- Email: [email protected]
Association of Pediatric Choroidal Neovascular Membranes at the Temporal Edge of Optic Nerve and Retinochoroidal Coloboma
Association of Pediatric Choroidal Neovascular Membranes at the Temporal Edge of Optic Nerve and Retinochoroidal Coloboma DILRAJ SINGH GREWAL, DU TRAN-VIET, LEJLA VAJZOVIC, PRITHVI MRUTHYUNJAYA, AND CYNTHIA A. TOTH PURPOSE:
To describe the characteristics of pediatric choroidal neovascular membranes (CNVs) associated with retinochoroidal and optic nerve coloboma using optical coherence tomography (OCT) and their response to treatment. DESIGN: Retrospective case series. METHODS: Retrospective review of children <16 years of age with CNV and retinochoroidal and optic nerve coloboma from 1995–2015 who underwent OCT imaging using either handheld (Bioptigen, Morrisville, NC) or tabletop OCT (Spectralis; Heidelberg, Carlsbad, CA). RESULTS: Eight eyes of 8 patients (3 males, 5 females) with a mean age of 4.1 ± 3.9 years (range 6 months–10 years) at diagnosis were included. Mean follow-up was 21.4 ± 12.1 months (range 7–38 months). An optic nerve coloboma was present in 2 eyes and combined optic nerve and retinochoroidal coloboma in 6 eyes. In all eyes, CNVs were located at the temporal margin of the coloboma closest to the macula. Fluorescein angiogram characteristics included staining without leakage suggesting inactivity (n [ 6) and leakage (n [ 2). OCT characteristics included subretinal fluid (n [ 5), intraretinal fluid and cysts (n [ 1), and subretinal hyperreflective material (n [ 7). Two eyes received intravitreal bevacizumab (range 3–6) injections, one of which also underwent focal peripapillary laser. Both eyes showed improvement in subretinal or intraretinal fluid on OCT. Vision at presentation among those quantified ranged from 20/200 to 20/40 and at final follow-up from 20/400 to 20/30. Genetic or systemic abnormalities were seen in 6 patients. CONCLUSIONS: Association of pediatric CNV occurrence at the temporal margin of retinochoroidal and optic nerve colobomas closest to the fovea has not been established before and careful OCT and angiographic assessment of this region is warranted. The CNV lesions exhibit a varied degree of response Supplemental Material available at AJO.com. Accepted for publication Oct 14, 2016. From the Department of Ophthalmology, Duke University, Durham, North Carolina. Inquiries to Dilraj Singh Grewal, Department of Ophthalmology, Duke University, 2351 Erwin Rd, Box 3802, Durham, NC 27710; e-mail: dilraj. [email protected]
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to treatment. (Am J Ophthalmol 2017;174: 104–112. Ó 2016 Elsevier Inc. All rights reserved.)
R
ETINOCHOROIDAL AND OPTIC NERVE COLOBOMA
results from the abnormal closure of the embryonic fissure during weeks 5–7 of fetal life and may involve the iris, lens zonules, ciliary body, choroid, retina, and optic nerve.1,2 They may be associated with serous retinal detachments, lenticonus, persistent hyaloid arteries, and optic disk pits.2 Genetic and environmental causes have been suggested to cause an intrauterine insult with a defective embryonal fissure closure leading to coloboma of the fundus.3 Histologically, there is no normal choroid, retinal pigment epithelium, or retina overlying a retinochoroidal coloboma, and the overlying tissue is an extension of the neurosensory retina called the intercalary membrane.2 Colobomas can vary from small defects located in the equatorial region that do not interfere with vision to larger ones involving the disc and macula with severe impairment of vision. Vision impairment may also be caused by retinal detachment, which has been estimated to _40% of these eyes, or choroidal neovascular occur in < membranes (CNVs), which are a rare cause of decreased vision in children with retinochoroidal colobomas.4,5 Optical coherence tomography (OCT) findings across a spectrum of coloboma severity have been described.2 In cases with retinal detachment, OCT has allowed for identification of the precise site of communication between the subintercalary membrane space and subretinal space.6 In some cases, subclinical retinal detachments have been identified along the margin of the coloboma. OCT characteristics of CNVs associated with pediatric optic nerve and retinochoroidal colobomas and their response to treatment have, however, not been well described before and are limited to isolated case reports. In these patients, it has been suggested that discontinuities of Bruch membrane and retinal pigment epithelium (RPE) at the margin of the coloboma may allow choroidal vessels to enter the subretinal space, resulting in CNV formation at the margin. This region at the coloboma margin has not yet been studied using high-resolution OCT in children. In this report, we describe the largest series of pediatric CNV associated with optic nerve and retinochoroidal
