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Review
. 2019 Jul 1;131(1):1-13.
doi: 10.3171/2019.3.JNS181724. Print 2019 Jul 1.

Cavernous angiomas: deconstructing a neurosurgical disease

Issam A Awad, Sean P Polster
Review

Cavernous angiomas: deconstructing a neurosurgical disease

Issam A Awad et al. J Neurosurg. .

Abstract

Cavernous angioma (CA) is also known as cavernoma, cavernous hemangioma, and cerebral cavernous malformation (CCM) (National Library of Medicine Medical Subject heading unique ID D006392). In its sporadic form, CA occurs as a solitary hemorrhagic vascular lesion or as clustered lesions associated with a developmental venous anomaly. In its autosomal dominant familial form (Online Mendelian Inheritance in Man #116860), CA is caused by a heterozygous germline loss-of-function mutation in one of three genes-CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10-causing multifocal lesions throughout the brain and spinal cord.In this paper, the authors review the cardinal features of CA's disease pathology and clinical radiological features. They summarize key aspects of CA's natural history and broad elements of evidence-based management guidelines, including surgery. The authors also discuss evidence of similar genetic defects in sporadic and familial lesions, consequences of CCM gene loss in different tissues at various stages of development, and implications regarding the pathobiology of CAs.The concept of CA with symptomatic hemorrhage (CASH) is presented as well as its relevance to clinical care and research in the field. Pathobiological mechanisms related to CA include inflammation and immune-mediated processes, angiogenesis and vascular permeability, microbiome driven factors, and lesional anticoagulant domains. These mechanisms have motivated the development of imaging and plasma biomarkers of relevant disease behavior and promising therapeutic targets.The spectrum of discoveries about CA and their implications endorse CA as a paradigm for deconstructing a neurosurgical disease.

Keywords: CA = cavernous angioma; CASH = CA with symptomatic hemorrhage; CCM = cerebral cavernous malformation; CD14 = cluster of differentiation 14; DCEQP = dynamic contrast enhanced quantitative perfusion; DVA = developmental venous anomaly; FDR = false discovery rate; MEKK = mitogen-activated protein kinase kinase; QSM = quantitative susceptibility mapping; SRS = stereotactic radiosurgery; SWI/VenBold = susceptibility weighted imaging/BOLD venographic imaging; T2*/GRE = gradient recalled echo acquired; TLR4 = toll-like receptor 4; VEGF = vascular endothelial growth factor; angioma; cavernoma; cavernous; epilepsy; hemangioma; hemorrhagic stroke; sCD14 = soluble form of CD14; sROBO4 = soluble form of Roundabout 4; vascular disorders; vascular malformation.

