Cerebral cavernous malformation

Created 20/04/2021, last revision 19/11/2023

cerebral cavernous malformation (CCM) is a well-circumscribed accumulation of dilated, thin-walled vessels that affect the brain
- only a layer of endothelium and subendothelial stroma is present; smooth muscle cells and elastic fibers are absent
- the pathogenesis of CM remains unclear
forms:
- sporadic
  - incidence in the population 0.4-0.9% [Sage, 1993]
  - accounts for 8-15% of all vascular malformations
  - usually one lesion (in about 70% of cases)
- familial
  - a genetically linked multiple cavernomatosis (AD)
  - often symptomatic
  - possible de novo CM formation
can be localized anywhere (approximately 80% are supratentorial)
CM-associated anomalies:
- Café au lait spots
- DVA (developmental venous angioma)

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familial cases of CCM have autosomal dominant (AD) inheritance with incomplete penetrance

account for 10–50% of all cases
mutations have been identified in three genes:
- KRIT1 (Krev interaction trapped 1) on 7q21-q22 (CCM1)
- MGC4067 (Malcavernin) on 7p13 (CCM2)
- PDCD10 (programmed cell death 10) on 3q26-q27 (CCM3)
genotype–phenotype correlations between the three forms are emerging
- CCM1 mutation carriers appear to have a milder hemorrhage phenotype but may present with more seizures and extraneurologic manifestations
- CCM3 patients may have a more aggressive clinical course with an earlier age of onset of symptoms and greater risk of ICH

erythrocyte diapedesis through the pathological cavernoma wall
- hemoglobin degradation products induce pathological excitability, oxidative damage, and gliosis, leading to epilepsy
bleeding into the cavernoma ⇒ ↑ malformation volume
bleeding into the surrounding area

asymptomatic in up to 44% of cases
epileptic seizures (45-70%) [Májovský, 2014] [Sage, 1993]
- mostly associated with lesions localized in the frontal and temporal lobes
- cavernous malformations account for approximately 4% of refractory epilepsy
bleeding
- low risk (0.25-0.7% per year), increased after prior bleeding episodes (⇒ 4.5% / year)
- higher risk with infratentorial lesions
- hemorrhages are generally non-fatal due to low pressure within the malformation; however, repeated hemorrhages may ultimately lead to severe neurological deficit
headache (20-30%)
focal neurological deficit (e.g., in case of cerebellar or brainstem lesion)
risk factors for adverse outcome
- multiple lesions
- presence of CCM3 genotype
- early clinical presentation
- infratentorial localization
- lesion diameter >1 cm
- associated developmental venous anomaly (DVA)

CT
- lesion usually poorly visible (negative CT in up to 50% of cases)
- cavernous malformation may appear slightly hyperdense, with small calcifications
- minimal or absent postcontrast enhancement
- no mass effect or collateral edema
- recent bleeding may be detected
MRI (sensitivity 100%)
- characteristic popcorn appearance
- heterogeneous lesion with a hemosiderin rim (T2-hypointense)
- prominent finding on GRE – “blooming artifact”
- slight enhancement possible [Pinker, 2006]
DSA is normal

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the Zabramski MRI classification has been proposed for the classification of cerebral cavernous malformations
primarily useful for scientific purposes

type I: subacute hemorrhage
- T1: hyperintense
- T2: hypo-/hyperintense
type II: classic “popcorn” lesion
- T1 and T2: mixed-signal intensity centrally
- T2*/GRE/SWI: hypointense rim with blooming
type III: chronic hemorrhage
- T1: hypointense/isointense centrally
- T2: hypointense centrally
- T2*/GRE/SWI: hypointense rim with blooming
type IV: multiple punctate microhemorrhages
- GRE/SWI: “black dots” with blooming
- difficult to distinguish from small capillary telangiectasias

microsurgical resection
- relatively safe procedure with low morbidity and mortality [Májovský, 2014]
- proven indications:
  - refractory epilepsy (up to 90% of patients are seizure-free after the surgery)
  - recurrent bleeding
- in infratentorial CMs, surgery is preferred in cerebellar lesions and hemorrhagic lesions localized near the ventricle or cistern [Amato, 2013]
stereotactic radiosurgery (SRS) may be considered for inoperable lesions [Liščák, 2013] [Liščák, 2000]
- indications and therapy results are controversial
- in contrast to AVMs, the direct effect of therapy is not immediately observable; the long-term clinical course may differ from that of untreated lesions

follow-up MRI is recommended every 1-2 years for asymptomatic lesions
keep blood pressure in the normal range
beta-blockers may reduce the risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM (Zuurbier, 2022)