Antivascular Endothelial Growth Factors for the Management of Choroidal Neovascularization Associated with Choroidal Osteoma: A Case Study-Based Review

Abstract

Purpose:

To present a 13-year-old patient with choroidal osteoma complicated by choroidal neovascularization (CNV) treated with antivascular endothelial growth factor (anti-VEGF) agents and to review the efficacy of these agents based on relevant literature.

Methods:

Case report.

Results:

A 13-year-old girl presented with sudden visual loss in her right eye. Ophthalmic examination revealed a large choroidal osteoma complicated by subretinal and subretinal pigment epithelium (sub-RPE) hemorrhage, suggestive of CNV. Intravitreal bevacizumab injections were administered, leading to substantial improvement in vision and resolution of subretinal and sub-RPE hemorrhage. Follow-up showed that further injections were unnecessary as the CNV regressed. Literature review identified 25 cases of CNV associated with choroidal osteoma, with bevacizumab being the most frequently used anti-VEGF agent. Multiple injections were often required, though single-dose injections also proved effective in some cases. The majority of patients experienced visual improvement following treatment.

Conclusion:

Anti-VEGF agents, like bevacizumab, appear to be a promising treatment option for CNV secondary to choroidal osteoma, potentially preserving and improving vision with limited injections.

INTRODUCTION

Choroidal osteoma is an uncommon ossifying benign tumor of the choroid, predominantly affects young, healthy women in their second and third decades of life, with unilateral manifestation observed in 80% of cases.1

Despite its benign nature, the tumor exhibits a notable growth in 51% of patients within a decade, thereby predisposing individuals to potential complications such as enlargement, decalcification and subsequent retinal pigment epithelium (RPE) and photoreceptors degeneration, choroidal neovascularization (CNV) and subretinal fluid (SRF) accumulation.2 While the fundamental ailment does not need therapeutic intervention, the occurrence of complications, especially CNV, necessitates initiation of treatment.3,4 In the literature, discerning observations have been made on the therapeutic efficacy of antivascular endothelial growth factor (anti-VEGF) agents in addressing serous retinal detachment, whether occurring in isolation or concurrently with CNV, in the context of choroidal osteoma.3,4,5,6,7

We aimed to present the case of a 13-year-old patient with choroidal osteoma complicated by CNV treated with anti-VEGF agents and to review the efficacy of these agents based on relevant literature.

CASE REPORT

A 13-year-old otherwise healthy girl presented to our clinic with the complaint of sudden visual loss in her right eye for 2 days ago. The patient, along with her family, reported no related medical, surgical, or familial history of systemic and ophthalmic diseases. She did not mention any trauma to the eye. The best-corrected visual acuity (BCVA) was counting fingers at 2 m in the right eye without relative afferent pupillary defect and 20/20 in the left eye. Anterior segment examination and intraocular pressure were normal in both eyes. In funduscopy, a large choroidal osteoma with massive subretinal and sub-RPE hemorrhage was evident in the right eye [Figure 1a]. Fundus examination of the left eye was normal.

Figure 1.

Baseline. (a) Color fundus photograph of the right eye shows large choroidal osteoma with massive subretinal and subretinal pigment epithelium (sub-RPE) hemorrhage in macular region. (b) Fundus autofluorescence image depicts speckled pattern of hyper and hypoautofluorescent area nasal to the disc. (c and d) Early and late phases of fundus fluorescein angiography demonstrates diffuse blockage due to subretinal and sub-RPE hemorrhage in the macula without obvious leaking point from choroidal neovascularization network. (e) Orbital computed tomography scan confirmed bone-like density of the lesion. (f) Ultrasonography A-B scan illustrates highly echogenic lesion with posterior acoustic shadowing, resembling a pseudo-optic nerve appearance. (g) Macular optical coherence tomography reveals intraretinal cysts, subretinal hemorrhage with posterior shadowing, subretinal fluid, sub-RPE hemorrhage, and choroidal elevation

Multimodal imaging was performed for better understanding the extension of underlying lesion and confirming the diagnosis [Figure 1]. Fundus autofluorescence showed juxtapapillary primary location of the tumor with extension to macular area [Figure 1b]. Diffuse blockage due to massive subretinal and sub-RPE hemorrhage made fundus fluorescein angiography unable to demonstrate CNV network [Figure 1c and d].

Orbital computed tomography scan revealed calcified nature of the lesion with density similar to the bone. The lesion extended both nasally and temporally to the optic disc [Figure 1e]. Ultrasonography B-scan illustrated highly echogenic lesion with posterior acoustic shadowing, resembling a pseudo-optic nerve appearance [Figure 1f].

The depth and extend of submacular hemorrhage were clearly evident in macular optical coherence tomography image [Figure 1g].

Upon the diagnosis of choroidal osteoma complicated by CNV, the patient underwent intravitreal bevacizumab injection. One month following the first injection, dramatic absorption of subretinal and sub-RPE hemorrhage occurred and BCVA improved to 20/120 [Figure 2]. Second bevacizumab injection was done due to residual SRF. BCVA increased to 20/80 with complete resolution of subretinal and sub-RPE hemorrhage [Figure 3]. Close follow-up was planned and further injection ceased.

Figure 2.

One month post 1^st injection. (a) Color fundus photograph depicts dramatic absorption of subretinal and subretinal pigment epithelium hemorrhage. (b) Macular optical coherence tomography confirms funduscopic findings. Moreover, ellipsoid layer disruption temporal to the fovea, residual subretinal fluid and decrease in choroidal elevation are evident

Figure 3.

One month post 2^nd injection. (a and b) Color fundus photograph and macular optical coherence tomography show nearly complete absorption of submacular hemorrhage and subretinal fluid with partial restoration of ellipsoid layer, respectively

All procedures performed in studies involving human participant were in accordance with the ethical standards of the Institutional Review Board of the Shahid Beheshti University of Medical Sciences and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the parents of the patient for publication.

A thorough search of PubMed database was conducted to identify studies reporting the use of anti-VEGF agents for CNV associated with choroidal osteoma. Data regarding patient demographics, treatment regimens, and outcomes were extracted and analyzed. Relevant data from each case as well as our case are summarized in Table 1.

Table 1.

Identified cases of choroidal osteoma complicated by choroidal neovascularization which received antivascular endothelial growth factor therapy in the literature

Case	Age (years)/gender	Laterality	Location of CO	Initial VA	Final VA	Type of anti-VEGF	Number of anti-VEGF injections	Follow-up duration (months)	CNV status at final visit
Present study (our case)	13/female	Unilateral	Juxtapapillary and extra fovea	CF	20/80	Bevacizumab	2	3	Completely regressed
Ahmadieh and Vafi7	19/female	Unilateral	Juxta fovea	20/200	20/25	Bevacizumab	1	9	Completely regressed
Sarıgül Sezenöz et al.8	47/female	Unilateral	Juxta fovea	20/125	20/25	Ranibizumab	4	24	Completely regressed
Papastefanou et al.9	1.36/female	Unilateral	Juxtapapillary	CF	6/24	Bevacizumab	10	15	Partially regressed
	2.27/female	Unilateral	Juxtapapillary	CF	6/12	Bevacizumab	4	12	Completely regressed
	3.32/female	Unilateral	Juxtapapillary	6/24	6/12	Bevacizumab	5	12	Completely regressed
	4.66/male	Unilateral	Subfovea	6/60	6/60	Bevacizumab	3	4	Partially regressed
	5.17/female	Unilateral	Extrafovea	6/12	6/7.5	Bevacizumab	5	7	Completely regressed
	6.21/female	Unilateral	Juxtapapillary	6/12	6/9	Bevacizumab	5	10	Partially regressed
	7.58/male	Unilateral	Juxta fovea	6/18	6/60	Bevacizumab	3	3	Completely regressed
	8.72/male	Unilateral	Extrafovea	6/60	CF	Bevacizumab	7	9	Completely regressed
MirNaghi et al.10	32/female	Bilateral	Multifocal	OD: 20/100 OS: 20/20	OD: 20/40	Bevacizumab (only right eye)	3	9	Completely regressed
Zhang et al.11	40/female	Unilateral	Multifocal	5/20	18/20	Ranibizumab	3	12	Completely regressed
Almubarak et al.12	17/female	Unilateral	Juxtafovea and peripapillary	20/125	Not mentioned	Not mentioned	7	14	Completely regressed
Arrigo et al.13	10/female	Bilateral	Juxtafovea	OD: 20/63 OS: 20/25	OD: 20/25 OS: 20/25	Aflibercept (only right eye)	1	3	Not mentioned
Rong et al.14	(2008) 25/male	Bilateral	Juxtapapillary	OD: 20/60 OS: 20/20	OD: 20/400	No injection (PDT in right eye)	-	84	Not mentioned
	(2014) 31/male	Bilateral	Juxtapapillary	OD: Not mentioned OS: 20/400	OD: 20/400 OS: 20/100	Ranibizumab (left eye)	4	36	Not regressed
Jabbehdari et al.15	6/female	Unilateral	Extrafovea	20/200	20/20	Bevacizumab	4	84	Completely regressed
Rao and Gentile16	24/male	Unilateral	Juxtafovea	20/60	20/30	Bevacizumab	3	5	Not mentioned
Yoshikawa and Takahashi17	1.34/male	Unilateral	Juxtafovea	20/30	20/30	Bevacizumab	2	44	Completely regressed
	2.53/male	Unilateral	Juxtafovea	20/22.5	20/100	Bevacizumab	1	56	Completely regressed
	3.14/female	Unilateral	Juxtafovea	20/25	20/200	Bevacizumab	3	23	Partially regressed
Agarwal et al.18	10/male	Bilateral	OD: Juxtafovea OS: Peripapillary and juxtafovea	OD: 20/40 OS: 20/100	OD: Not mentioned OS: 20/60	Bevacizumab (only left eye)	3	12	Completely regressed
Saitta et al.19	45/male	Unilateral	Juxtafovea	20/50	20/32	Bevacizumab Ranibizumab Aflibercept	2 Bevacizumab 3 Ranibizumab 3 Aflibercept	10	Completely regressed
Kubota-Taniai et al.20	12/female	Unilateral	Juxtapapillary and Extrafovea	20/100	20/30	Bevacizumab	2	48	Completely regressed
Lekha et al.21	30/male	Bilateral	Juxtafovea	OD: CF OS: 20/200	OD: 2/200 OS: Not mentioned	Bevacizumab (only right eye)	4	12	Not mentioned
Gupta et al.22	9/male	Unilateral	Juxtafovea	20/400	20/400	Ranibizumab	3	30	Completely regressed

CNV: Choroidal neovascularization, VEGF: Vascular endothelial growth factor, CO: Choroidal osteoma, VA: Visual acuity, OD: Right eye, OS: Left eye, PDT: Photodynamic therapy, CF: Counting fingers

Our review comprised 17 studies involving 25 cases of CNV associated with choroidal osteoma and treated with anti-VEGF agents. The mean age of individuals was 30.48 ± 1.8 years (range: 6–72 years), with a notable majority (72%) under 40 years old. Female patients outnumbered males (14 vs. 11). Bilateral involvement was observed in 5 cases, with treatment administered to a single eye in each instance. First visit visual acuity was worse than 20/40 in 80% of cases and 58% of reported final visual acuity was 20/40 and better. Follow-up duration varied from 3 to 84 months (mean: 20.1 ± 1.97). Bevacizumab was the most frequently utilized agent (19 cases), followed by ranibizumab (5 cases) and aflibercept (2 cases). One study did not specify the anti-VEGF agent employed. Remarkably, a patient described by Saitta et al. received all three agents, with aflibercept serving as rescue therapy after inadequate responses to bevacizumab and ranibizumab.19 The majority of cases received multiple injections, while only three patients were treated with a single dose injection of anti-VEGF agents (mean: 3.92; range: 1–10). Seventeen patients demonstrated complete regression of CNV in their last follow-up visit [in some cases as shown in Table 1, the final CNV status was not clear].

