Cerebral cavernous malformation

Definition

Cerebral cavernous malformations (CCM) are tangles of malformed blood vessels located in the brain and/or spinal cord.

Description

The blood vessels composing a cerebral cavernous malformation are weak and lack supporting tissue, thus they are prone to bleed. If seen under a microscope, a cavernous malformation appears to be composed of fairly large blood-filled caverns. A characteristic feature of a CCM is slow bleeding, or oozing, as opposed to the dangerous sudden rupture of an aneurysm (a weak, bulging area of a blood vessel). However, depending on the size and location of the CCM, and the frequency of bleeding, a CCM can also create a dangerous health emergency. Cerebral cavernous malformations are also known as cavernomas or cavernous angiomas.

CCM is usually distinct from the surrounding brain tissue and resembles a mass or a blood clot. It can occur either sporadically or in a familial (inherited) pattern. Usually, only one or two lesions are present when the CCM occurs sporadically. Those with a familial pattern of CCM usually have multiple lesions of malformed blood vessels, along with a strong family history of stroke or related neurological difficulties. Familial CCM has a pattern of auto-somal dominant inheritance, meaning that only one parent must have the illness for it to be passed on to offspring, and the risk of an affected parent passing the condition to an offspring is 50%. The first gene (CCM1) involved in this disease was recently identified and mapped to the long arm of chromosome 7. Additionally, two other genes responsible for CCM formation were also identified, one mapped to the short arm of chromosome 7 (the CCM2 gene) and the other mapped to the long arm of chromosome 3 (the CCM3 gene).

The size of the malformation varies greatly and can change depending on the amount and severity of each bleeding episode. Typically, they range from something microscopic to something the size of an orange. It is possible for a CCM not to bleed, and the ones that do so, may not necessarily bleed with the severity or intensity that requires surgery. Depending on the size and location of the lesion, the blood can reabsorb causing symptoms to disappear.

Demographics

Cavernous malformations occur in people of all races and both sexes. The male-female ratio is about equal. Family history may be predictive, especially in patients of Hispanic descent. CCM can be found in any region of the brain, can be of varying size, and present with varying symptoms. In a general population of one million people, 0.5% or 5,000 people may be found to have a cavernous malformation, although many are not symptomatic.

In the United States alone, 1.5 million people, or 1 in 200, are estimated to have some form of CCM. This translates to approximately 0.5% of the population. Approximately 20–30% of the diagnoses are made in children and 60% of affected adults are diagnosed in their 20s and 30s. It is estimated that approximately 20 million people worldwide have some kind of vascular malformation.

Causes and symptoms

Most familial cerebral cavernous malformations are present at birth (congenital). They are thought to arise between three and eight weeks of gestation, although the exact mechanism of CCM formation is not understood.

Vascular malformations can potentially occur many years after radiation therapy to the brain. Additionally, it is also assumed that severe or repeated head trauma can cause cerebral capillaries to bleed. Over time, the brain attempts to repair itself and control the bleeding by developing a lesion. Researchers assume that these theories may answer the question why some people develop the sporadic form of CCM.

Although these common neurovascular lesions affect almost 0.5% of the population, only 20–30% of these individuals experience symptoms. Symptoms include seizures , dizziness , stroke, vomiting, uncontrollable hiccups, periodic weakness, irritability and/or changes in personality, headaches , difficulty speaking, vision problems or, rarely, brain hemorrhage.

Symptoms are caused by the pressure of accumulated blood in and around the CCM on adjacent brain tissue. If the area of bleeding is small, it may take several subsequent bleeding episodes until enough pressure is built up in order for symptoms to be noticeable. The CCM could also bleed substantially, causing immediate problems and symptoms. Finally, the CCM could remain dormant without any evidence of bleeding.

Diagnosis

Cerebral cavernous malformations are usually diagnosed by computerized axial tomography (CAT) scan or, more accurately, a magnetic resonance imaging (MRI) scan with gradient echo sequencing.

MRI has provided the ability to image and localize otherwise hidden lesions of the brain and provide accuracy of diagnosis before surgery. Both the MRI and CAT scans produce images of slices through the brain. These tests help physicians to see exactly where the cavernoma is located. Cavernomas cannot be seen on a cerebral angiogram.