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FIGURE 1. A 6-month-old boy with bilateral uveal coloboma involving the iris, retina/choroid, and optic nerve who developed a choroidal neovascular membrane at the temporal margin of the retinochoroidal coloboma with subretinal hemorrhage in the left eye (Top, first column, white arrow) with leakage on fluorescein angiography (Top, second and third column) and overlying subretinal fluid on optical coherence tomography (Top right, white star). After 2 bevacizumab injections there was resolution of the subretinal hemorrhage (Bottom, first column, black arrow), reduction of leakage on fluorescein angiography (Bottom, second and third columns), and resolution of subretinal fluid on optical coherence tomography (Bottom last column).
coloboma reviewed over a period of 20 years, and show the OCT characteristics of CNV and response to treatment.
RESULTS EIGHT EYES OF 8 PATIENTS (3 MALES, 5 FEMALES) WITH A
METHODS THIS WAS A RETROSPECTIVE ANALYSIS OF CLINICAL RE-
cords of patients <16 years of age with retinochoroidal or optic nerve coloboma and associated CNV from March 1995 to March 2015 who were examined at the Pediatric Retina Service, Duke Eye Center (Durham, NC). Imaging was performed under an institutional review board– approved prospective observational study for pediatric retina imaging. Images from this database were analyzed. The study was approved by the Duke University Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. The Duke Enterprise Data Unified Content Explorer (DEDUCE) database was searched for patients diagnosed with retinochoroidal coloboma or optic disc coloboma (based on receipt of International Classification of Diseases, 9th revision [ICD-9] codes 743.52 or 743.57) and who had an associated CNV (ICD-9 code 362.16) as identified by billing records.7 Imaging was performed using either handheld spectral domain OCT during examination under anesthesia (Envisu; Bioptigen Inc, Morrisville, NC) or a tabletop unit in clinic when the child was old enough to co-operate (Spectralis; Heidelberg, Carlsbad, CA). Fluorescein angiography was performed using RETCAM (Clarity Medical Systems, Pleasanton, CA) during examination under anesthesia. VOL. 174
mean age of 4.1 6 3.9 years (range 6 months-10 years) and with available OCT imaging at diagnosis were included. Mean follow-up was 21.4 6 12.1 months (range 7–38 months). An associated iris coloboma was present in 5 eyes. None of the eyes had a lens or lens zonule coloboma. One of the patients had microphthalmia. An optic nerve coloboma was present in 2 eyes and a combined optic nerve and retinochoroidal coloboma in 6 eyes. The fovea was involved within the coloboma in 4 eyes and spared in 4 eyes. In all 8 eyes, the CNV was located at the temporal margin of the coloboma: temporal to the colobomatous nerve (n ¼ 3) and at the temporal edge of the combined optic nerve–retinochoroidal coloboma closest to the fovea (n ¼ 5). Figures 1–4 provide representative examples and OCT characteristics. Fluorescein angiographic characteristics included window defects in the area of coloboma or staining but no leakage, suggesting inactivity (n ¼ 6; Figure 3), and leakage (n ¼ 2; Figures 1 and 2). Leakage was observed at the temporal edge of optic nerve (n ¼ 1; Figure 2) and retinochoroidal (n ¼ 1; Figure 1) coloboma. Seven patients underwent imaging with handheld spectral domain OCT during examination under anesthesia, while 1 patient could be imaged using the tabletop OCT unit in the clinic. OCT characteristics included subretinal fluid (n ¼ 5; Figures 1 and 2), intraretinal fluid and intraretinal cysts (n ¼ 1; Figure 3), and subretinal hyperreflective material consistent with a subretinal fibrovascular
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FIGURE 2. A 2-year-old boy with coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality (CHARGE) syndrome with bilateral optic nerve coloboma (top left) and associated active choroidal neovascular membrane at the temporal margin of the optic nerve coloboma (top, first column) with leakage on fluorescein angiogram in the left eye (top, second and third columns) and surrounding subretinal fluid on optical coherence tomography (top last column). After 4 injections of intravitreal bevacizumab (1.25 mg/0.05 mL; Middle, first column) there was a reduction in leakage on fluorescein angiogram (Middle, second and third columns) and subretinal fluid on optical coherence tomography (Middle, last column). After continued bevacizumab therapy (n [ 5) and focal peripapillary 532-nm green diode laser (n [ 1; Bottom, left column), there was further reduction in leakage on fluorescein angiogram (Bottom second and third columns) and reduction of retinal thickening and consolidation of subretinal hyperreflective material on optical coherence tomography (Bottom, last column).
