim on T2weighted images (Fig. 2). Lesions were considered subacute (or typel) until the TI hyperintensity became iso-or hypointense with the surrounding brain.
Type II lesions have a reticulated, mixed signal core due to loculated areas of thrombosis and haemorrhage of varying age (the  'popcorn-like' core) surrounded by the haemosiderin ring (Figs 3a, 4c) hypointensity on T2-weighted images (Fig 3d). The marked T2 hypointensity is due to a large quantity of haemosiderin in and around the CM. Type IV lesions are poorly visualised on both Tl an T2-weighted sequences being very small (Fig. 7). They are really only visualised as tiny punctate hypointensities on gradient echo sequences. There is a debate as to whether these lesions represent minute CMs or a transitional type of lesion. Two such lesions have in fact been verified patholgically as capillary telangiectasias/ Zambraski et al.' found that most clinically symptomatic lesions were type I or type II (93%).

Labauge et al"
found in their series that the haemorrhagic risk was greater in type I lesions. Willinsky et a1. 42 found, however, that this classification system was not useful in predicting future bleeds in their study. They did note that mass effect and oedema were found most often with type I lesions. Follow-up of individual lesions often shows increase in size due to intralesional haemorrhage and decrease in size with increased T2 hypointensity during periods of quiescence or resolution of haemorrhage. However, not all type I or type II lesions were seen to progress to a type III appearance over time in the above studies and as type III lesions can also bleed it is possible that the different types represent either a spectrum or continuum of histological types rather than a temporal progression of lesions.':"

Extra-axial and spinal cavernomas
Extra-axial CMs are uncommon lesions found most frequently related to the cavernous sinus and middle cranial fossa.57.61.62.63 Others have been reported in the torcula and petrosal sinus and involving the optic chiasm, sella turcia and chiasmatic cistem.r':" Cranial nerve lesions have also been described":" affecting the II nd, III rd, VII th and VIII th nerves. Most extra-axial lesions affect the cavernous sinus and expand the sinus. Histologically they are identical to intra-axial CMs but have very different clinical presentations, natural history and imaging features. Ninety-four per cent of cases are women, with a large number of Japanese origin." These lesions are also termed cavernous haemangiomas, which is a misnomer as they are not tumours although they are locally aggressive due to mass effect. Early symptoms of cavernous sinus CMs include retroorbital pain, headaches and symptoms related to the cranial nerves . supplying the extra-ocular muscles.
Other signs and symptoms include visual deterioration, exophthalmos, endocrine disturbances and trigeminal neuralgia.
Haemorrhage is much less common. Although histologically identical to parenchymal CMs, the extra-axial ones tend to show more homogeneous density or. signal intensity and contrast enhancement on CT and MR imaging respectively. They closely resemble meningiomas or schwannomas on sectional imaging but are angiographically occult. The lesions are difficult to treat surgically because of excessive bleeding, with a significantly high morbidity and mortality.59.61 Spinal cord lesions are rare. Patients range in age from 12 to 87 years, with a 2: 1 female preponderance." Ojemann et al." and Ogilvy et al. 73 reviewed 36 patients with 37 lesions in 1991 and found that 69% of cases were female, 8% occurred at the cervi comedullary junction, 32% in the cervical cord, 54% in the thoracic region, 3% in the lumbar cord and 3% in the conus. They described four clinical categories of symptoms.
1. Recurrent episodes of clinical deterioration followed by remission.
The episodes would last hours to days and the interval between events from months to years.
2. Slowly progressive neurological deterioration over several years.
3. Acute onset of symptoms followed by rapid progressive worsening over days.
4. Acute onset of symptoms followed by a slow progressive neurological decline over weeks to months.
Intramedullary CMs vary in size cord Clvls are described but rare.":" Extra-axial spinal lesions can occasionally be found in the intradural extramedullary space, the spinal epidural space and even in the vertebral bodies." They are also extremely difficult to resect due to excessive bleeding.

Clinical features
eMs occur with an approximately equal incidence in males The commonest presenting feature in brain eMs is seizure, occurring in 23 -52% of patients."?" .•I. '3.79 Headache occurs in between 6% and 30% of cases.9. 16

Differential diagnosis
Any rounded lesion exhibiting Tl shortening can mimic a Clvl. This Tl shortening can be due to subacute haemorrhage (methaemoglobin), high protein content or fat." The differential diagnoses of eMs are listed in Table II.

