What is Cerebral Cavernous Malformations?
Cerebral cavernous malformations, known as CCMs, are unusually big groups of slow-flowing blood vessels without brain tissue in between. CCMs are one of four types of blood vessel abnormalities in the brain the others being arteriovenous malformations (AVM), developmental venous anomalies (DVA), and capillary telangiectasia. The symptoms and progression of CCMs can vary greatly from person to person. They’ve been called several different names in medical studies, including cavernomas, cavernous angiomas, and cavernous hemangiomas, but CCM is the preferred term. These malformations can be as small as a dot or as large as a few centimeters, and they can show up anywhere in the central nervous system, with up to 20% found in the brainstem.
CCMs can be diagnosed in children and adults, and may appear spontaneously or even disappear throughout a person’s life. It’s critical to fully understand the progression of this condition in order to avoid unneeded and possibly harmful treatments. Due to the variability of this condition, the origin, diagnosis, and management strategies for CCMs are currently a topic of discussion among brain scientists, and the best way to handle them is still changing.
What Causes Cerebral Cavernous Malformations?
Scientists are still learning about CCMs (cerebral cavernous malformations), abnormal clusters of small blood vessels in the brain, but it’s clear that genes have something to do with it. Most CCMs just happen out of the blue, but around 20% of them are familial, meaning that they run in families. When a person has familial CCM, they’ll often have more than one CCM.
Researchers have found that three genes, named CCM1, CCM2, and CCM3, are involved in causing CCM. Changes or mutations in any of these genes can result in multiple CCMs, and these genes tend to have a high “penetrance”, which means if someone carries a mutation, they are likely to develop the condition.
Some scientists have suggested that two events, or ‘hits’, might combine to cause familial CCM. The first ‘hit’ is having a mutated CCM gene, and the second ‘hit’ could be an environmental exposure, for example, radiation. This might also be why these sorts of CCMs become more common over time and after exposure to radiation. For sporadic CCMs, research suggests that new mutations in the CCM genes are involved.
The proteins these genes produce help with cell communication and blood vessel formation. The most important problem with mutated CCM genes is that they can cause leaky blood vessels, due to interactions with pathways called Notch1 and Rho kinase. This matches the typical characteristics of CCMs seen under a microscope, such as a lack of normal vessel wall structure and mature blood-brain-barrier (a protective barrier between the brain’s blood vessels and cells).
One way to distinguish CCMs from other malformations in the brain’s blood vessels is that CCMs don’t have direct connections between arteries and veins. Also, there are no normal brain cells in between the vessel malformations.
Risk Factors and Frequency for Cerebral Cavernous Malformations
Cerebral cavernous malformations (CCMs) are the second most common unexpected blood vessel-related discovery on brain magnetic resonance imaging (MRI), after aneurysms. They can be found in about 1 in 625 people who show no neurological symptoms. CCMs commonly occur in two distinct age groups: adolescents and middle-aged adults.
- There’s no noticeable difference in prevalence between genders.
- Though, there’s some debate about whether the outcome varies between men and women.
Interestingly, familial CCM is particularly common in individuals of Northern Mexican heritage, due to a common genetic mutation. The detection of CCM has risen significantly because of the frequent use of MRI technology. About 75% of CCMs are located in the supratentorial compartment of the brain, which is expected given the amount of neural tissue present in that region.
Signs and Symptoms of Cerebral Cavernous Malformations
When it comes to symptomatic cavernous malformations, also known as CCMs, their symptoms can change depending on where they are located in the body. That being said, the most frequently seen symptoms include seizures, which are observed in 50% of cases, bleeding in the brain, seen in 25% of cases, and specific nervous system issues without clear signs of recent bleeding, also seen in 25% of cases. Usually, lesions that are located above the tentorium, the membrane that separates the cerebellum from the rest of the brain, are linked to seizures. However, having nervous system issues or issues with coordination are more common in those who have lesions below the tentorium.
Interestingly, between 20% and 50% of individuals with CCMs do not show any symptoms. These people typically find out that they have a CCM incidentally, when they undergo a brain MRI for another purpose. To determine if a person has a CCM, doctors will need to get detailed information about their medical history to determine if there were any previous cases of symptomatic bleeding. They’ll also need to do a thorough neurological assessment to identify any potentially undiscovered deficits. Individuals with CCM often experience headaches, and it can sometimes be difficult to determine whether the CCM is the cause or not.
- Cause of seizures in 50% of patients
- Results in brain bleeding in 25% of patients
- Can lead to specific nervous system issues without clear evidence of recent bleeding in 25% of patients
- Often does not cause symptoms in 20-50% of patients, only being discovered through a brain MRI for other reasons
CCM-related epilepsy can also be a challenge to diagnose, as it can be hard to pinpoint the exact location of the seizure focus. When it comes to CCM-related epilepsy, experts have developed categories such as “definite,” “probable,” or “unrelated to CCM” which depend on how close the localized seizure focus is to the CCM. Since CCM often runs in families, it’s recommended, after a new CCM diagnosis, to take a detailed family history going back three generations. If multiple CCMs are found, or there’s a positive family history, testing for the CCM1, CCM2 and CCM3 genes should be considered. With the knowledge that CCM is usually passed down in families (an autosomal dominant pattern), it’s helpful to discuss familial risk and the pros and cons of testing family members who aren’t showing symptoms.