membrane (n ¼ 6; Figures 1–4). Among patients in whom vision could be quantified, it ranged from 20/200 to 20/40 at presentation and at final follow-up ranged from 20/400 to 20/30. Individual vision for all patients is listed in Table 1. Among the fellow eyes, a coloboma was present in 7 eyes (retinochoroidal coloboma n ¼ 5, retinochoroidal and optic nerve coloboma n ¼ 2, iris coloboma n ¼ 2, and lens coloboma n ¼ 1). A retinal detachment associated with the coloboma was present in 3 fellow eyes, and 1 fellow eye had micro-ophthalmia. None of the patients had a family history of uveal colobomas. Genetic abnormalities were observed in 2 of 3 patients that underwent genetic testing. These included a 2-copy gain of chromosome 8q11.21 and chromosome 4 (4q35.2) microdeletion. However, neither of these abnormalities has been shown to be associated as a cause of retinochoroidal or optic nerve coloboma. There was a syndromic association of coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality (CHARGE) syndrome 106
with the optic nerve and retinochoroidal coloboma in 2 patients. An additional 4 patients had associated systemic abnormalities but did not undergo formal genetic testing. These included cardiac anomalies (e.g., double outlet right ventricular hypertrophy, ventricular septal defect, patent foramen ovale, coarctation of aorta, tricuspid regurgitation, or bicuspid aortic valve), pulmonary anomalies (e.g., tracheoesophageal fistula, tracheomalacia, or pulmonary atresia), cerebral ventriculomegaly, facial hemangioma, cleft lip, hip dysplasia, and hydronephrosis. TREATMENT:
Two eyes with active leakage on angiogram underwent intravitreal bevacizumab (1.25 mg/0.05 mL Avastin; Genentech, South San Francisco, CA) (range 3–6 injections). One of these eyes also underwent focal peripapillary laser (532-nm green diode laser). Among these 2 eyes that underwent bevacizumab treatment, OCT response included resolution of subretinal fluid (n ¼ 2) and improvement in intraretinal cysts and intraretinal fluid
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FIGURE 3. A 5-year-old boy with an optic disc, inferior retinochoroidal and iris coloboma in the right eye with a gray choroidal neovascular membrane at the temporal margin of the coloboma (Left) with leakage on fluorescein angiogram (Middle) and subretinal hyerreflective material with overlying intraretinal cystic fluid on optical coherence tomography (Right). Given absence of subretinal fluid, the choroidal neovascular membrane was observed.
FIGURE 4. A 3.5-year-old boy with an optic disc and inferior retinochoroidal coloboma in the right eye (Top) with a choroidal neovascular membrane at the temporal margin of the coloboma visualized as a grayish membrane (white arrow). Optical coherence tomography shows sub retinal hyerreflective material without overlying intraretinal cystic fluid or associated subretinal fluid (Bottom). Given absence of associated fluid, the choroidal neovascular membrane was observed.