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Figures

FIG. 1.
FIG. 1.
A: Artist rendition of the mulberry-like CA. B: 3D MRI slab of a human lesion, T2 acquisition at 3 Tesla, highlighting the characteristic “popcorn appearance” of a CA with a hemosiderin ring. C: Confocal immunofluorescence photomicrograph with staining (CD31, green) of endothelial cells (ECs) lining the lesion’s vascular spaces (caverns). Red blood cells (red) fill the caverns and extravasate beyond the “leaky” endothelium. Bar = 40 μM. D: Comparative image of normal brain capillaries. Bar = 20 μM.
FIG. 2.
FIG. 2.
MRI features of CA. A: MRI features of a solitary CA at the floor of the 4th ventricle, clustered around a developmental venous anomaly traversing the pons. B: Autosomal dominant familial multifocal CAs, including punctate lesions on SWI, which are not seen on conventional (T2 and GRE-weighted) sequences. C: Pontine CA with the characteristic features of symptomatic hemorrhage, with acute blood expanding the lesion with a surrounding fluid-attenuated inversion recovery (FLAIR) signal of edema (left). T1+C = contrast-enhanced T1-weighted image.
FIG. 3.
FIG. 3.
A: QSM image of a CA shown with a color-coded map of iron content (ppm). B: DCEQP permeability map of the same lesion with color scale Ki units (ml/100 g/min). C: T2-weighted image of the same lesion, provided for lesion size and definition of “region of interest” for the lesional QSM and DCEQP assessment. Figure reproduced with permission from Mikati AG, Tan H, Shenkar R, et al.: Dynamic permeability and quantitative susceptibility: related imaging biomarkers in cerebral cavernous malformations. Stroke 45:598–601, 2014.
FIG. 4.
FIG. 4.
Spectrum of clinical manifestations of CAs. Symptomatic hemorrhage, with a rigorously adjudicated definition, is a singular clinical event with distinct clinical implications regarding future risk and deploying clinical interventions. Figure modified with permission from Al-Shahi Salman R, Berg MJ, Morrison L, Awad IA: Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Angioma Alliance Scientific Advisory Board. Stroke 39:3222–3230, 2008.
FIG. 5.
FIG. 5.
A: 3D volumetric micro-CT scan of a mouse brain with a rich repertoire of CA lesions, which developed by the 3rd month of life in the Ccm3± Trp53−/− model. B: 3D volumetric micro-CT of a mouse brain with a robust cluster of CA lesions, which developed in the hindbrain by the 10th day of life, after tamoxifen injection on postnatal day 1, inducing an endothelial Ccm3−/− state in mice expressing endothelial-specific Pdgfb promoter–driven tamoxifen-regulated Cre recombinase in combination with loxP-flanked Pdcd10 exon 4. C: Photomicrograph illustrating the histological characteristics of a primordial CA lesion, consisting of a single ballooned capillary, without bleeding, a nonheme iron deposit, or inflammatory cell infiltrate (H&E, bar = 200 μM). D: Multicavernous mature CA with all the histological features of human lesions with hemosiderin deposits (H&E, bar = 200 μM). E: Process of image acquisition by micro-CT, 3D reconstruction, and semiautomated volumetric assessment of the lesion burden.
FIG. 6.
FIG. 6.
Diagram of signaling aberrations associated with CA model systems. ANGPT2 = angiopoietin 2; APC = activated protein C; BMP6 = bone morphogenetic protein 6; CDC42 = cell division control protein 42; EndMT = endothelial-to-mesenchymal transition; EPCR = endothelial protein C receptor; EPHB4 = ephrin type-B receptor 4; ERK = extracellular signal–regulated kinase; FVa = factor Va; FVIIa = factor VIIa; GDP = guanosine diphosphate; GTP = guanosine triphosphate; HEG1 = Heart of Glass; ICAP1 = integrin cytoplasmic domain-associated protein–1; KLF = Krüppel-like factor; LPS = lipopolysaccharide; MEF2 = myocyte enhancer factor 2; MST3 = serine/threonine kinase 24; MST4 = serine/threonine kinase 26; NOTCH = translocation-associated Notch protein; pMLC = phosphorylated myosin light-chain; pSmad = transforming growth factor–beta–signaling protein 1; Rap1 = Ras-related protein 1; RhoA = Ras homolog gene family member A; ROCK = Rho-associated protein kinase; SMURF1 = SMAD specific E3 ubiquitin protein ligase 1; SOK1 = serine/threonine kinase 25; STRIPAK = striatin-interacting phosphatase and kinase; TGFβ1R = transforming growth factor–β1 receptor; TIE2 = TEK receptor tyrosine kinase; TLR4 = Toll-like receptor 4; TM = thrombomodulin; TSP-1 = thrombospondin-1; UNC13 = UNC13 homolog; VAMP3 = vesicle-associated membrane protein 3; VE-cadherin = vascular endothelial cadherin; VEGFA = vascular endothelial growth factor A; VEGFR2 = VEGF receptor 2; ZO1 = zona occludens-1.
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References

    1. Abdulrauf SI, Kaynar MY, Awad IA: A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 44:41–47, 1999 - PubMed
    1. Akers A, Al-Shahi Salman R, Awad IA, Dahlem K, Flemming K, Hart B, et al.: Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery 80:665–680, 2017 - PMC - PubMed
    1. Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA: Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 18:919–930, 2009 - PMC - PubMed
    1. Al-Shahi Salman R, Berg MJ, Morrison L, Awad IA: Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Stroke 39:3222–3230, 2008 - PubMed
    1. Al-Shahi Salman R, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, et al.: Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol 11:217–224, 2012 - PMC - PubMed