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The secret of blood vessels: Why is CCM mysteriously linked to venous malformations?
Cerebral cavernoma (CCM) is a cavernous hemangioma that appears in the central nervous system and is a variant of hemangioma. This lesion is characterized by enlarged blood vessels and large vascular channels that are poorly defined in the tissue and more connected to deeper structures. Apart from the thin-walled blood vessels of CCM that look like glandular cavities filled with stagnant blood, the lesion contains no neural tissue. Depending on the patient's condition, these vessels vary in diameter from a few millimeters to several centimeters.
Clinical symptoms of CCM include recurrent headaches, focal neurological deficits, hemorrhagic stroke, and epilepsy, but some patients may be asymptomatic.
In fact, the connection between CCM and venous vascular malformations has attracted great attention from the scientific community. In about 30% of CCM patients, venous vascular effects are also found. This venous malformation is also called developmental venous anomaly. These lesions may appear as enhanced linear vessels or may exhibit a distribution of small radial vessels like the hair of Medusa in Greek mythology. These anomalies are considered developmental abnormalities of normal venous drainage.
Due to the presence of venous malformations, these lesions should not be removed as venous infarction has been reported. In cases where CCM resection is required, great care must be taken to avoid disturbing the venous malformation.
Genetics connection
Familial forms of CCM are known to be associated with three genetic loci. The CCM1 gene encodes KRIT1 (krev interaction trapped 1), and recent studies have shown that it has an important interaction with integrin cytoplasmic domain-associated protein α (ICAP1alpha). Specific CCM1 gene mutations, such as the Q455X mutation, are responsible for the formation of a cluster of cases in the southwestern United States, which is mainly due to the influence of early Hispanic immigrants.
In addition, the protein encoded by the CCM2 gene is called malcavernin. Although its exact biological function is unknown, its relevance is still under investigation.
The recent discovery that CCM1 and CCM2 proteins and ICAP1alpha form a giant molecular complex in cells has given us a new understanding of the biological mechanisms of CCM. CCM3 gene, as a recently identified CCM gene, has been shown to play an important role in the process of programmed cell death. Mutations in these four genes account for 70% to 80% of CCM cases.
CCM pathological mechanism
In terms of pathology, many molecular mechanisms have been identified to be involved in the formation of CCM. Research in 2015 showed that the endothelial cells that form cerebral vascular malformations undergo a process of endothelial cell transformation into mesenchymal cells in the presence of CCM.
This indicates that a variety of cells, including CCM mutant endothelial cells, may undergo clonal expansion and recruit non-mutated cells into the diseased area, demonstrating its complexity.
In addition, the processes of immune thrombosis and hypoxia also show abnormal regulation in CCM. These findings are of great significance for a deeper understanding of the pathology of CCM.
Diagnosis and Treatment
Diagnosis of CCM relies primarily on magnetic resonance imaging (MRI), specifically using an MRI technique called a gradient echo sequence, which can reveal small or punctate lesions. Such lesions are more conspicuous under FLAIR imaging, a technique that, unlike traditional T2-weighted imaging, effectively suppresses the signal from free-flowing fluid.
If bleeding is suspected, a CT scan is more effective at showing new blood, but after an MRI, sometimes symptoms may still be unclear, so the neurosurgeon will sometimes order a further angiogram for confirmation. Because CCM is a low-flow lesion, it is extremely invisible on angiography.
Arteriovenous malformations (AVMs) are considered as a primary concern when lesions are evident.
For symptomatic CCM patients, surgery becomes the only treatment. At this stage, there are no specific drugs that can treat CCM. According to statistics, the incidence of these vascular lesions in the general population is approximately 0.5%. Clinical symptoms usually appear between the ages of 20 and 30, suggesting that these lesions are not only congenital but may also appear randomly.
With the increasing research on CCM, can we fully reveal the relationship between the causes of these lesions and venous malformations?