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TABLE 1. Clinical and Anatomic Characteristics of Study Population and Response to Treatment Age at Diagnosis (months)
Case No.
Eye
1
OD
30
M
2
OS
25
M
3
OS
6
4
OS
5
Sex
Coloboma
Fellow Eye
Initial VA
Final VA
Follow-Up Duration (months)
Treatment
Retinochoroidal and ON ON
Normal
Unable
LP
30
None
Retinochoroidal coloboma not involving macula
LP
20/400
14
M
Retinochoroidal and ON
F&F
F&F
32
13
M
LP
LP
13
OS
120
F
20/100
20/300
38
6
OS
114
F
Retinochoroidal and ON Retinochoroidal and ON ON
20/40
20/30
29
7
OD
5
M
F&F
F&F
7
None
8
OD
47
M
Retinochoroidal and ON coloboma–associated RD, microphthalmia, iris coloboma Retinochoroidal and ON coloboma–associated RD Retinochoroidal and ON coloboma–associated RD Retinochoroidal coloboma–associated RD Retinochoroidal and ON coloboma Retinochoroidal coloboma
IB (36), focal 532-nm green diode laser (31) IB (33)
20/50
20/50
8
None
Retinochoroidal and ON Retinochoroidal and ON
Retinal detachment repair Retinal detachment repair None
F ¼ Female; F&F ¼ fix and follow; IB ¼ intravitreal bevacizumab (1.25 mg/0.05 mL); LP ¼ light perception; M ¼ male; OD ¼ oculus dexter; ON ¼ optic nerve; OS ¼ oculus sinister; RD ¼ retinal detachment; VA ¼ visual acuity.
overlying the subreretinal hyperreflective material (n ¼ 1) (Figures 1 and 2). There was reduction of leakage on angiogram in both eyes. Vision was stable in 1 eye (fix and follow) and improved in the second eye (from wince to light to count fingers). Patients were also concurrently treated for amblyopia. Clinical and anatomic characteristics for the patients in the series and their response to treatment are summarized in Table 1. Two patients progressed to develop a retinal detachment associated with the coloboma during the followup period with an associated reduction in vision and required surgical intervention. Neither of these patients had received intravitreal bevacizumab or laser. One patient underwent a scleral buckle, lensectomy, vitrectomy with laser to the coloboma margin, and silicone oil tamponade, while the other patient underwent vitrectomy with fibrin glue, laser to the coloboma margin, and gas tamponade. The retina remained reattached in both eyes during the follow-up period; however, vision remained poor because it was limited by the coloboma, CNV, and ambylopia.
DISCUSSION WE DESCRIBE THE CLINICAL AND ANATOMIC CHARACTERIS-
tics of 8 eyes of 8 patients with CNV associated with 108
varying sizes of retinochoroidal and optic nerve coloboma and demonstrate the occurrence of CNV at the junction of the normal and abnormal retina at the temporal margin of the coloboma in all eyes. Natural history data for pediatric CNV associated with coloboma is scarce, and such an association of CNV occurrence at the temporal margin of the coloboma has not been categorically recognized before. In addition, OCT characteristics of coloboma-associated pediatric CNV along with serial OCT imaging to monitor the treatment response of fluid exudation have not been well described before. We found that CNV appeared in eyes that were often at risk to progress to a retinal detachment, and while some colobomas were isolated, most were associated with genetic abnormalities or multisystem syndromes. To the best of our knowledge, this is the largest series of pediatric CNVs associated with retinochoroidal and optic nerve coloboma. We hypothesize separate anatomic explanations for the occurrence of CNV at the coloboma margin and specifically at the temporal margin of the coloboma closest to the fovea. Histologic studies can help to partially explain the predisposition of CNV occurrence at the margin of retinochoroidal colobomas. The coloboma margin has a thickened and folded RPE with a point of reversal and disorganization of the photoreceptor layer.8 There is possibly a schisis-like split of the neurosensory retina at the level of the inner nuclear layer, outer plexiform layer, or both to form the locus minoris resistentiae (junction of
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FIGURE 5. Diagram demonstrating the occurrence of choroidal neovascular membrane at the coloboma margin and specifically at the temporal margin of the coloboma closest to the fovea (Top). Cross sectional view of the margin (inset, Below) showing the anomalies with a thickened and folded retinal pigment epithelium with a point of reversal of the photoreceptor layer which becomes disorganized, and possibly a schisis-like split of the neurosensory retina to form the locus minoris resistentiae and the transition zone prior to merging with the intercalary membrane. The termination of the choriocapillaris, retinal pigment epithelium, and Bruch membrane in the area of duplication of the retina disrupts the barrier function of the Bruch membrane and is postulated to allow aberrant growth of retinal pigment epithelium and nearby choroidal vessels into the subretinal space at the margin of the coloboma, predisposing to choroidal neovascular membrane formation at the margin location.