Often, CCMs are diagnosed when the person becomes symptomatic. However, it is common for CCMs to be diagnosed by accident when a CAT scan or MRI is conducted to investigate other health problems. Despite the presence of a CCM, it often remains inactive, meaning there is no evidence that the lesion produces bleeding.

Treatment team

Treatment for CCMs must be specific for each case. A team of cerebrovascular experts (neurologists, neurosurgeons, neuroradiologists, and radiation oncologists), together with the patient and families, decide on whether treatment is necessary and the best treatment option.

Treatment

There are three main treatment options for CCM, including observation, stereotactic radiosurgery, and surgery. If the person with CCM has no symptoms, the first treatment option is to simply observe the CCM with periodic MRI scans to assess for change. This option may be indicated if the lesion is discovered incidentally.

Stereotactic radiosurgery involves delivering highlyfocused radiation in a single treatment to the CCM. This has been used almost exclusively for lesions causing repeated hemorrhages located in areas of the brain that are not surgically accessible. It is often difficult to determine if radiosurgery is effective unless the lesion never bleeds again. In certain cases, radiosurgery has likely decreased the repeat hemorrhage rate; however, radiosurgery has never been shown to completely eliminate the malformation.

Surgery is the most common option when treatment is necessary. Because these malformations are so distinct from the surrounding brain tissue, cavernous malformations often can be completely removed without producing any new problems. It is very important to remove the entire malformation as it can regenerate if a small piece is left behind. The risk of the operation depends on the size and location of the cavernous malformation and the general health of the patient.

Clinical trials

Although there are no clinical trials for treatment of CCM ongoing as of early 2004, much of the current research focuses on the genetics of the disorder. Duke University's Center for Inherited Neurovascular Diseases was recruiting individuals with familial CCM for participation in research designed to develop a blood test for detecting CCM. For information about participating in the study, contact Ms. Sharmila Basu at (410) 614–0729, or via email at sbasu4@jhmi.edu.

Prognosis

Persons experiencing CCM-related symptoms are likely to remain symptomatic or experience a worsening of symptoms without treatment. Frequent or uncontrolled seizures, increase in lesion size on MRI, or hemorrhage are indications for removal of surgically accessible CCM lesions. Persons treated surgically experience remission or a reduction of symptoms in most cases. Approximately half of patients experience elimination of seizures, and the remainder usually have fewer, less frequent seizures. Successfully excised CCM lesions are considered cured, and it is unusual for them to return.

Special concerns

There are differing opinions about activity restriction for a person diagnosed with CCM lesions. Some physicians encourage their patients to continue their usual activities; others advocate avoiding activities where the risk for head trauma is high, such as sports including football, soccer, hockey, skiing, or skating. It is important to discuss this issue with the physician, wear approriate protective equipment when particiapting in sports, and make decisions pertaining to activity level based on the current status of the CCM and general health. It is also helpful to keep an activity record, to document any relationship between activities and symptoms.

Resources

BOOKS

Klein, Bonnie Sherr, and Persimmon Blackbridge. Out of the Blue: One Woman's Story of Stroke, Love, and Survival. Berkeley, CA: Wildcat Press, 2000.

PERIODICALS

Labauge, P. et al. "Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations." Neurology 57 (November 2001): 1825–1828.

Laurans, M. S., et al. "Mutational analysis of 206 families with cavernous malformations." Journal of Neurosurgery 99 (July 2003): 38–43.

Narayan, P., and D. L. Barrow. "Intramedullary spinal cavernous malformation following spinal irradiation." Journal of Neurosurgery 98 (January 2003): 68–72.

Reich, P. et al. "Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas." Neurology 60 (April 2003): 1135–1138.

OTHER

"NINDS Cavernous Malformation Information Page." National Institute of Neurological Disorders and Stroke. (March 1, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/cavernous_malformation.htm>.

"What Is Cavernous Angioma?" Angioma Alliance. (March 1, 2004). <http://www.angiomaalliance.org>.

ORGANIZATIONS

Brain Power Project. P.O. Box 2250, Agoura Hills Englewood, CA 91376. (818) 735-7335; Fax: (818) 706-8246. lee@thebrainpowerproject.org. <http://www.thebrainpowerproject.org>.

National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100 or (800) 999-NORD (6673); Fax: (203) 798-2291. orphan@rarediseases.org. <http://www.rarediseases.org>.

Beatriz Alves Vianna

Iuri Drumond Louro, M.D., Ph.D.