Familial cerebral and retinal cavernous malformations

• the sporadic type, usually as single lesion and with no familial context
• and the familial type thatis clinically defined by the presence of multiple lesions and the existence of at least one relative who also has cavernous angiomas. To date, three genes have been found to be implicated in these hereditary forms.

Definition

Cavernous angiomas are vascular malformations consisting of small cavities filled with blood. In most cases, the lesions are well-delineated. They are more or less spherical in shape and look like « raspberries » to the naked eye. They vary in size from a few millimetres to a few centimetres. Cavernous angiomas are mainly found in the brain but they may also be located in the spinal cord and, more rarely, outside the central nervous system (retina, skin, peripheral nerves etc.).Cerebral cavernous angiomas may be complicated by ICHs but of small volume because of very low blood flows through the malformations.

In 40% of cases, there is a venous malformation close to the cavernous angiomas. It is often referred to as a « developmental venous anomaly » (DVA) and it produces no clinical symptoms.

There are two types of cerebral cavernous malformation:

• the sporadic type , usually with a single lesion and with no familial context
• and the familial type which is clinically defined by the presence of multiple lesions and the existence of at least one relative who also has cavernous angiomas. To date, three genes have been found to be implicated in these hereditary forms.

Epidemiology

Cerebral cavernous angiomas are estimated to affect approximately 0.5% of the general population. They are thought to represent between 5% and 10% of all cerebral vascular malformations.

Some 20% of patients diagnosed with cavernous angiomas have a genetic form of the disease. To date, 200 non-related families have been identified in France. Cavernous angiomas are found in patients at all age but the types diagnosed in childhood (i.e. before the age of 18) account for at least 25% of familial cases.

Clinical Description

Most asymptomatic cavernous angiomas are discovered by chance. They usually become symptomatic between the third and fifth decade. The commonest symptoms include epileptic seizures and focal neurological symptoms resulting from the occurrence of cerebral haemorrhages or the local compression of cerebral tissue by the malformation.

Little is known about the natural development of cavernous angiomas. However, some authors estimate that only 5% of patients with a single cavernous angiomas will eventually have clinical signs relating to the lesion. Certain factors such as the number, position and size of the cavernous angiomas are thought to affect the risk of occurrence of such signs.

At the time of diagnosis, epilepsy is the commonest sign (50%). The risk of epilepsy is particularly dependent on the position of the cavernous angiomas. It is higher when the malformations are located close to the cerebral cortex. The seizures may be partial or secondarily generalised. In most cases, there is either a single seizure or a few repeated seizures, leading to the prescription of anti-epileptic treatment.

ICHs are usually minor, with few symptoms. The risk of a bleed is higher in patients who have already had a haemorrhage. Bleeding may occur inside the cavernous malformation, resulting in an increase in its size, or may spread directly into the cerebral tissue, to a limited extent, forming a thin crown. More rarely, the bleed is significant and accompanied by sudden-onset neurological signs (headache, vomiting, hemiplegia, impaired speech or vision etc.).

The consequences of the haemorrhage vary depending on the location of the haemangioma. Damage to the brain-stem is the most serious consequence and may cause a range of signs such as double vision, loss of balance and coordination etc. In some cases, the outcome can be fatal. The use of anticoagulant medication increases the risk of haemorrhage. The role of pregnancy as an aggravating factor   has not been clearly established.

Increase in the size of the cavernous malformation results from repeated bleeds of small size or the growth of the malformation itself. It is sometimes accompanied by focal neurological signs whose nature and severity depend mainly on location (hemiplegia, impaired vision etc.).

The occurrence of headache in patients with one or more cavernous angiomas can make the diagnosis difficult in the absence of any significant haemorrhage.

In familial cases of cavernous malformation, the occurrence of clinical signs seems to be much more frequent for sporadic forms, affecting almost 50% of patients.

Symptoms are identical to those reported in sporadic type’s i.e. epileptic seizures, ICHs, neurological deficits and headaches. The initial clinical signs occur earlier, in most cases before the age of 30. The frequency of bleeds also appears to be higher, estimated at approximately 4% per year and per patient.

In familial forms, the functional prognosis seems to depend less on the number of malformations and more on their location. When the brain-stem is unaffected, the long-term prognosis seems to be good, with 80% of patients remaining independent.

Genetic cavernous angiomas are sometimes accompanied by extraneurological signs (retinal haemangiomas and skin, in particular). The frequency of combined cerebral and retinal problems is estimated at 5% of all patients with a hereditary type of cavernous malformation. Retinal haemangiomas are usually one-sided, asymptomatic and stable. They may occur in isolation, with no associated damage to the central nervous system. The skin lesions described most commonly are very specific and are always associated with damage to the central nervous system. They are flat angiomas with an underlying venous contingent, topped by a hyperkeratotic reaction.

Etiology – Pathophysiology

The precise origin of isolated (i.e. sporadic) cavernous angiomas remains unclear.

In the familial forms, three CCM genes (cerebral cavernous malformations) have been identified: the KRIT1 or CCM1 gene and the MGC4607 or CCM2 gene situated on chromosome 7 and the PDCD10 or CCM3 gene situated on chromosome 3.

In approximately 50% of cases, the mutation lies in the CCM1 gene, in 15% of cases it is in the CCM2 gene and in 10% of cases it lies in the CCM3 gene.