reversal and duplication of the outer layers of retina) (Figure 5).7 Gopal and associates7 described 2 forms of the transition zone between undifferentiated and differentiated retina using OCT: an abrupt transition or a more gradual transition with relative preservation of the layers or merging with the intercalary membrane.8,9 The termination of the choriocapillaris, RPE, and Bruch membrane in the area of duplication of the retina disrupts the barrier function of the Bruch membrane and is postulated to allow aberrant growth of RPE and nearby choroidal vessels into the subretinal space at the margin of the coloboma, predisposing to CNV formation at the margin location (Figure 5).6,7,10 CNV can occur in ocular disorders associated with discontinuities in the Bruch membrane and RPE, including lacquer cracks, pathologic myopia, angioid streaks, choroidal rupture, excessively strong laser burns, and age-related macular degeneration (AMD).11 It is not unreasonable to expect that the choriocapillaris could enter the subretinal pigment epithelial space through defects in the Bruch membrane within the coloboma, resulting in the development of subretinal neovascularization at VOL. 174
the coloboma margin, an area that has been shown to be very vascular.8 These aberrant vessels then tend to grow toward the fovea at the temporal edge of the coloboma, which may in part be attributable to an angiogenic signaling response because the macular vascularization proceeds by vascular endothelial growth factor–dependent angiogenesis. This is in contrast to the peripapillary vessels, which are formed by vasculogenesis from the vascular precursor cells proceeding from disc anteriorly.8,10,12–16 Baer and associates17 reported that 86% of recurrences of CNV after 360-degree macular translocation surgery for neovascular AMD involved the margin of the bed closest to the fovea. They proposed a ‘‘foveal signaling hypothesis,’’ wherein angiogenic signaling from the fovea was the impetus for recurrent CNV, possibly because of an increased concentration of proangiogenic factors under the more metabolically active fovea.17 The influence of this effect was inversely proportional to the distance of the translocated fovea from the original lesion. The recurrent CNV almost always involved the temporal edge of the bed closest to the repositioned fovea. An ischemic stimulus has also been suggested to
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TABLE 2. Review of Prior Reports of Pediatric Choroidal Neovascularization Associated With Optic Nerve and Retinochoroidal Colobomas and Their Response to Treatment
Report
Age at Examination,
Systemic
Location of
Sex
Association
Coloboma
Guirgis and 21 months, M CHARGE Optic nerve Leuder (2003)21 coloboma Shaikh and Trese (2003)27
1 year, F
None
Goodwin et al. (2009)24
19 months, M None
Naithani et al. (2010)22
5 years, F
None
8 years, F von Eicken et al. (2007)23
5.5 years, F
None
Brodsky et al. (1991)5
1 year, F
None
Bondalapati et al. 2 years, F (2016)20
None
Bilateral inferonasal iris coloboma, optic nerve and inferior retinochoroidal coloboma Optic nerve and retinochoroidal coloboma
Location of CNV
Treatment
Temporal margin of Transpupillary diode optic nerve laser coloboma Temporal margin of Argon laser optic disc and photocoagulation inferior retinochoroidal coloboma in both eyes
Pre-VA
NA
20/100a
CSM
CSM
Temporal margin of Intravitreal ranibizumab NAb retinochoroidal (0.25 mg/0.025 mL) 3 coloboma 2, and focal argon laser photocoagulation Temporal margin of Intravitreal bevazicumab 20/400 optic nerve and (1.25 mg/0.05 mL) 3 2 retinochoroidal coloboma
Inferior retinochoroidal coloboma and optic nerve coloboma Bilateral optic nerve coloboma Retinochoroidal Supero-temporal coloboma margin of retinochoroidal coloboma (subfoveal location) Inferior Temporal edge of retinochoroidal coloboma and optic nerve coloboma Retinochoroidal No photographic coloboma in documentation macula
Intravitreal bevazicumab 20/60 (1.25 mg/0.05 mL) 31 PDT with veteporfin 20/500 (2.46 mL verteporfin, 4500 mm spot size, 83 sec treatment time)
Focal argon green laser photocoagulation
Bevacizumab (1.25 mg/0.05 mL) 3 1
Post-VA
NA
20/400
20/40 20/100
Did not Followed follow optikinetic optikinetic stimuli stimuli 20/540 20/310
CHARGE ¼ Coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality; CSM ¼ central steady and maintained; F ¼ female; M ¼ male; PDT ¼ photodynamic therapy; VA ¼ visual acuity. a Visual acuity was not measured at the baseline visit. Follow-up vision was assessed at 7 years of age. b Visual acuity was not measured because of the patient’s age.
