Cerebral cavernous malformations (somatic)

Overview

Cerebral cavernous malformations (CCMs) are irregularly shaped blood vessels, often described as resembling a 'mulberry' due to their bumpy appearance. These lesions are typically found in the brain but can also occur in the spinal cord [PMID:33678082]. Unlike other vascular malformations, CCMs are known for their fragile walls, which can lead to leakage or bleeding. While some individuals may have inherited forms of CCM, somatic CCMs arise from genetic changes acquired during a person's lifetime, meaning they are not passed down through families [PMID:29665511]. The presence of CCMs can range from a single lesion to multiple malformations, and their clinical impact varies widely among individuals.

Symptoms & clinical features

The symptoms of cerebral cavernous malformations can be quite diverse, depending on the number, size, and location of the lesions. Many individuals with CCMs may not experience any symptoms, and the malformations are often discovered incidentally during imaging for other reasons. When symptoms do occur, they are typically related to bleeding from a CCM, pressure on surrounding brain tissue, or irritation of the brain [PMID:32525796]. Common symptoms include seizures, headaches (which can be severe), and focal neurological deficits such as weakness, numbness, or problems with vision, speech, or balance. In some cases, a significant bleed can lead to more acute and severe symptoms, including stroke-like events.

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Affected organs

Cerebral cavernous malformations primarily affect the central nervous system. This includes the brain, encompassing areas like the cerebrum, cerebellum, and brainstem. They can also be found in the spinal cord. The impact of CCMs is directly related to these locations, as lesions can disrupt the normal function of these critical neurological structures. While less common, CCMs have occasionally been noted in other parts of the body, but the most significant clinical concerns are typically associated with those in the brain and spinal cord.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of cerebral cavernous malformations can vary from asymptomatic individuals with a single lesion to those with multiple lesions experiencing significant neurological impairments. The risk of bleeding from a CCM is a primary concern, and this risk can fluctuate based on factors such as the lesion's location and previous bleeding history. While the exact prevalence of somatic CCMs is not well established, it is understood that the overall prevalence of CCMs in the general population is approximately 0.5%. The age of symptom onset is highly variable, ranging from childhood to adulthood, with a peak incidence often noted between 20 and 50 years of age. Some individuals may experience progressive neurological deficits over time, while others may remain stable.

Genetic causes

Somatic cerebral cavernous malformations are caused by genetic changes that occur in cells after conception, rather than being inherited from a parent. These changes typically affect specific genes involved in blood vessel development and integrity. The genes most commonly associated with CCMs are CCM2, KRIT1, and PDCD10. The proteins produced from these genes play crucial roles in maintaining the structure and function of blood vessels. For instance, KRIT1 (also known as CCM1) and PDCD10 (CCM3) are thought to work together to regulate cell signalling pathways essential for proper vascular development. Pathogenic variants in these genes can disrupt these normal processes, leading to the formation of the fragile, abnormal blood vessels characteristic of CCMs [PMID:29665511].

• CCM2
  CCM2 scaffold protein
• KRIT1
  KRIT1 ankyrin repeat containing
• PDCD10
  programmed cell death 10

Inheritance pattern

Somatic cerebral cavernous malformations are not inherited in the typical sense. Instead, they arise from genetic changes that occur spontaneously in some cells early in development or later in life. This means that an individual with a somatic CCM generally does not pass the condition on to their children, and their relatives typically do not have an increased risk of developing the same condition compared to the general population. This pattern is distinct from inherited forms of CCM, where a genetic change is present in all cells of the body and can be passed down within families.

Diagnosis & testing

Diagnosing cerebral cavernous malformations typically begins with a clinical evaluation based on reported symptoms, followed by neuroimaging. Magnetic resonance imaging (MRI) of the brain or spinal cord is the most sensitive method for detecting CCMs, often revealing their characteristic appearance. If CCMs are suspected, genetic testing can be considered to determine if the condition is somatic or inherited. For confirmed or suspected cases, referral to a clinical genetics service within the NHS Genomic Medicine Service (GMS) may be appropriate. The GMS uses specific R-codes for genetic testing, such as R222 for familial cerebral cavernous malformation, to guide diagnosis and management. A clinical geneticist or genetic counsellor can help interpret test results and discuss implications for individuals and their families.

Management & lifestyle

The management of cerebral cavernous malformations is individualised and depends on the presence and severity of symptoms, as well as the location and number of lesions. For individuals without symptoms, a 'watch and wait' approach with regular neuroimaging surveillance may be recommended to monitor the lesions for any changes. For those experiencing seizures, anti-seizure medications are often prescribed to help control them. In cases where CCMs cause significant symptoms, such as recurrent bleeding or neurological deficits, surgical removal of the lesion may be considered by a neurosurgeon. Currently, there are no specific medications to prevent the formation or growth of CCMs. Management within the NHS typically involves a multidisciplinary team, including neurologists, neurosurgeons, and genetic counsellors, to provide comprehensive care and support.

UK care pathway

Within the NHS in the UK, individuals with suspected or diagnosed cerebral cavernous malformations are generally referred to specialist neurology and neurosurgery centres. Genetic testing, when appropriate, is accessed via the NHS Genomic Medicine Service (GMS). This service uses specific R-codes to ensure the correct genetic tests are ordered, such as R222 for suspected familial forms. Referral to a clinical genetics service is essential to discuss the implications of genetic test results and access to genetic counselling, providing support and information to patients and their families.

Related conditions

While cerebral cavernous malformations are distinct, they can sometimes be confused with other vascular malformations of the brain, such as arteriovenous malformations (AVMs) or capillary telangiectasias. Although all involve abnormal blood vessels, their structure, bleeding risk, and underlying causes differ. Genetic testing and specialised imaging are crucial in distinguishing between these conditions to ensure accurate diagnosis and appropriate management.

Frequently asked questions