Introduction

Cerebral Cavernous Malformations (CCM), also recognised as cavernoma or cavernous angioma, are unusual clusters of capillaries (thin blood vessels) commonly found in areas of the central nervous system, such as the brain and spinal cord.¹ This disorder impacts 0.1% to 0.8% of the general population, typically people between the ages of 20 to 50, who tend to experience either no symptoms (asymptomatic) or serious symptoms like seizures, brain bleeding, and even dysfunction of certain regions of the brain (focal neurological deficits).^1,2,3,4

The majority (80%) of CCM cases are sporadic, meaning they are irregular, accounting for a single lesion and are generally asymptomatic. On the other hand, rarer familial cases (20%) of CCM give rise to multiple lesions and are hereditary,often causing mutations of genes essential for vascular (blood vessel) integrity, disrupting their normal function.^2,3,5

Management and treatment strategies differ for every person with CCM depending on their symptoms or genetic background. Fortunately, there are various treatment options offered to them.⁶ It is important that awareness for CCM is raised and maintained due to its unpredictable nature, as it can be further prevented with accurate diagnosis and appropriate management when detected early in its development.

What are Cerebral Cavernous Malformations and how do they form - Pathophysiology

CCMs are single or multiple lesions that take the form of compact capillary ‘caverns’ with a similar resemblance to blackberries as a result of the enlargement (dilation) and leaking of the capillaries. These caverns lack vital structural elements needed for a functional mature blood vessel, which are: smooth muscle, elastic tissue, and a strong endothelial barrier.^2,4

In CCM, the blood vessels are protected only by a single thin layer of endothelium (interior surface) due to decreased contact between endothelial cells, making them weak and very leaky (permeable).^2,4 This causes a significant loss of endothelial integrity and a compromised blood-brain barrier, which increases the risk of bleeding (haemorrhage), blood clotting (thrombosis) and further infection that result in severe symptoms.^2,7 Hemosiderin is a byproduct susceptible to leaking from the abnormal capillaries and is often found to surround the cavernous lesions, being directly responsible for these symptoms.⁸ 

The role of genetics: Sporadic vs. familial cases

The more common form of CCM, sporadic CCMs (SCCM), are non-hereditary and asymptomatic, in which 44% of people experience no symptoms at all, thus not requiring treatment.^1,6 SCCM presents as a singular spontaneous lesion due to loss-of-function somatic mutations (where any cell can be affected) of important protein-encoding genes that play a big role in maintaining integrity between endothelial cells: CCM1 (KRT1), CCM2 (MGC4607) and CCM3 (PDCD10).³ Mutations in just one gene out of the three can be enough to cause disease. CCM3 mutations tend to be linked to a more severe prognosis with higher risk of recurrent bleeding and increased lesion burden, often found in younger age groups.^3,5,8

Whereas familial CCM (FCCM) affects individuals with a positive family history of CCM as they inherit germline mutations,which only affect reproductive cells, CCM1 mutations are the most common, accounting for 53-65% of FCCM cases.¹ FCCM are characterised by multiple vascular lesions identified in different locations that can increase in size and number over a period of time, manifesting severe symptoms.² 

The most widely-accepted explanation for the development of CCM lesions is the ‘two-hit hypothesis’, which states the ‘first hit’ is the inherited loss-of-function mutation already existing in all cells of the individual, followed by the ‘second hit’ which is the acquired somatic mutation 

of remaining healthy alleles of the same CCM gene in endothelial cells.^7,8 This then promotes inactivation of the gene, losing its function and contributing to the formation of one or multiple CCM lesions.^2,3

Inheriting the condition: What families should know

FCCM follows an autosomal dominant inheritance pattern.^1,2 This means every affected carrier has a 50% chance of passing the mutated CCM gene down to their offspring and only one parent needs to carry the gene to inherit FCCM.^3,5 However, FCCMs can exhibit something called ‘incomplete penetrance’ where not every individual who inherits the mutated gene will display visible symptoms or lesions, however 25-40% of carriers shall likely remain asymptomatic.^1,5

It is recommended that those with a family history of CCM should consider genetic testing to screen family members at risk of inheriting the disease. This can aid with early diagnosis, allowing you to better utilise and consider  appropriate medical decisions and management of the condition. This is especially relevant with CCM3 mutations that have more critical outcomes, thus l requiring different treatment.^5,8

