Cavernous Malformations or Cavernomas are lesions comprising of abnormal blood vessels which lack the usual muscle and elastic tissue in their walls. They can occur anywhere in the nervous system and may be multiple. Although a cause of epilepsy and disability many remain clinically silent or behave in a relatively benign manner.
What is a Cavernoma?
The blood contained within cavernous malformations is under very little pressure and they do not attract a very large blood supply themselves. In life their appearence is frequently compared with that of rasberries, blackberries or mulberries. They range in size from millimetres to several centimetres. It is estimated that about 1 in 600 persons harbour a cavernoma although many experience no symptoms from them.
Cavernomas occasionally associated with malformations of the veins in the brain where they are located. These malformations are called Developmental Venous Anomalies (DVA). DVAs are considered normal variants and they drain blood from the brain to the normal circulation. They are frequently mistaken for arteriovenous shunts. DVAs are carefully preserved when removing a cavernoma to prevent stroke in the surrounding brain.
How Common Are Cavernoma?
With the increased availability of MR scanning it has been recognised that cavernomas are relatively common being found in between 1 in 200 and 1 in 600 MR scans. It has also been recognised that cavernomas may develop de-novo and that they become visible on MR images when blood leaks from them staining the brain or spinal cord.Cavernoma are best seen on MR scans. Certain specialised MR scan sequences (Gradient echo imaging, T2*-Susceptibility weighted imaging) which are particularly sensitive for blood-breakdown products in the brain increase the chances of detecting small cavernomas. Cavernomas which have not bled overtly may appear as relatively high density lesions on CT scan. Sometimes calcification can be detected within them. They are not visible on angiography although assosciated developmental venous anomalies may be demonstrated.
What is the Risk of Stroke?
This is a more complicated question than it first appears. Firstly one must be clear what precisely one means by "bleeding".
.The egress of small amounts of blood from a cavernoma is characteristic of their development and does not always result in symptoms. Furthermore symptoms that are difficult to otherwise explain are sometimes attributed to the leakage of such small volumes of blood that it may not be evident on imaging. Such "microhaemorrhage" is a plausible explanation for brainstem symptoms occurring int he presence of a brainstem cavernoma but it is more difficult to relate to less-specific symptoms (e.g. a bitemporal headache). Occasionally there will be overt bleeding from a cavernoma which damages the surrounding nervous tissue and results in stroke.
In reviewing the medical literature on this subject, it is often unclear what authors specifically mean by 'bleeding,' and it is important to recognize that these various types of bleeding should not necessarily be considered equivalent in terms of patient risk. Generally, new bleeding confined within the cavernoma (intra-lesional hemorrhage) should be differentiated from extra-lesional bleeding, where blood escapes from the cavernoma and damages the surrounding brain tissue. Both types may lead to symptoms, but those caused by extra-lesional bleeding are typically more severe.
Moreover the risk of overt bleeding appears influenced by the location of the cavernoma and whether there has been bleeding previously. It may also be the case that certain genetic alterations impose an elevated risk for bleeding.
The meta-analysis conducted by Horne et al.1 suggested that the five-year risk of bleeding for a cavernoma other than in the brainstem was 3·8% (95% Confidence Interval 2·1–5·5). If presenting with intracranial bleeding or a focal neurological deficit (e.g. a facial weakness or limb weakness) that five-year risk was 18·4% (95% 13·3–23·5).Brainstem cavernomas appeared to harbour significantly higher risk in the same study. If asymptomatic to begin with the five-year risk of bleeding was 8·0% (95% CI 0·1–15·9) and if there was a history of bleeding or neurological deficit 30·8% (95% CI 26·3–35·2).
Genetic and Environmental Influences
Familial Cavernomas (Constitutional/Germline Mutations)
The majority of cavernomas are isolated lesions without a known genetic cause. On occasion the cavernoma is the result of a gene mutation. In these cases multiple cavernomas are usually present.
