Cavernous hemangiomas of the retina are rare vascular tumors characterized by grape-like clusters of saccular aneurysms, otherwise normal retinal vasculature, and absence of exudation or angiographic leakage.1 The condition is generally sporadic, but in rare cases can occur alongside central nervous system angiomas and/or cutaneous vascular malformations as part of an autosomal dominant phacomatosis.2 Lesions can be variable in size but in almost all cases are non-progressive.3 Patients are usually asymptomatic unless there is associated vitreous hemorrhage or hyphema, or the tumor involves the macula or optic nerve.
Histopathologic examinations of retinal cavernous hemangiomas are rare due to the tumor's benign nature precluding enucleation in most cases. Published descriptions have therefore relied on grossly abnormal eyes removed for concern of malignancy, or end-stage eyes enucleated after long-term, severe complications.4,5 More recently, optical coherence tomography angiography (OCTA) has provided a noninvasive method of capturing high-resolution, three-dimensional images of retinal vasculature with capillary-level detail,6,7 thereby allowing for the structural examination of small, asymptomatic vascular tumors. Here, we report a first case of a patient with cerebral cavernous malformations (CCM) and an incidental finding of retinal cavernous hemangiomas, which were imaged using swept-source OCTA (SS-OCTA). This case illustrates key features of retinal cavernous hemangiomas on OCTA imaging and their correlation to characteristic histopathologic descriptions of these lesions.
A 31-year-old emmetropic man with no past ocular history presented to clinic with 1 week of floaters without flashes in both eyes. His medical history was notable for hypertension and seizures that were both well-controlled with medications. He carried a diagnosis of familial CCMs due to an autosomal dominant mutation in KRIT1. As a result of this condition, the patient had previously suffered refractory seizures for which he underwent a right frontal lobectomy at 19 years of age. There was also an extensive history of seizures affecting five generations of the patient's family. Recent magnetic resonance images of the patient's brain showed multiple cerebral angiomas. On initial ophthalmic examination, visual acuity was 20/20 in both eyes, intraocular pressures were 15 mm Hg in both eyes, and there was no afferent pupillary defect or confrontation field defect in either eye. The anterior segment exam was unremarkable. The posterior examination in the right eye was unremarkable; however, incidentally in the left eye, two clusters of small saccular aneurysms were found along the distal end of the superior vascular arcade. A gray-white epiretinal membrane (ERM) was also observed overlying one of the aneurysmal clusters (Figures 1A and 1B).
Clinical images of a retinal cavernous hemangioma. (A) Widefield fundus photography shows two peripheral lesions along the superior arcade in the left eye. (B) Closer inspection reveals a cluster of saccular aneurysms (black arrow), as well as a more distal lesion with an overlying gray-white fibrotic membrane (black arrowhead). (C) A late frame of the fluorescein angiogram demonstrates punctate staining of the aneurysms (yellow arrows) without overt leakage.
Widefield fluorescein angiography (Optos, Dunfermline, UK) of the left eye revealed two foci of punctate staining without overt leakage corresponding to the aneurysmal clusters seen on exam (Figure 1C). SS-OCTA images were obtained through the larger of the two lesions using the PLEX Elite 9000 swept-source OCT platform (Zeiss, Oberkochen, Germany). En face images illustrated an arborizing network of vascular dilatations and narrowings at the level of the inner retina. Corresponding OCT revealed a hyperreflective epiretinal membrane superficially. Flow overlay B-scan cross-sections showed blood flow through the lesion that appeared to be organized in a septated pattern (Figures 2A and 2D; Video below).
Optical coherence tomography angiography (OCTA) reveals structural features of cavernous hemangioma that correlate with previously reported histopathology. (A) A five-field swept-source OCTA (SS-OCTA) montage of the left eye captures the cavernous hemangioma peripherally in the superotemporal quadrant. (B) A magnified en face view reveals that the lesion is composed of alternating areas of vascular narrowing (red arrows) and dilatations with heterogenous signal intensity (yellow arrowheads) suggesting areas of blood flow mixed with stagnation. The anomalous vascular lesion is located in the inner retina within the same segmentation plane as the normal retinal vasculature. (C) SS-OCTA B-scans through the lesion demonstrate additional structural features including an epiretinal membrane (white arrow) and (D) lobulated areas of blood flow with structural flow overlay. These structural features acquired noninvasively via SS-OCTA correlate with previously reported histopathologic findings.
On the basis of their characteristic appearance, and the patient's neurologic history, the retinal lesions were diagnosed as cavernous hemangiomas. No ophthalmic intervention was pursued. Three months after initial presentation, the patient had no visual complaints, and the appearance of the vascular lesions was unchanged.
This case presents a rare example of retinal cavernous hemangiomas inherited as part of a familial CCM syndrome. The unique OCTA findings described in this case have not been previously reported. Our patient's disease gene, KRIT1, was the first gene identified in association with familial CCMs and accounts for approximately 40% of all cases.8,9 Patients with KRIT1 mutations can present with an array of cavernous hemangiomas affecting the brain, skin, retina, and choroid.10 Therefore, in patients without an established neurologic diagnosis, incidental retinal cavernous hemangiomas may prompt further screening of the patient or family members for systemic lesions that may predispose to more serious sequelae.10
This case uses novel SS-OCTA imaging to reinforce several important insights regarding retinal cavernous hemangiomas. Unlike other vascular tumors such as capillary or racemose hemangiomas, cavernous hemangiomas generally are not associated with exudation or angiographic leakage. Histopathologic studies suggest this is due to preservation of the blood-retinal barrier by a continuous, non-fenestrated monolayer of normal endothelial cells that form the walls and septa of cavernous hemangiomas.4 Although OCTA is unable to resolve the vascular endothelium, flow overlay B-scans of our patient give the impression of blood flow only through the lobulated lesion, corresponding to previous histologic images and descriptions by Messmer, et al. (Figure 2D). Likewise, aneurysmal dilatations and narrowings have been described via angiography and microscopy, but with SS-OCTA we can noninvasively capture high-resolution images of the hemangioma vasculature en face and adjacent to normal retinal vessels (Figure 2B). Notably blood does not appear to fill the lobulations completely, as evidenced by the patchy dark areas intermixed with the bright blood flow signal on SS-OCTA. This recalls, and perhaps corroborates, canonical angiographic descriptions of a “fluorescein cap” and prolonged dye pooling within cavernous hemangiomas that suggested areas of stagnant or clotted blood.3
Finally, as seen in Figure 2C, an ERM is present overlying the cavernous hemangioma. Although ERMs commonly form from proliferation and contracture of hyalocytes after separation of the vitreoretinal interface, earlier histopathologic studies by Messmer suggest instead that for cavernous hemangiomas, ERMs develop from glial cells within the retina that migrate upward through the internal limiting membrane and proliferate onto the retina surface, in essence an internal rather than external pathogenesis.4 Clinically, ERMs can produce artifacts and obscure details of the underlying lesion in conventional imaging and angiography but appear not to affect image quality on SS-OCTA.
Conventional OCT has been used previously to capture certain static structural features of cavernous hemangiomas, such as the glial ERM or the saccular aneurysms in cross-section.11 Although these features are also apparent on SS-OCTA, the advantage of this new modality for posterior segment vascular tumors is its ability to noninvasively visualize blood flow — and, therefore, the tumor's behavior and structure — at varying depths throughout the retina and choroid (Video below). SS-OCTA also possesses advantages over older spectral-domain OCT. These include higher scan rates (providing higher resolution), deeper tissue penetration, wider fields of view, and a more extensive reach into the peripheral retina, the latter of which was critical to imaging our case patient's pathology.12 Even among SS-OCTA platforms, the PLEX Elite device used in this report appears to confer unique advantages both in increased imaging depth and an expanded peripheral reach through image montaging that doubles the standard 50° field-of-view.13,14
Yet artifacts can limit image quality and utility even on swept-source platforms. In particular, artifacts from signal thresholding pose a problem for imaging the slow rate of blood flow within hemangiomas. OCTA relies on areas of differences, or decorrelation, within repeated scans over time to detect what is interpreted as blood flow. But if blood flows very slowly, as can happen within vascular tumors, then repeated scans of the lesion may not have sufficient decorrelation to meet the threshold for a blood flow signal and may instead be removed as background noise.15 Adjusting the interscan time interval can decrease this detection threshold and improve the ability to image areas of slow blood flow,16 but even so this limitation remains a salient one in cases such as ours that rely on the precise delineation between blood flow and stationary tissue to infer structural information about a vascular lesion.
In conclusion, symptomatic cavernous hemangiomas of the retina may be found incidentally as part of a multisystem presentation of familial cerebral cavernous malformations. OCTA provides a non-invasive method of imaging these retinal lesions and highlights key structural elements that correlate with previously described histopathologic features.
- Gass JDM. Cavernous hemangioma of the retina. A neuro-oculo-cutaneous syndrome. Am J Ophthalmol. 1971;71(4):799–814. https://doi.org/10.1016/0002-9394(71)90245-5 PMID: doi:10.1016/0002-9394(71)90245-5 [CrossRef]5553009
- Goldberg RE, Pheasant TR, Shields JA. Cavernous hemangioma of the retina. A four-generation pedigree with neurocutaneous manifestations and an example of bilateral retinal involvement. Arch Ophthalmol. 1979;97(12):2321–2324. https://doi.org/10.1001/archopht.1979.01020020537005 PMID: doi:10.1001/archopht.1979.01020020537005 [CrossRef]229814
- Messmer E, Laqua H, Wessing A, et al. Nine cases of cavernous hemangioma of the retina. Am J Ophthalmol. 1983;95(3):383–390. https://doi.org/10.1016/S0002-9394(14)78309-6 PMID: doi:10.1016/S0002-9394(14)78309-6 [CrossRef]6829684
- Messmer E, Font RL, Laqua H, Höpping W, Naumann GO. Cavernous hemangioma of the retina. Immunohistochemical and ultrastructural observations. Arch Ophthalmol. 1984;102(3):413–418. https://doi.org/10.1001/archopht.1984.01040030331031 PMID: doi:10.1001/archopht.1984.01040030331031 [CrossRef]6538410
- Shields JA, Eagle RC Jr, Ewing MQ, Lally SE, Shields CL. Retinal cavernous hemangioma: fifty-two years of clinical follow-up with clinicopathologic correlation. Retina. 2014;34(6):1253–1257. https://doi.org/10.1097/IAE.0000000000000232 PMID: doi:10.1097/IAE.0000000000000232 [CrossRef]24849703
- Huang Y, Zhang Q, Thorell MR, et al. Swept-source OCT angiography of the retinal vasculature using intensity differentiation-based optical microangiography algorithms. Ophthalmic Surg Lasers Imaging Retina. 2014;45(5):382–389. https://doi.org/10.3928/23258160-20140909-08 PMID: doi:10.3928/23258160-20140909-08 [CrossRef]25230403
- Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015;133(1):45–50. https://doi.org/10.1001/jamaophthalmol.2014.3616 PMID: doi:10.1001/jamaophthalmol.2014.3616 [CrossRef]
- Laberge-le Couteulx S, Jung HH, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. 1999;23(2):189–193. https://doi.org/10.1038/13815 PMID: doi:10.1038/13815 [CrossRef]10508515
- Denier C, Goutagny S, Labauge P, et al. ; Société Française de Neurochirurgie. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet. 2004;74(2):326–337. https://doi.org/10.1086/381718 PMID: doi:10.1086/381718 [CrossRef]14740320
- Sarraf D, Payne AM, Kitchen ND, Sehmi KS, Downes SM, Bird AC. Familial cavernous hemangioma: an expanding ocular spectrum. Arch Ophthalmol. 2000;118(7):969–973. PMID:10900112
- Say EA, Shah SU, Ferenczy S, Shields CL. Optical coherence tomography of retinal and choroidal tumors. J Ophthalmol. 2012;2012:385058. Epub 2011 Jun 8. https://doi.org/10.1155/2011/385058 PMID:23008756
- Told R, Ginner L, Hecht A, et al. Comparative study between a spectral domain and a high-speed single-beam swept source OCTA system for identifying choroidal neovascularization in AMD. Sci Rep. 2016;6(1):38132. https://doi.org/10.1038/srep38132 PMID: doi:10.1038/srep38132 [CrossRef]27917889
- Ohayon A, Sacconi R, Semoun O, Corbelli E, Souied EH, Querques G. Choroidal neovascular area and vessel density comparison between two swept-source optical coherence tomography angiography devices. Retina. 2018;1; epub ahead of print. https://doi.org/10.1097/IAE.0000000000002430 PMID:30589664
- Zhang Q, Rezaei KA, Saraf SS, Chu Z, Wang F, Wang RK. Ultra-wide optical coherence tomography angiography in diabetic retinopathy. Quant Imaging Med Surg. 2018;8(8):743–753. https://doi.org/10.21037/qims.2018.09.02 PMID: doi:10.21037/qims.2018.09.02 [CrossRef]30306055
- Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence angiography. Retina. 2015;35(11):2163–2180. https://doi.org/10.1097/IAE.0000000000000765 PMID: doi:10.1097/IAE.0000000000000765 [CrossRef]26428607
- Choi W, Moult EM, Waheed NK, et al. Ultrahigh-speed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy. Ophthalmology. 2015;122(12):2532–2544. https://doi.org/10.1016/j.ophtha.2015.08.029 PMID: doi:10.1016/j.ophtha.2015.08.029 [CrossRef]26481819