Testing for Cerebral Cavernous Malformations
The American College of Radiology (ACR) offers guidelines for the best type of imaging to use when experiencing acute neurological symptoms like headaches, functional neurological disorder (FND), or altered consciousness. If there’s suspicion of a bleeding in the brain tissue, a contrast-enhanced MRI (an MRI done with a special dye to highlight certain areas) is recommended.
When it comes to diagnosing cerebral cavernous malformations (CCMs, a condition characterized by abnormal blood vessels in the brain), MRI is the most effective tool. It can detect nearly all CCMs and is especially helpful in cases where multiple lesions are present. On a certain type of MRI, called a T2 weighted MRI, CCMs often appear as a mixed signal with a low-intensity rim, resembling “popcorn.”
Interestingly, the lining around CCMs creates a strong signal on gradient-echo MRI, which is a type of MRI scan that can highlight certain tissues. This can make the lesion appear larger than it actually is. Regardless, MRI has become the gold standard for diagnosing and staging CCMs. While there aren’t clear guidelines for how often you need an MRI if you have a known CCM, if you have new symptoms, doctors generally recommend another imaging test to check for any bleeding.
CCMs are usually not observed in angiography (a type of imaging that visualizes blood vessels), making CT angiography and digital subtraction angiography less useful for diagnosing CCMs. However, these tests can reveal adjacent developmental venous anomalies (DVAs), vascular malformations often seen together with CCMs.
A non-contrast head CT (a CT scan without using a special dye), may show irregular calcium deposits associated with CCMs. But further imaging with an MRI is typically required to confirm the diagnosis. Non-contrast head CT mainly helps in detecting bleeding in patients with symptoms.
Advanced MRI techniques are increasingly helpful in managing complex cases of CCM. Diffusion tensor imaging (DTI, a type of MRI that can visualize nerve fibers) can identify crucial white matter pathways prior to surgery for brainstem CCM. Similarly, a type of MRI technique known as blood oxygen level-dependent (BOLD) task-activation mapping has proven valuable in the pre-surgery evaluation of CCMs. Specialized techniques using high field strength SWI (susceptibility-weighted imaging, a type of MRI that highlights certain tissues) can provide detailed information about the vascular structure of CCMs, potentially helping to identify risky lesions.
Treatment Options for Cerebral Cavernous Malformations
The location of Cerebral Cavernous Malformations (CCM) – a condition where abnormal, tiny blood vessels form a “cavern” in the brain – significantly influences the treatment approach. Because CCM can manifest differently in different individuals, doctors discuss and evaluate the patient’s ability to tolerate risk before making treatment decisions.
Removal by surgery is usually the preferred treatment for CCM causing symptoms. However, some cases might not be suitable for surgery due to the lesion’s difficult-to-reach location, in which case targeted radiation therapy is used instead.
Surgical removal is the definitive treatment for CCM, despite potential post-surgery complications. Doctors usually prefer to monitor single, symptom-free CCM cases without surgery. However, for patients experiencing severe symptoms due to CCM in certain parts of the brain, known as the supratentorial regions, surgery can typically be performed with a high success rate and few complications.
CCMs located deep within the brain pose a different challenge for treatment. Brain imaging studies reveal some of these cases involve critical nerve tracts in the brain, complicating surgical treatment. While surgical removal performed at specialized centers may yield good results, there might be a high rate of complications and expected postoperative neurological problems in more than half of the cases. Therefore, aggressive intervention in these areas is usually reserved for patients who have experienced a single severe bleed or have a high cumulative risk of future bleeding due to a long life expectancy. With the right imaging guidance and in-depth knowledge of the brain’s anatomy, these troublesome cases can be handled with positive outcomes.
During surgery, the aim should be complete removal of the lesion. Studies suggest better outcomes for the patient if the surgeon also removes the surrounding area affected by the CCM, especially in cases where treatment is sought due to unmanageable seizures. However, the specific techniques used may vary from case to case.
Stereotactic Radiosurgery (SRS), a type of radiation therapy that targets a well-defined area, serves as an alternative to surgery for those with hard-to-reach lesions or high-risk profiles. SRS is precise and can protect the surrounding healthy brain tissue. However, the works of SRS are still somewhat unclear – the size of lesions might decrease, stay the same, or even increase. A significant reduction in the risk of bleeding usually occurs after a two-year period following SRS treatment.
While current research is exploring potential medication options to reduce symptoms and slow down disease progression, medical management of CCM at present is primarily limited to following established guidelines for related complications. For instance, if a CCM leads to internal bleeding in the brain, existing guidelines and protocols apply.
In making a medical decision, it’s crucial to weigh the trade-offs between the risks of surgical complications and the disease’s natural progression. Where the person’s case permits, doctors often prefer to monitor the person’s condition over time and manage symptoms with medication, instead of opting for surgery or radiation therapy. Emerging therapies, such as MRI-guided laser interstitial thermal therapy, show promise, underlining the potential for further advancements in less invasive treatment options for CCM.
