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Cerebral Cavernous Malformation
Monday, 02 February 2004
Tuesday, 23 November 2004

What

Cerebral cavernous malformations (CCMs) are a knot of closely clustered blood vessels. Under a microscope, they look like large blood-filled “caverns”. The walls of these blood vessels are weak and have only a single layer of lining tissue (endothelium). Since the blood vessel wall is thin and weak, it is prone to slow bleeding. Unlike similar lesions, there is no brain tissue within the malformation. They are most commonly located in the brain or along the spinal cord. There is an inherited form of CCM and a sporadic (not inherited or familial) form.

Who

It is estimated that cerebral cavernous malformations are present in about 0.5% of the general population, but a large majority of people have no symptoms and may never be diagnosed. It is also estimated that approximately 1 in 200 children have a CCM, whether symptomatic or asymptomatic. There is a particularly high incidence of CCMs, both familial and sporadic, in individuals of Mexican descent. Familial CCM is inherited in an autosomal dominant pattern, which means that one parent with the altered gene can pass it to a child 50% of the time with each pregnancy. Many individuals with CCMs are never diagnosed because the lesions produce no symptoms and this may prevent the recognition of the familial form. Individuals with familial CCM typically have multiple CCMs in different locations throughout the brain. Sporadic CCM is not inherited and is caused by a gene mutation that occurred after birth. Therefore, an individual with a sporadic CCM does not have an increased chance of having a child with a CCM. The proportion of cases caused by new gene mutations is unknown. Individuals with sporadic CCM typically have only one CCM.

Signs and Symptoms

At least 25% of individuals with CCM remain without symptoms throughout their lives. This number may be much higher since many individuals with CCM are not diagnosed. Therefore, approximately 50-75% of persons with CCM become symptomatic. CCM have been reported in infants and children, but the majority of cases are reported between the teenage years to the age of 40’s. The degree of symptoms depends on the size and the location of the CCM. CCMs are dynamic and change in size and number over time. This is caused by episodes of bleeding that change the size and shape of the CCM. Individuals with symptomatic CCM will most commonly present with seizures (40-70% of cases). Other less common presenting symptoms are focal neurological deficits (35-50%) and headaches (10-30%). Focal neurological deficits are stroke-like symptoms (such as weakness or blindness) that are related to the location of the CCM. For example, if the CCM is located in the area of the brain that controls motor function of the left leg, an individual may present with left leg weakness. As mentioned, these lesions are much more common in the white matter of the brain where many of the motor and sensory centers are located. However, some lesions can be found in the brainstem where the areas that control breathing and other basic functions are located. Lesions in this area can be life threatening.

Possible Causes

Familial CCM is caused by a gene mutation inherited from a parent. There are three areas on a gene that have been linked to CCM; CCM1, CCM2 and CCM3. This means that a mutation in these areas causes CCM. Although three areas have been named, only the CCM1 gene has been identified and can be tested for. The CCM1 gene is also known as KRIT1 or CAM and is located on chromosome 7. Researchers are still studying how this faulty gene leads to the formation of cavernous malformations. Studies show that approximately 40% of affected families test positive for CCM1 and it is more commonly identified in affected Hispanic families. The genes located at CCM2 and CCM3 have not yet been identified, but are located on chromosome 7 and chromosome 3, respectively. Initial estimates show that 20% of familial CCM is linked to CCM2 and 40% of familial CCM is linked to CCM3. Since these genes have not been identified yet, there are no tests available. The sporadic form of CCM is caused by a gene mutation that occurs after birth. Because of this, it is not found in every cell in an individual’s body and cannot be tested for or identified. No one has identified a cause for sporadic CCM, but several theories have been suggested. One theory is that CCMs develop many years after radiation therapy to the brain. Another theory is that they develop secondary to severe or repeated head trauma. However, there are patients with neither of these events in their history who still have CCMs.

Diagnosis

A high percentage of CCMs are never diagnosed because many individuals remain without symptoms for their lifetime. However, when an individual develops certain symptoms, such as weakness, seizures, or headaches, studies will be performed to identify a cause. CCMs can be diagnosed by several imaging studies or a biopsy. CCMs have a characteristic appearance on imaging studies like MRI. Cerebral angiography can also identify CCM. This type of study involves using a dye injected into the blood vessels to better visualize the vessels and the malformation. If the decision has been made to remove the lesion, the appearance of the malformation under the microscope will confirm the diagnosis. Genetic testing is available to identify familial CCM associated with the CCM1 gene mutation. This can be used to confirm a diagnosis or to identify affected family members. Genetic testing for CCM2 and CCM3 is available on research basis only. Familial CCM is diagnosed when two or more family members are diagnosed with CCM. If the familial form of CCM is identified, family members should be evaluated to see if they are affected.

Treatment

Treatment of CCM depends on the size, location and symptoms. Management usually involves close monitoring, treating seizures with medications, or sometimes, surgical removal. If a CCM is found, but is causing little or no symptoms, there is no indication for treatment. Most doctors and surgeons would choose to monitor the lesion, rather than interfering in any way. Seizure control is discussed in conjunction with a neurologist who can prescribe medications to suppress the seizures. Brain surgery can be helpful in specific situations, but is associated with many risks. Indications for surgery include, but are not limited to, uncontrollable seizures or severe bleeding. If there are many lesions or if the lesion is very large, surgery is very difficult to perform. It is important to remember that surgery is not a cure and carries tremendous risk. Radiation therapy has also been studied in the treatment of CCM, but there is no evidence to suggest that this provides any benefit. Currently there is no cure for CCM, but research is ongoing. The identification of the CCM1 gene was a tremendous breakthrough and researchers hope that further research of this gene and the other associated genes will lead to the development of a cure.

Prognosis

The long-term course of CCM is extremely variable. Many people live long and healthy lives with little or no symptoms. Others may have mild neurologic problems that may remain stable, while others may have more severe neurologic problems that may become worse with time. Some individuals may have lesions that are either very large or are located in dangerous and vital areas of the brain. These people may be severely impaired and are at risk of death. There is some controversy about whether or not individuals with CCM should be restricted from certain activities. Certain contact sports and strenuous activities, such as football, hockey and weightlifting, may present a risk to some individuals with CCM.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

The Brain Power Project
Provides information about CCM, including diagnosis, genetic testing, ongoing research, and links to other sites.

Angioma Alliance
Provides information about CCM, links to forums and other links and information about ongoing research studies.

Google Search for Cerebral Cavernous Malformation

References and Sources

www.thebrainpowerproject.org www.geneclinics.org www.yalenewhavenhealth.org