Choroideremia is a rare, X-linked, recessive, inherited retinal dystrophy characterized by progressive atrophy of the choroid, retinal pigment epithelium (RPE), and photoreceptors. Patients experience nyctalopia and progressive loss of peripheral vision starting in the first or second decades but typically maintain central vision until the fifth or sixth decades.1 Choroideremia can rarely be complicated by choroidal neovascularization, with premature central vision loss.2–8 Herein, we report a 13-year-old male with choroideremia who presented with a chronic choroidal neovascular membrane (CNVM) that was treated with intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) and followed with optical coherence tomography (OCT) and swept-source OCT angiography (SS-OCTA).
A 13-year-old male with a diagnosis of choroideremia presented to the retinal dystrophy clinic with a 1-year history of metamorphopsia that progressed to a central “blind spot.” The patient had multiple maternal male relatives affected by choroideremia, and genetic testing confirmed the presence of a pathogenic hemizygous c.1437dupA mutation in the CHM gene. Best-corrected visual acuity (BCVA) on presentation was 20/15 in the right eye (OD) and 20/80 in the left eye (OS). Fundus exam was significant for circumferential atrophy of the peripheral choriocapillaris and RPE, macular pigmentary changes in both eyes (OU), and a subfoveal gray lesion OS (Figure 1). OCT of the macula OS showed perifoveal choroidal and RPE loss with subfoveal hyperreflective material and subretinal fluid (SRF). Fluorescein angiography demonstrated late leakage, and SS-OCTA was significant for the presence of a neovascular network with positive Doppler flow (Figure 1). These findings were diagnostic of active subfoveal CNVM.
Multimodal imaging of choroidal neovascular membrane (CNVM) in choroideremia. (A) Color fundus photograph of the left eye (OS). Note the subfoveal gray membrane and peripheral choriocapillaris and retinal pigmentary epithelium atrophy. (B) Late-stage fluorescein angiography OS showing leakage corresponding to the location of the subfoveal membrane. (C) En face swept-source optical coherence tomography angiography (SS-OCTA) 6 mm × 6 mm scan OS showing lacy neovascular network corresponding to CNVM. (D) B-scan SS-OCTA 6 mm × 6 mm scan showing CNVM with associated subretinal fluid. Note the positive Doppler flow through the CNVM.
The patient underwent examination under anesthesia with IVB. One month later, he reported a decrease in the size of the blind spot. OCT showed decreased SRF. The size of the lesion and Doppler flow did not change on SS-OCTA with treatment (Figure 2). He subsequently received five additional intravitreal injections for reaccumulating fluid during a period of 13 months, with stable 20/70 visual acuity (VA) at last follow-up. The patient is scheduled for continued as-needed treatment with IVB.
Swept-source optical coherence tomography angiography of choroidal neovascular membrane in choroideremia. Compared to baseline en face imaging (A), the size of the neovascular lesion did not change significantly at 1-month post-injection (B) or at last follow-up (C). There appears to be pruning of small vessels compared to baseline 1-month post-injection (B), with regrowth after a 3-month injection holiday (C). Doppler flow through the lesion persists with treatment (D–F). Subretinal and intraretinal fluid is decreased at 1-month post-injection (E) but reaccumulates with prolonged 3-month injection holiday (F).