Jabbehdari et al. reported a 5-year-old girl with asymptomatic choroidal osteoma that underwent photodynamic therapy (PDT) due to tumor progression toward the fovea. Subsequent CNV formation in the macular region prompted treatment with 4 intravitreal bevacizumab injections over 24 weeks, resulting in 7 years of CNV activity-free follow-up.15

Rong et al. reported a 25-year-old man with bilateral choroidal osteoma who underwent PDT for active CNV in his right eye, with unsatisfactory visual outcomes. In 2014 (7 years later), intravitreal ranibizumab administration for CNV in the left eye yielded improved outcomes compared to the fellow eye.14

DISCUSSION

Choroidal osteoma, an infrequently encountered benign tumor, is characterized by a classic clinical presentation, ocular examination, and radiological findings that collectively aid in establishing an accurate diagnosis.3,6,23 While the majority of cases present unilaterally, instances of bilateral tumor development have been reported.24 Despite its benign nature, choroidal osteoma gives rise to significant complications, including CNV, subretinal and intraretinal hemorrhages, as well as serous and hemorrhagic retinal detachments. These complications can result in substantial vision loss, particularly when CNV, subfoveal fluid, and photoreceptor degeneration are involved.3,14 Reports indicate that CNV affects 31% of patients within 5 years and 31%–47% within a decade of follow-up.3 The development of CNV is attributed to the disruption of the RPE, facilitating the growth of underlying choroidal vessels, thinning of Bruch’s membrane, and choriocapillaris, or the osteoma itself may harbor neovascular membrane extensions.25,26 Although no standardized treatment exists for choroidal osteoma beyond observation, therapeutic interventions are directed at managing complications arising from CNV and SRF. Studies suggest that intravitreal anti-VEGF therapy has shown success in managing CNV secondary to choroidal osteoma.7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 The accelerated regression of CNV in response to choroidal osteoma following a single-dose intravitreal bevacizumab injection may be attributed to enhanced drug penetration through the thinned and degenerated RPE and Bruch’s membrane, thereby increasing efficacy.7 However, spontaneous resolution of subretinal hemorrhage unassociated with CNV in a patient with choroidal osteoma has been reported after 2 years.27 It was postulated to be the consequence of spontaneous rupture of distorted choroidal vessels in the absence of even valsalva maneuver. It should be kept in mind this is a rare event and CNV should not be overlooked when subretinal/sub-RPE hemorrhage occurs in patients with choroidal osteoma, as it may cause irreversible visual loss when left untreated. Multimodal imaging may help detect small tufts of choroidal new vessels but may be inconclusive in the presence of massive submacular hemorrhage. In this situation, the clinician should weigh the benefits and disadvantages of each therapeutic modality. This issue exactly fits to our patient. In the present case, we preferred to start intravitreal injections based on the patient age, history, severity of ocular involvement, and visual loss, instead of watchful waiting, although imaging findings did not show underlying CNV. Unfortunately, the parents denied repeating angiography when good visual outcome achieved by injections.

An alternative approach for controlling CNV growth is PDT, which has demonstrated success not only in managing CNV secondary to choroidal osteoma but also in preventing tumor growth toward the foveolar.28 However, the potential for reperfusion following PDT may lead to CNV formation and tumor decalcification.15 Thermal laser photocoagulation and transpupillary thermotherapy may exhibit certain efficacy in cases of CNV secondary to choroidal osteoma, although they may also increase retinal damage.29 Since PDT and TTT complications are notable, these modalities may be better suited for the treatment of extrafoveal choroidal osteoma. Although decalcification is rarely observed following anti-VEGF treatment, it remains a possible consequence of PDT.

As a conclusion, intravitreal anti-VEGF drugs seem to be a promising treatment modality for patients with CNV associated with choroidal osteoma.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.