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Rigamonti et al. Vessel Plus 2021;5:47 https://dx.doi.org/10.20517/2574-1209.2021.65 Page 3 of 8

The possibility to diagnose CCMs without pathological/surgical confirmation allowed clinicians to confirm
the CCM prevalence as ranging between 0.16% and 0.9%, corroborating the pathological data of
[20]
[4]
Otten et al. , Morris et al. and Flemming .
[21]
MRI also made possible the conduction of prospective epidemiological studies that fundamentally
corroborated the older data regarding clinical presentation .
[12]
Furthermore, MRI allowed the definitive recognition of the frequent co-existence of CCM and DVA, also
known as venous angiomas. This had the important consequence of avoiding the tragic decision to extirpate
[22]
the innocent DVA and only focus on the resection of the bleeding CCM .
MRI became invaluable to reach a presumptive preoperative diagnosis of the surgically very challenging
middle fossa lesion .
[23]
The exquisite sharpness of MRI pictures made it possible to detect the co-existence of different vascular
malformations (anomalies) and to study their respective natural histories in adults as well as children [22,24-30] .
MRI also confirmed that CCMs are dynamic lesions: they may remain stable for years, they might grow
with or without a hemorrhage, and they may contract in volume. Prospective studies carried out to study
the natural history of CCMs demonstrated the dynamic nature of these lesions and confirmed that the
majority of CCMs, cranial or spinal, might be in fact characterized by a relatively more benign course than
originally feared [31-37] .

T2 gradient recalled echo was later introduced as being more sensitive for smaller CCMs than conventional
T2 sequences, as well as susceptibility-weighted imaging, which demonstrated detection rates of 1.7× more
lesions than gradient recalled echo [38,39] .

Rare complex phenomena such as superficial siderosis, obstructive hydrocephalus, hypertrophic olivary
degeneration, and the novo lesions have been demonstrated [40-44] .

MOLECULAR
It is now very well established that CCMs can occur in either a sporadic or familial form. MRI opened a new
chapter in the history of CCMs with the discovery of the prevalence of the familial form characterized by an
autosomal dominant pattern of transmission . CCMs can appear de novo or after radiation therapy .
[45]
[43]
The natural history of the familial form has been reported by some studies to be more aggressive than that
of the sporadic form [37,46,47] . However, some other meta-analyses do not support this statement.

In parallel to the study of their clinical course, better clarification of the pathological ultrastructure of CCMs
and their complicated relationship with other rarer and more complex genetically transmitted conditions
began to occur [33,34,48,49] .

Within a relatively short amount of time after the confirmation of a clear genetic component causing the
genesis of CCMs, the study of the molecular biology of the lesion rapidly progressed. Mutations were found
in three genes: CCM1 (KRIT 1), CCM2 (MGC4607), and CCM3 (PDCD10) [50-58] .