explain the growth of the vessels toward the intercalary membrane.8,18 The observations made in the current series lend further support to an angiogenesis-dependent signaling mechanism directing development of CNV at the foveal margin in eyes with abnormal macular anatomy. In all 8 eyes in our report, the CNV was visualized as a grayish membrane sometimes associated with subretinal fluid, and subretinal hemorrhage at the temporal edge of the coloboma. A review of previous reports of 7 pediatric eyes identified in literature with available photographic documentation of CNV associated with coloboma revealed 110
that CNV occurred as a grayish membrane at the temporal margin of the coloboma in all eyes (Table 2). It is important to recognize this focal grayish subretinal membrane and differentiate it from the choroidal thickening and retinal pigment epithelial hyperplasia that often also occurs as a gray fibroglial membrane at the coloboma margin.17 Clinicians should consider screening with OCT and fluorescein angiography for signs of CNV at the temporal edge of the coloboma closest to the fovea (or in setting of vision changes) or if anomalous pigmentary changes are seen at the edge of the coloboma.
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Colobomas are commonly associated with visual loss attributable to the abnormalities in retinal architecture for which there is little treatment other than amblyopia management. However, treatment of retinal detachment and subretinal fluid associated with CNV can potentially improve vision.17 CNV associated with coloboma is a rare cause of vision loss, with few reports describing CNV associated with retinochoroidal coloboma in children and their treatment with focal laser photocoagulation, photodynamic therapy, or anti-VEGF therapy.8 Surgical removal of CNV associated with coloboma has not been reported in children. OCT is helpful in the diagnosis of CNV and determining its location, which can help guide treatment options and monitor treatment response. Argon and diode laser photocoagulation have been demonstrated to be effective in ablating extrafoveal CNV, despite the inherent sequelae of scarring and potential scotoma.19,20 Photodynamic therapy has been described for subfoveal CNVs.5,21 More recent reports have described the use of intravitreal anti-VEGF therapy, and the long-term side effects of anti-VEGF therapy in children—especially in infant populations—are still being investigated.21–23 Previous cases of pediatric CNV associated with coloboma and their treatment are summarized in Table 2. The literature and also our series do not report any recurrence of CNV in pediatric cases associated with a retinochoroidal coloboma, suggesting that once involuted, it may not require long-term treatment, which is different from other causes of pediatric CNV.24 In this regard, it may be similar to myopic CNV, which often involutes
and requires a substantially lower number of injections compared to neovascular AMD.25 Retinochoroidal colobomas may be associated with other ocular disorders, such as microphthalmia, with multisystem syndromes, such as CHARGE syndrome, or they may be found in isolation.26 Upon review of medical records over a 40-year period, Nakamura and associates described a prevalence of ocular coloboma of approximately 1 in 2077 live births, and reported that CHARGE syndrome was diagnosed in 1 in 8 study patients.22,27,28 Patients with CHARGE syndrome association may develop CNV with serous retinal detachments in association with optic nerve colobomas.29 We found a syndromic association (CHARGE) in 2 patients in our series, suggesting the need for a careful systemic evaluation in such cases. The genetic abnormalities found in 2 patients in our series were of unknown significance, suggesting that the utility of genetic screening in such eyes has yet to be fully established. All patients with syndromic association and genetic abnormalities had bilateral disease. In conclusion, we describe the largest series of pediatric eyes with CNV associated with optic nerve and retinochoroidal coloboma and report the occurrence of CNV at the temporal margin of the coloboma closest to the fovea in all cases. OCT imaging of this margin allowed for diagnosis of CNV and serial imaging permitted treatment response monitoring. Careful attention should be paid to this area with OCT surveillance and fluorescein angiography during examination. The lesions exhibited a varied degree of anatomic response to treatment and visual acuity improvement was noted.