In some 25% of patients with familial haemangioma, screening for these three genes does not reveal any mutation. These types « without any identified mutation » are, however, likely to be genetic and they can possibly be explained by: 1) the existence of other CCM genes that have not yet been identified, 2) the existence of mutations that cannot currently be detected using only sequencing of the regions coding for one of the 3 CCM genes, or 3) the possibility of mosaics (some cells contain the mutation; others do not).

In some cases, the mutation may appear « de novo » in a patient, neither of whose parents is ill. The patient will then present the usual signs of multiple cavernous angiomas and may pass on to his/her children the mutation responsible for the disease.

Diagnosis

Brain scans

Magnetic resonance imaging (MRI) of the brain is the standard examination for the diagnosis of cerebral cavernous angiomas because of its significant ability to detect traces of bleeds in cerebral tissue. An MRI not only enables a diagnosis to be made; it can also date the bleed, monitor changes in the cavernous malformation(s) and reveal any associated developmental venous anomaly.

A 4-category classification has been proposed, based on the MRI appearance of the cavernous angiomas (hyperintense, hypointense) in various sequences (T1, T2, gradient echo). For each type, there is corresponding information on the malformation’s characteristics (Type I: recent bleed, Type II: heterogeneous lesions with bleeds and thromboses of varying ages, Type III: old bleed, Type IV: appearance suggesting the current formation of haemangioma)

Follow-up studies of familial haemangiomas have confirmed the dynamic character of the malformations through brain scans. The development of cavernous malformation may include the appearance of new lesions and changes to their characteristics (in particular, their size). Evidence of endothelial proliferation on the periphery of the vascular cavities suggests that angiogenesis may be involved in the increase in size of certain cavernous angiomas.

Blood vessel scans

Cavernous angiomas are not visible using angiography techniques (angioscanner, MRA or conventional angiography) because blood circulates very slowly within the « caverns » (the cavities that make up the vascular malformation) and the vessels supplying blood to the malformation are very small. In some cases, it may be necessary to scan the vessels in the brain to eliminate any other type of vascular malformation.   This examination sometimes reveals a developmental venous anomaly associated with a haemangioma.

Genetic diagnosis

The identification of CCM genes now makes it technically possible to screen for these three genes in a hospital environment. In most cases, the identified mutations lead to the appearance of a premature stop codon or the partial or complete deletion of one of the 3 CCM genes.

The sensitivity of the screening in a patient with a familial cavernous malformation is approximately 94% (cf. above). It is only 57% in a sporadic case with multiple lesions.

Once the mutation has been identified in a patient, the test sensitivity rises to 100% for his/her relatives.

The decision to carry out a genetic test can only be taken after prior analysis of the real benefit of testing for the patient, especially when he/she is asymptomatic. Because of this, the indication for these tests appears to vary greatly, depending on the context (cf. following chapter).

Familial types – Genetic counselling

The genetic forms of cerebral cavernomatosis (CCM) are autosomal dominant. The disease affects men and women alike, with the proportion of people affected reaching almost 50% among the children of sufferers.

Most patients with a genetic cavernous malformation are shown to have multiple lesions when a brain scan is carried out.

For asymptomatic patients, no screening is carried out until they reach age 18 years.

Molecular testing is not indicated for patients with only one lesion (revealed by the gradient echo sequence of an MRI) and with no family history of the disease (sporadic form).

To meet the demand of clinicians and the requirements of genetic counselling, the Genetics Unit at Hospital Lariboisière has introduced a routine diagnostic procedure.

Treatment

Treatment for a cerebral cavernous malformation must be discussed on a case-by-case basis.

A range of therapeutic options is available:

• No treatment:this is the commonest decision for cases of asymptomatic cavernous angiomas or malformations discovered by chance.
• Medical treatment:there are no drugs capable of shrinking malformations or decreasing the risk of bleeding. However, drugs are available to treat the symptoms relating to the malformation. Antiepileptic drugs are usually effective if epileptic seizures have occurred. A range of analgesics can be offered to patients suffering from headaches.
• Surgical treatment:surgical removal is discussed mainly in cases where the cavernous angioma is symptomatic. The indication for surgery is based on a number of criteria: 1/ location: cortical or juxta sub-cortical (easily accessible) or deep within functional regions (less accessible). 2/ symptoms leading to discovery e.g. bleeds, epileptic seizures or focal neurological deficits (in the case of epilepsy, for example, surgical treatment is considered in drug-resistant cases) 3/ number of lesions: in the case of multiple lesions, it is sometimes difficult to identify the malformation responsible for the particular symptom(s).
• Gamma knife treatment:This technique consists of applying a dose of radiation that is precisely centred on the malformation. This is an exceptional indication but it is sometimes envisaged for cavernous angiomas that are not accessible through surgery and present a high risk of haemorrhage. However, the protection provide by this treatment is incomplete and delayed and its effectiveness remains open to discussion. It is a less invasive technique than surgery but is not risk-free.

In all cases, the prescription of anticoagulant medication (e.g. warfarin or heparin) must be avoided. Moreover, anti-platelet drugs (including aspirin and certain Nonsteroidal Anti-inflammatory Drugs (NSAIDs)) such as analgesics or antipyretic drugs are not recommended because of the increased risk of bleeding, although the risk is lower than with anticoagulant agents.

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