Choroideremia is an X-linked retinal dystrophy caused by mutations in the CHM gene, which encodes a vesicular trafficking protein, Rab escort protein 1 (REP-1). Affected male patients present in the first or second decade with nyctalopia and progressively worsening peripheral vision, with choroidal thinning and retinal pigmentary changes starting in the fundus periphery. Central vision is typically maintained until the fifth to sixth decade.1 CNVM is a rare complication of choroideremia and can present with unilateral central vision loss. It typically occurs in younger males in whom the subfoveal choriocapillaris remains intact, but it has also been reported in older males and female carriers.2–8 The majority of reported cases of CNVM in choroideremia have been historically observed, owing to the lack of effective therapy (Table 1). More recently, two cases have been treated with intravitreal anti-vascular endothelial growth factor (VEGF), with varying results. Palejwala et al. described the case of a 13-year-old male treated with serial intravitreal bevacizumab whose vision remained stable despite mild anatomical improvement; Patel et al. reported the case of a 14-year-old male treated with intravitreal bevacizumab, with improvement in VA from 20/100 to 20/50.6,8
Prior Reports of Choroidal Neovascularization in Choroideremia
Limited functional improvement despite anatomical improvement has been attributed to subretinal fibrosis.6 Our patient started having metamorphopsia 1 year prior to presentation and most likely had a chronically untreated, active CNVM. Despite the chronicity of the lesion, he still had anatomic response to treatment and improved VA. It is important to counsel patients with choroideremia regarding regular ophthalmologic follow-up and educate about more prompt examination particularly if they notice a sudden change in their vision. Amsler grid might be recommended.
CNVM in choroideremia may often present with weak leakage on FA, and OCTA may be a useful adjunct to confirm its presence. In our patient, OCTA with doppler showed active flow through the suspected CNVM, confirming the diagnosis (Figure 1). Although OCTA biomarkers for CNVM activity are not well-established, Patel et al. further used quantitative OCTA to monitor response to treatment, showing increased neovascular growth associated with injection holiday.8,9 In our patient, the superonasal branches of the CNVM appeared to be pruned at 1 month post-injection, but the overall lesion area remained unchanged (Figure 2). This may be related to the chronicity of the lesion or to our patient's inconsistent follow-up. In previous studies of anti-VEGF treatment in CNVM in neovascular age-related macular degeneration (nAMD), maximum reduction of the lesion area on OCTA was found at 2 weeks, with reproliferation of vessels at 4 weeks.10,11 Other studies have shown that CNVM lesion area decreased significantly more in treatment-naïve patients with nAMD undergoing scheduled monthly therapy compared to pro re nata treatment.12 Although CNVM in choroideremia may respond differently than in nAMD, it is possible that earlier intervention, earlier re-assessment with OCTA, and more consistent monthly anti-VEGF treatment may have shown a larger response in our patient.
Continued treatment with intravitreal anti-VEGF may be important to maintaining VA. In our patient, there was worsening of intraretinal fluid after a 3-month injection holiday (Figure 2F). Similarly, Patel et al. noted recurrence of SRF, with concurrent decrease in VA after an injection holiday.8 Of the three patients with untreated CNVM who had follow-up, two had significant decline in VA.3,4,7 The administration of intravitreal injections may present a challenge for young patients, who may require repeated examinations under anesthesia. In our patient, we transitioned from injections in the operating room to injections in the clinic.
In conclusion, we report a rare case of chronic CNVM complicating choroideremia in a 13-year-old male who was treated with intravitreal bevacizumab. The current case emphasizes that intravitreal anti-VEGF can be helpful in improving and maintaining VA in such cases, but early detection may be important for best visual outcome. OCTA is useful for diagnosis and may aide in treatment monitoring. Patients with choroideremia should be monitored and counseled for acute changes in vision or metamorphopsia.
- Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genetics. 2012;33(2):57–65. doi:10.3109/13816810.2011.620056 [CrossRef]
- Robinson D, Tiedeman J. Choroideremia associated with a subretinal neovascular membrane. Retina. 1987;7(2):70–74. doi:10.1097/00006982-198700720-00002 [CrossRef]
- Endo K, Yuzawa M, Ohba N. Choroideremia associated with subretinal neovascular membrane. Acta Ophthalmologica Scandinavica. 2000;78(4):483–486. doi:10.1034/j.1600-0420.2000.078004483.x [CrossRef]
- Potter MJ, Wong E, Szabo SM, McTaggart KE. Clinical findings in a carrier of a new mutation in the choroideremia gene. Ophthalmology. 2004;111(10):1905–1909. doi:10.1016/j.ophtha.2004.04.028 [CrossRef]
- Sawa M, Tamaki Y, Klancnik JM Jr., Yannuzzi LA. Intraretinal foveal neovascularization in choroideremia. Retina. 2006;26(5):585–588. doi:10.1097/00006982-200605000-00016 [CrossRef]
- Palejwala NV, Lauer AK, Weleber RG. Choroideremia associated with choroidal neovascularization treated with intravitreal bevacizumab. Clinical Ophthalmology. 2014;8:1675–1679. doi:10.2147/OPTH.S68243 [CrossRef]
- Campos-Pavon J, Torres-Peña JL. Choroidal neovascularization secondary to choroideremia. Arch Soc Esp Oftalmol. 2015; 90(6):289–291. doi:10.1016/j.oftal.2014.03.012 [CrossRef]
- Patel RC, Gao SS, Zhang M, et al. Optical coherence tomography angiography of choroidal neovascularization in four inherited retinal dystrophies. Retina. 2016;36(12):2339–2247. doi:10.1097/IAE.0000000000001159 [CrossRef]
- Al-Sheikh M, Iafe NA, Phasukkijwatana N, Sadda SR, Sarraf D. Biomarkers of neovascular activity in age-related macular degeneration using oct angiography. Retina. 2018;38(2):220–230. doi:10.1097/IAE.0000000000001628 [CrossRef]
- Lumbroso B, Rispoli M, Savastano MC. Longitudinal optical coherence tomography-angiography study of type 2 naïve choroidal neovascularization early response after treatment. Retina. 2015;35(11):2242–2251. doi:10.1097/IAE.0000000000000879 [CrossRef]
- Huang D, Jia Y, Rispoli M, et al. Optical coherence tomography angiography of time course of choroidal neovascularization in response to anti-angiogenic treatment. Retina. 2015;35(11):2260–2264. doi:10.1097/IAE.0000000000000846 [CrossRef]
- Miere A, Oubraham H, Amoroso F, et al. Optical coherence tomography angiography to distinguish changes of choroidal neovascularization after anti-VEGF therapy: Monthly loading dose versus pro re nata regimen. J Ophthalmol. 2018;3751702.
Prior Reports of Choroidal Neovascularization in Choroideremia
|Report||Age/Sex||Eye||Presenting VA||Findings/Location||Treatment||Follow-Up||VA at Last Follow-Up|
|Robinson and Tiedeman, 19872||14-year-old male||OD||20/200||Subretinal heme, gray subretinal membrane, retinal pigment epithelium tear; foveal/nasal to fovea||Observe||None||N/A|
|Endo et al., 20003||17-year-old male||OD||20/100||Subretinal fibrous lesion, subretinal hemorrhage on follow-up; subfoveal||Observe||3 years||20/200|
|Endo et al., 20003||46-year-old female (carrier)||OD||20/80||Subretinal fibrous lesion; nasal to fovea||Observe||None||N/A|
|Potter et al., 20044||27-year-old female (carrier)||OD||20/40–20/80||Subretinal hemorrhage and fibrosis; subfoveal||Observe||2 years||20/400|
|Sawa et al., 20065||72-year-old male||OU||CF||Subretinal/retinal fibrovascular plaque; subfoveal||Observe||None||N/A|
|Palejwala et al., 20146||13-year-old male||OS||20/100||Subretinal fibrosis and hemorrhage; subfoveal||IVB||12 months||20/150|
|Campos-Pavon and Torres-Pena, 20147||30-year-old male||OS||20/100||Subretinal hemorrhage; temporal to fovea||Observe||6 months||20/25|
|Patel et al., 20168||14-year-old male||OS||20/150 to 20/200||Subretinal fibrosis; subfoveal||IVB||16 months||20/50|
|Present case||13-year-old male||OS||20/80||Subretinal membrane; subfoveal||IVB||6 months||20/70|