What else can Cerebral Cavernous Malformations be?
Typically, it’s not difficult to diagnose Classic Cerebral Cavernous Malformation (CCM) because it causes a unique change (T2* artifact) on a non-enhancing MRI, a type of brain scan. However, when there are many small CCM, the diagnosis can be challenging. This often occurs in people with a family history of CCM.
In these situations, the doctors need to make sure that tiny spots that could be CCM are not actually due to something else. Some of the common conditions that can cause similar spots on an MRI scan include:
- Cerebral amyloid angiopathy (a brain disorder caused by buildup of an abnormal protein)
- Chronic hypertension (long-term high blood pressure)
- Hemorrhagic or previously treated metastases (spread of cancer cells that cause bleeding)
If calcium deposits (calcifications) are seen on a regular CT scan of the head, it points more towards CCM. Furthermore, if a type of blood vessel malformation called a developmental venous anomaly (DVA) is also present, the diagnosis of CCM is strongly supported.
What to expect with Cerebral Cavernous Malformations
Cerebral Cavernous Malformation (CCM), a condition affecting the blood vessels in the brain, has been studied extensively. Each year, around 2.4% of untreated patients experience a hemorrhage (bleeding) in the brain, which results in a five-year risk of bleeding of 15.8%. However, if the CCM is found by chance without the patient experiencing any symptoms, the risk of bleeding is significantly lower at 0.33% each year. Furthermore, the chances of having seizures with these incidental findings are also quite low, at 1 to 2%.
On the other hand, patients who have previously had a brain bleed from CCM are at a higher risk of another one (23% over the next five years). There’s a pattern where these re-bleeds usually occur within the first two to three years after the initial bleed. This period is followed by a quieter time when there are usually no noticeable bleeds.
Several factors can increase the chances of a CCM rupturing, such as the location and size of the malformation, if there are multiple malformations, and if the patient also has a condition known as a Developmental Venous Anomaly (DVA).
Studies show that supratentorial lobar CCMs, which are located near the surface of the brain, are less of a concern than those located deeper in the brain. For instance, those located in the brainstem (the part of the brain connecting to the spinal cord) are more likely to rupture. Another crucial finding is that patients who had a hemorrhage when first diagnosed are linked with a higher risk of more bleeds in the five years that follow. There is some debate whether being female increases the risk of bleeding.
In cases where CCM is inherited, it has been observed that patients with a certain type of mutation (CCM3) have a more aggressive disease course compared to those with a different mutation (CCM1 deletion), who usually have a milder course.
Possible Complications When Diagnosed with Cerebral Cavernous Malformations
Deciding to conduct surgery or use radiation therapy should be personalized for every patient. This is because the potential risks of not treating cavernous malformations in the brain (CCM) need to be matched with the expected additional harm from these treatments. Death from bleeding in the brain due to CCMs is actually quite rare, approximately 2.2%. Yet, over time a patient may experience progressively worsening neurological symptoms that can affect their daily life.
Thankfully, with skilled surgeons and careful patient selection, the potential for additional health complications due to surgery can be extremely low, approximately 1.5%. On the other hand, choosing not to operate might be the better option as shown by recent studies. These found that removing CCMs may actually potentially worsen a patient’s disability in the short term and increase the risk of neurological impairment or repeated bleeding in the brain.
Highlighted Risks and Benefits:
- The decision of surgery should be patient-specific
- Untreated CCMs carry potential risk
- Death due to CCM bleeding is estimated at 2.2%
- Progressive neurological issues may arise over time
- Skillful surgeons can potentially minimize surgical complications, estimated at 1.5%
- Not operating might be a better option according to recent studies
- CCM removal might result in temporary increased disability
- Surgery might increase the risk of neurological issues or repeated bleeding
Recovery from Cerebral Cavernous Malformations
There aren’t any specific rules about whether or not people should continue taking anti-seizure medicine after surgery to remove a brain disorder called “Cavernous Malformations” (CCM). However, it is common for patients to stay on single drug therapy for seizures after surgery.
Whether a patient will have seizure-free life after surgery depends on several factors. These include the frequency of seizures before surgery, how much of the CCM was removed, how much of the surrounding hemosiderin ring (a ring of iron left by blood leakage) was removed, and when the surgery was performed related to the time of diagnosis.
For those who plan to stop their anti-seizure medicine after surgery, it’s crucial to gradually decrease the dose to lessen the chances of seizures coming back.
Preventing Cerebral Cavernous Malformations
If you have cavernous malformation (CCM), it’s highly recommended to visit the official website of the Angioma Alliance (AA). This is a cross-functional group focused on giving you the latest resources. These include educational videos to help you better understand CCM.
The Alliance provides important information about genetic testing, an option that helps doctors understand the cause of this condition. They also share news about ongoing clinical research, which are studies aimed to discover better treatments for CCM. Additionally, they inform you about tissue banking which involves storing tissue samples that might be needed for future treatment.
The Angioma Alliance also creates an online community where you can connect with other people who have CCM. Through their online forums and social media platforms, patients and their families can support each other and share their own experiences dealing with this condition.