Management
There are three possible methods of treating eMs of the eNS, namely surgery, radiation therapy (radiosurgery) and conservative treatment.
As with any medical therapy the risk of complications associated with the treatment must not be greater than those associated with the natural history of the disease. It is therefore vital to understand the natural history of any disease as fully as possible before contemplating the need for and possible method of any therapeutic measure. With Clvls other factors to be considered include the age of the patient, number and location of   For women diagnosed with a eM during pregnancy, normal vaginal delivery can probably be recommended based on the low-flow characteristics of the eM. S2 Surgical excision of superficial eMs generally carries good operative outcomes with low mortality and morbidity rates of 0 -6% (mean 3%) and 0 -12% (mean 3.6%) respectively," Review of the seizure-related outcomes suggest that 75 -100% of patients with 5 seizures or less or less than a 12month history of seizures were found to be seizure-free after removal of a eM compared with 50 -62.5% of patients with more than 5 seizures or a seizure history of more than 1 year pre-operatively." The suggestion made is that early surgery rather than medical treatment with anticonvulsants may be preferable for patients presenting with seizures. Lesionectomy is suggested as the early surgical technique, with more extensive excision reserved for patients with a longer history or greater number of seizures associated with eMs.
The surgical management of deep-seated eMs (basal ganglia, thalami, IIIrd ventricle) is associated with a significantly higher mortality and morbidity of 0 -12.5% (mean 5%) and 6 -67% (mean 22%) respectively," Surgery for those lesions is recommended when there are recurrent episodes of haemorrhage or progressive neurological deficits.
Brainstem eMs carry a greater risk still for surgical intervention based on the extreme eloquence of the brainstem itself, with mortality rates of . 0 -6%, transient complication rates of 25 -70% and permanent complication rates of up to 25%? Surgical management of brainstem eMs is recommended for symptomatic lesions abutting the pial surface.?" Any DVAs associated with Clvls must always be preserved during surgical resection.
Surgical resection of Clvls done solely to prevent significant haemorrhage represents a highly controversial indication. Here the known natural history must be carefully weighted against the patient's neurological status and age, location of the lesion and risk of operative approach." Spinal cord Clvls are rare and the number of reported series is small. Ogilvy  deeply located Clvls with a history of two or more prior haemorrhages (high-risk, authors' definition) or where the haemorrhagic risk reduction more than justifies the sideeffects (26% neurological worsening of which three-quarters were transient) and costs of the radiosurgery in patients who had suffered from two or more haemorrhages. The morbidity at radiosurgery is considered too high to justify its use in Clvls that have never bled." In a more recent report by the same group" the authors concluded that in patients with symptomatic imaging-confirmed haemorrhages from Clvls at high risk for surgical resection, gamma knife radiosurgery conferred a reduction in the risk of haemorrhage which was only significant after 2 years post treatment (12.3% annual haemorrhage rate for the first 2 years post treatment followed by a risk of 0.76% per year thereafter). They also recommended that treatment after one major haemorrhage be considered in selected younger patients. Stereotactically-guided radiofrequency ablation is yet another modality currently under investigation for the treatment of selected cerebral Clvls, In familial/multiple eMs the recommendation is that surgery be considered only for lesions that produce repetitive or progressive symptoms and that prophylactic resection of asymptomatic lesions is not recommended.' Almost

Conclusion
It is obvious that our understanding of the pathogenesis and natural history of CNS CMs is far from complete. In conclusion let us summarise all the pertinent points concerning CMs discussed above. The classical four category patho-anatomical classification of cerebral vascular malformations has recently become complicated by the recognition of mixed and transitional malformation types. CMs are low-flow lesions which 'grow' by recurrent episodes of intralesional haemorrhage and thrombosis. They may be found in close anatomical association with DVAs and may share a common pathogenesis with capillary telangiectasias. CMs can be sporadic or familial. Familial ones tend to be multiple. A genetic defect has been identified in the familial form. CMs are dynamic lesions and some have been identified as arising de novo in children and adults. Clinically significant events are due to haemorrhage or thrombosis within the lesions, mass effect or parenchymal irritation by the surrounding haemosiderin ring. Not all intralesional haemorrhages produce clinical effects, leading to con-fusion about the significance of reported haemorrhagic rates in the literature. The rate of rebleeding appears greater in patients who have already had one or more previous documented bleeds. The haemorrhagic and event rates are higher in deep-seated (diencephalic, basal ganglia, cerebellar nuclei) and brainstem lesions than in superficial ones. Some studies suggest a higher risk of bleeding during pregnancy. The risk of haem orrhage is higher in familial (multiple) lesions. CMs are low-flow lesions and thus angiographically occult. MRI is the preferred imaging modality for diagnosis and follow-up. The MR characteristics are fairly typical and have been characterised into four morphological types although there is some debate as to whether these represent different stages of development or different pathological entities.
The radiological differential diagnosis includes any lesion that can haemorrhage or contain melanin, calcium or fat.
Extra-axial CMs are rare and can mimic skull base tumours such as meningiomas and schwannomas in both clinical presentation and imaging features. Spinal lesions are also rare and can exhibit various modes of presentation from acute to slowly progressive. Brain CMs can present clinically with seizures, headaches and acute or slowly progressive neurological deficits. Treatment options are primarily surgical, with good clinical outcomes and low rates of mortality and morbidity reported for symptomatic superficial lesions but poorer results for deep-seated and brainstem ones. Stereotactic radio- surgery appears to offer protection against haemorrhage for high-risk lesions but only beyond 2 years after treatment. Evidence suggests that early surgery for CMs presenting with seizures may lead to abetter long-term seizure-related outcome. There is no justification for prophylactic surgery in asymptomatic lesions. Regular radiographic and clinical follow-up is required in asymptomatic lesions regardless of location, and in deep-seated symptomatic ones in high-risk or eloquent areas of the brain. Thanks go to all of my colleagues at Sunninghill Hospital for providing many of the images for this article.