Three gene mutations have been identified: CCM1(KRT1), CCM2 and CCM3(PDCD10) but there are cases of inherited cavernoma within families where none of these mutations can be identified suggesting that other mutations remain to be discovered. Also there are reports of cavernomas developing in the context of other genetic conditions e.g. Cowden's Syndrome.
In common with other genetic conditions it is postulated that a "two hit" process leads to the develop of the cavernoma. The first "hit" is that the individual is born with two copies of the games described, one that functions normally and the other does not. There is then contact with an environmental factor that inactivates the remaining gene and that set in train events that lead to the formation of the cavernoma. The precise nature of these second hits is not yet known although some of the possible candidates are mentioned below.
If only a single lesion is visible on imaging it is improbable that it is linked to the gene mutations described above. The specific characteristics conferred by any given mutation to the cavernoma are still under investigation, such as whether certain gene mutations are associated with an increased risk of hemorrhage. The currently recognized genetic forms of cavernoma exhibit an autosomal dominant pattern of inheritance, meaning that a child with one parent carrying the gene mutation has a 50% chance of inheriting it. An individual with the faulty gene may not have a detectable cavernoma themselves but has the same probability as an affected individual of passing the gene mutation on.
The underlying mechanisms of cavernoma formation are not fully elucidated and are likely more complex than described bove. It is hypothesized that the protein products of various gene mutations may interact, such as within the CCM Signaling Complex (CSC), or with other biochemical entities, to facilitate the development of cavernomas.
Non-familial Cavernoma (Somatic gene mutation?)
It appears less likely that sporadic cavernomas form in the same way as described above. If the susceptibility (the genetic mutation) is not being passed down through the parental chromosomes then the second "hit" would in theory altered the individual genetic code unique to the affected cells of the individual (a somatic gene mutation). However only about 10% of sporadic cavernomas examined have shown mutations of the CCM1-3 genes in their cells. It is possible that other genes involved in the development of of vascular structures have undergone somatic mutations.
Environmental Causes
Cavernoma has been described developing in the wake of radiotherapy to the brain although there is no evidence these malformations behave in a more aggressive way. Cavernomas that develop after radiation therapy may do so many years, even decades, after the treatment was originally given.
It is possible that ionising is acting as a "second-hit" in genetically susceptible individuals.
Gut Microbiome
The inner lining of the gastrointestinal tract is made up of layers of cells themselves consisting a complex organ of metabolism that regulates the breakdown of ingested food, absorption of its constituent elements needs for metalolism and the regulation of water absorption. An element of this organ are bacteria that normally reside in this environment and assist with some of its functions for example vitamin absorption. Changes in the make up of this bacterial colony- the "microbiome"- have been implicated in susceptibility to disease.
Studies in mice with CCM1 and 2 gene mutations suggested that changes in their gut flora resulting in increased circulation lipopolysacchride was associated with an increased propensity to cavernoma formation.
While interesting it is important to be clear this does not mean this mechanism is clinically meaningful in human beings or that particular diets, probiotics or faecal transplants are going to be of any benefit. While hard to argue that processed foods are a good thing in general heath terms it is premature to advie that alterations to diet will reduce risks from cavernoma.
Treatment
Microsurgical removal is the best established treatment for cavernoma although the optimal indications for surgery remain uncertain. Most neurosurgeons will wait on one, if not two, clinical events related to bleeding before recommending removal.
It may be there are particular presentations that might benefit from earlier surgery where it is safe and feasible e.g. early after the onset of a seizure disorder related to a cavernoma.
Stereotactic radiosurgery has been advocated as an alternative treatment with the potential to reduce the rebreeding risk from cavernoma by about three years post treatment. There are no high-quality, adequately powered comparative studies to date to support this assertion and most evidence comes from retrospective institutional series.
There are currently no proven medical therapies that modify the behaviour of cavernomas. Various drugs have been proposed as potential therapies and some trials are underway e.g. statins or the beta blocker, propranolol. These should not be prescribed as a means to reduce risk of cavernoma bleeding outside of a research setting based on current understanding.
The precise location of a cavernoma impacts on its risks and the difficulty of effective treatment. To learn more about cavernomas in specific parts of the nervous system please use the links below:
