Cerebral cavernous malformations: natural history and clinical management

Abstract

Cavernous malformations (CMs) are angiographically-occult clusters of dilated sinusoidal channels that may present clinically with seizures, focal neurological deficits and/or hemorrhage. Across natural history studies, the annual hemorrhage rate ranged from 1.6–3.1% per patient-year, decreasing to 0.08–0.2% per patient-year for incidental CMs and to 0.3–0.6% for the collective group of unruptured CMs. Prior hemorrhage is a significant risk factor for subsequent CM hemorrhage. Hemorrhage clustering, particularly within the first 2 years, is an established phenomenon that may confound results of natural history studies evaluating the rate of rehemorrhage. Indeed, rehemorrhage rates for hemorrhagic CMs range from 4.5–22.9% in the literature. Surgical resection is the gold standard treatment for surgically-accessible, symptomatic CMs. Incidental CMs or minimally symptomatic, surgically inaccessible eloquent lesions may be considered for observation. Stereotactic radiosurgery is a controversial treatment approach of consideration only for cases of highly aggressive, surgically inaccessible CMs.

Keywords:

• brainstem
• cavernoma
• cavernous malformation
• hemorrhage
• natural history
• radiosurgery
• surgery

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• MRI is the optimal imaging modality to diagnose and follow cavernous malformations (CMs) as they are angiographically occult. Their radiographic appearance may be classified as Type I (T2-hyperintense from recent hemorrhage), Type II (Classic mixed T2 hyper- and hypointensity with hypointense hemosiderin rim), Type III (T2 hypointense) or Type IV (Hypointense and seen only on gradient echo sequences).

• The overall annual risk of developing seizures from a CM is 2.4% per patient-year. The 5-year risk of developing epilepsy after a first time seizure from a CM is 94%.

• Reported annual hemorrhage rates for cerebral CMs range from 1.6 to 3.1% per patient-year. For incidental CMs, they range from 0.08 to 0.2% per patient-year. For any unruptured CMs, they range from 0.3 to 0.6%.

• Prior hemorrhage is an established risk factor for subsequent CM hemorrhage. Rehemorrhage rates vary widely in the literature from 4.5 to 22.9%, potentially a result of hemorrhage clustering. Rebleed rates within the first year range from 14 to 18%.

• Female sex and brainstem location may independently increase the risk of CM hemorrhage. The latter is at least in part due to increased detection of small hemorrhages and more subtle CM morphological changes as a result of the sensitivity of highly eloquent adjacent brain parenchyma.

• CM multiplicity, lesion size, pregnancy and antiplatelet/antithrombotic use do not increase the risk of CM hemorrhage.

• Given their low prospective risk of seizures and hemorrhage, incidental CMs may be observed. Eloquent CMs with a remote history of symptoms and/or hemorrhage may also be considered for observation.

• Seizure freedom (Engel class I) after surgical resection of epileptogenic CMs is seen in approximately 75% of cases. This rate is enhanced by gross total resection of the CM, surgery within 1 year of seizure onset, CM size less than 1.5 cm, solitary CMs, partial seizures only and medical control of the seizures preoperatively.

• A review of surgical resection of 1390 brainstem CMs revealed a 91% rate of complete resection. Rates of transient morbidity, permanent morbidity and mortality were 45, 14 and 1.5%, respectively. Only symptomatic, hemorrhagic brainstem CMs with pial representation should be considered for surgical resection.

• Stereotactic radiosurgery is a controversial treatment consideration only for highly aggressive, surgically inaccessible CMs. Statistically significant reductions in hemorrhage rates 2 years after stereotactic radiosurgery may reflect CM natural history and may also not translate into clinical significance as the hemorrhage risk still persists.