Cavernous malformations

CMs, also known as cavernomas, cavernous angiomas, or cavernous hemangiomas, are low-flow vascular lesions composed of abnormally dilated, endothelium-lined capillary spaces without intervening normal brain parenchyma, typically occurring sporadically or as part of an inherited disorder and most commonly located in the cerebral hemispheres, brainstem, or spinal cord.

CMs are vascular hamartomas composed of dilated, endothelium-lined sinusoidal channels lacking normal vessel wall architecture, including smooth muscle, tight junctions, and elastic lamina. These lesions are embedded within a collagenous matrix, typically devoid of intervening neural tissue, and often show evidence of slow flow, intralesional thrombosis, calcification, and recanalization. Hemosiderin-laden macrophages are commonly found within and around CMs, reflecting recurrent microhemorrhages and a compromised blood-brain barrier that facilitates erythrocyte extravasation and iron deposition. CMs associated with developmental venous anomalies tend to have a higher propensity for bleeding. Hereditary cerebral CMs result from loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), which encode proteins forming a cytoskeletal-associated signaling complex involved in vascular stability. Familial forms exhibit autosomal dominant inheritance with incomplete penetrance. Notably, a founder mutation in CCM1 is observed among many Hispanic patients. The CCM protein complex plays a key role in endothelial function, vasculogenesis, and angiogenesis, although the precise mechanisms linking genetic mutations to lesion formation remain incompletely understood. Emerging evidence also suggests a modulatory role of local immune responses. Oligoclonal IgG bands and specific B-cell receptor clonotypes have been identified in CM lesions, distinct from those in peripheral lymphocytes. Inflammatory infiltrates vary by lesion type, with CD20+ B cells and CD68+ macrophages enriched in lesions associated with venous anomalies, and CD3+ T cells more prominent in sporadic than familial cases. These findings raise the possibility that immunologic mechanisms contribute to lesion behavior, including hemorrhagic risk and growth.

CMs are relatively common vascular anomalies, with estimated prevalence ranging from 0.16% based on incidental MRI findings to 0.5% in autopsy studies. Prevalence increases with age and is expected to rise further due to broader MRI access. The annual detection rate in adults has been estimated at 0.56 per 100,000 but is likely underestimated in the modern imaging era. CMs can occur sporadically or as part of familial CM, an autosomal dominant condition characterized by multiple lesions and germline mutations. Spinal CMs represent a minority of cases, accounting for roughly 5% of intramedullary lesions in adults and 1% in children.

CMs may occur sporadically or be inherited in an autosomal dominant pattern due to mutations in KRIT1, CCM2, or PDCD10. Familial forms are more likely to present with multiple lesions. Additional risk factors include female sex and prior cranial radiation.

CMs often remain clinically silent, with up to 40% of patients asymptomatic. When symptomatic, they typically present between the second and fifth decades of life. Presenting symptoms include seizures in up to 50% of cases, ICH in 25%, and new focal neurological deficits without radiographic evidence of recent hemorrhage in another 25%. Seizures may be secondary generalized (27-70%), complex partial (6-58%), or simple partial (21-44%), and are not confined to any specific cortical region. Headaches (6-52%) and focal deficits (20-45%) such as hemiparesis or diplopia are also common, with wide variation based on lesion location. Brainstem cavernomas produce region-specific symptoms: mesencephalic lesions often cause diplopia, hemiparesis, and ataxia; pontine lesions may present with cranial nerve palsies (V-VIII), hemianesthesia, vertigo, and hemiparesis; and medullary lesions frequently manifest with dysphagia, hemiparesis, and ataxia. Spinal CMs typically cause radiculopathy or myelopathy, with symptoms such as limb weakness, sensory loss, pain, and sphincter dysfunction, evolving acutely, step-wise, or progressively. Many CMs are incidentally discovered on brain MRI performed for unrelated indications.

Prognosis varies depending on lesion location, number, and prior symptomatology. The annual hemorrhage rate is estimated at 0.10% per lesion or 0.25% per patient, but increases substantially for brainstem lesions (up to 4.2% per year) and in those with prior hemorrhage. Seizure risk is estimated at 1.3% per year for solitary lesions and 2.5% for multiple lesions. Larger lesion size and symptom onset before age 35 are associated with higher bleeding risk.