Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: a susceptibility-weighted imaging study with 7-Tesla MRI

Abstract

OBJECTIVE Multiple cerebral cavernous malformations (CCMs) are rare lesions that occur in sporadic or familial form. Depending on the disease form, the natural history and treatment of the lesions strongly vary. Molecular analysis of an underlying germline mutation (CCM1-3) is the most sensitive screening method to distinguish between sporadic and familial cases. However, based on the different pathomechanisms that are believed to be involved in either form, significant distinctions in the CCM-associated cerebral venous angioarchitecture should be detectable. This has not been systematically studied. METHODS A consecutive series of 28 patients with multiple CCMs (681 total) diagnosed on 1.5-T MRI underwent genetic screening for CCM1-3 mutations and high-resolution susceptibility-weighted imaging (SWI) of the cerebral venous angioarchitecture with 7-T MRI. Imaging data were analyzed to examine the CCM-associated venous angioarchitecture. Results were correlated with findings of molecular analysis for CCM1-3 mutations. RESULTS Two different SWI patterns (sporadic and familial) were found. The presence of associated developmental venous anomalies correlated with negative screening for germline mutations (11 sporadic) in all cases. All patients with confirmed familial disease showed normal underlying venous angioarchitecture. Additionally, a very unusual case of a probable somatic mutation is presented. CONCLUSIONS The SWI results of the venous angioarchitecture of multiple CCMs correlate with sporadic or familial disease. These results are consistent with the theory that venous anomalies are causative for the sporadic form of multiple CCMs.

Cerebral Cavernous Malformation: What a Practicing Clinician Should Know

“…2 Our understanding of the commonly associated DVA and its angioarchitecture has improved due to 7-T MRI SWI sequences ( Figure 3F). 29 Zabramski type II (eg, Figure 3B) and III lesions are fairly characteristic on MRI; however, type I and type IV lesions are not specific ( Table 2). The diagnosis of a CM may not be obvious on imaging in the presence of a sizable associated acute hemorrhage, type 1 lesion.…”

“…Evolving data using 7-T susceptibility-weighted imaging (SWI) suggest that all sporadic CMs have an associated DVA. 28,29 Up to 20% of patients have the familial form of the disease. 14 There are 3 known protein-encoding genes resulting in familial CM disease: KRIT1 (CCM1), malcavernin (CCM2), and PDCD10 (CCM3) ( Figure 2).…”

Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up

“…2 However, we detected CCMs in only a small percentage of cases (4.9%), in keeping with the theory that nonfamilial CCMs are acquired lesions related to DVAs through the process of hemorrhagic angiogenic proliferation. 28,29 Taken together, our findings suggest that in the neonatal period, there is a higher risk of flow-related complications in DVAs, potentially leading to venous hypertension and associated venous congestion, hemorrhage, and/or infarction. Putative neonatal risk factors of hemodynamic decompensation include mechanical distortion during vaginal birth and immaturity of the venous, immune, and hemostatic systems as well as hypercoagulability, which may be potentiated by maternal factors or inflammation.…”

Cerebral cavernous malformations: Prevalence of cardiovascular comorbidities and allergic diseases compared to the normal population

“…In population‐based studies approximately half of the patients present with incidentally discovered and asymptomatic CCM [3] Genetic germline mutations among one of the three CCM genes ( CCM1‐3 ) account for only up to 15%–20% of the total cases, while the majority occurs sporadically . Sporadic CCM typically present in the form of a single lesion, whereas familial cases are characterized by multiple lesions [4] In contrast to familial cases, sporadic cases are frequently associated with developmental venous anomalies (DVAs), suggesting a different developmental mechanism [5–7] In addition, both familial and sporadic cases show an astonishing variability of disease severity in terms of lesion burden, symptoms and ICH rate [3,8] These findings support the hypothesis that multiple intrinsic and environmental additional factors may contribute to disease development and maintenance. While potential environmental and genetic risk factors have been studied in populations of familial cases [9,10] this has not been sufficiently carried out in sporadic cases [11,12]…”