Diagnosis and monitoring

Magnetic Resonance Imaging (MRI) is considered the primary diagnostic choice for detecting CCM due to its high sensitivity, alongside Computed Tomography (CT), and should be carried out within one to two weeks of symptoms arising.^1,6,8 Techniques like Susceptibility-Weighted Imaging (SWI) are also integrated into MRI protocols to maximise accuracy, as they are significantly sensitive in identifying hemosiderin deposits from capillaries, making it easier to discover lesions, which can be very useful prior to surgery.^1,5,8

Unlike for SCCMs, it is important for FCCM cases to be regularly monitored because of its volatile nature. People with FCCM showing new or worsened symptoms of seizures or severe headaches may indicate a new haemorrhage.^1,5,6

Treating Cerebral Cavernous Malformations

Treatment options for CCM differ depending on various patient factors, including CCM type (sporadic or familial), symptomatic status (asymptomatic or experiencing severe symptoms) and lesion location (e.g CCM located at the brainstem is heavily linked to intracranial haemorrhage risk).⁹ People with asymptomatic lesions have a very low risk of becoming symptomatic and experiencing haemorrhages, with a 0.08% to 0.33% chance per year, therefore not requiring any intervention but rather regular conservative treatment like clinical surveillance.^1,8

Surgical resection (removal) remains the only curative option for CCM and is catered towards patients experiencing a more severe disease course, which is more common in FCCM patients. However, it is seen as a riskier approach compared to conservative treatment due to its association with possible post surgery death (6% overall risk) and other negative outcomes like brain bleeds and neurological deficits. Therefore those with asymptomatic lesions are generally not advised to take the risk of surgical resection.^1,8,9

Stereotactic radiosurgery (SRS) is another treatment option for cases where surgery would pose a high death risk.⁹ It is a non-invasive alternative often used to target high-risk symptomatic lesions that aren’t as easily accessible. SRS aims to stop recurrent haemorrhages by delivering high dosages of radiation to lesions to reduce their size and make them more stable. Consequently, SRS has its own risks of forming new lesions induced by radiation.^6,8

Future genetic treatments like gene therapy are in the process of development to deliberately target CCM mutations and repair dysfunctional proteins responsible for loss of vascular integrity.⁶ However, these methods naturally require more rigorous testing and approval before regular use.

There are also a wide range of medical management options to minimise symptoms: 

• Antiepileptic drugs: For CCM-related epilepsy/seizures⁵
• Standard migraine therapies and NSAIDs (Non-steroidal anti-inflammatory drugs): Used for headaches¹
• Anticoagulant and Antiplatelet therapies: Primarily for people with unrelated co-morbidities (co-existing diseases)^1,6
• Pharmacotherapy:  Drugs such as RhoA Kinase inhibitors, Fasudil, Statin target CCM lesion progression at a cellular level^1,5,9

Summary 

Cerebral Cavernous Malformations are clumps of atypically dilated capillary caverns, commonly found in the brain and spinal cord that bear a resemblance to blackberries when detected through an MRI scan. CCM affects approximately 0.1-0.8% of the population and occurs in two forms: sporadic and familial. Common sporadic CCM is non-hereditary and usually involves a single lesion, while familial CCM is inherited from ancestors and results in more than one lesion varying in location in the central nervous system, giving them a higher risk of complications.

CCM vascular lesions lack key structural components of normal capillaries and other blood vessels, making them fragile and prone to leakage of blood components like hemosiderin that is now used as a biomarker to smoothly identify lesions. Somatic and germline mutations causing loss of function in CCM genes (CCM1, CCM2 and CCM3) are responsible for the development of these lesions, as these genes play a big role in maintaining vascular barriers. Familial CCM follow an autosomal inheritance pattern in which there is a 50% chance of passing the germline mutation down to offspring and only one parent carrier is needed for it to be successfully inherited. Genetic testing and counselling are widely endorsed by medical professionals in order to enable early diagnosis and intervention. 

CCM patients of all types have treatment options tailored to them based on their lesion type, location and the severity of their symptoms. Surgical resection of symptomatic lesions is the most common treatment, but are typically reserved for severe cases due to high risk of morbidity after surgery. Alternatives to this include stereotactic radiosurgery, antiepileptic medications for seizure symptoms, RhoA kinase inhibitors to prevent lesion development and gene therapies are currently emerging as a future treatment option to prevent CCM gene mutations.