FUNDING/SUPPORT: PUBLICATION OF THIS ARTICLE WAS SUPPORTED BY THE HEED OPHTHALMIC FOUNDATION, SAN FRANcisco, California (D.S.G.) and the Ronald G. Michels Fellowship (D.S.G.), The Hartwell Foundation (C.A.T.), and an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, Inc, New York, New York. Financial Disclosures: The following authors have no financial disclosures: Dilraj Singh Grewal, Du Tran-Viet, Lejla Vajzovic, Prithvi Mruthyunjaya, and Cynthia A. Toth. All authors attest that they meet the current ICMJE criteria for authorship. Design of the study (D.S.G., P.M., L.V., C.A.T.); conduct of the study (D.S.G., D.T.V., P.M., L.V., C.A.T); data collection and management, analysis, and interpretation of data (D.S.G., D.T.V., P.M., L.V., C.A.T); preparation, review, and approval of the manuscript (D.S.G., P.M., L.V., C.A.T.).
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11. Ohno-Matsui K, Hirakata A, Inoue M, Akiba M, Ishibashi T. Evaluation of congenital optic disc pits and optic disc colobomas by swept-source optical coherence tomography. Invest Ophthalmol Vis Sci 2013;54(12):7769–7778. 12. Steahly LP. Laser treatment of a subretinal neovascular membrane associated with retinochoroidal coloboma. Retina 1986; 6(3):154–156. 13. Gupta V, Gupta A, Dogra MR. Subretinal neovascularization associated with retinochoroidal coloboma. Indian J Ophthalmol 1997;45(2):116–117. 14. Maberley AL, Gottner MJ, Antworth MV. Subretinal neovascularization associated with retinochoroidal colobomas. Can J Ophthalmol 1989;24(4):172–174. 15. Lingam G. Pattern of blood vessels in eyes with coloboma. Indian J Ophthalmol 2013;61(12):743–748. 16. Lutty GA, Chan-Ling T, Phelps DL, et al. Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). Mol Vis 2006;12: 532–580. 17. Baer CA, Rickman CB, Srivastava S, Malek G, Stinnett S, Toth CA. Recurrent choroidal neovascularization after macular translocation surgery with 360-degree peripheral retinectomy. Retina 2008;28(9):1221–1227. 18. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 1967;63(3 suppl):1–139. 19. Gopal L, Badrinath SS, Sharma T, et al. Surgical management of retinal detachments related to coloboma of the choroid. Ophthalmology 1998;105(5):804–809. 20. Bondalapati S, Jalali S, Chhablani J. Antivascular endothelial growth factor monotherapy for choroidal neovascularization associated with retinochoroidal coloboma: case series. Asia Pac J Ophthalmol (Phila) 2016;5:344–348.
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21. Guirgis MF, Lueder GT. Choroidal neovascular membrane associated with optic nerve coloboma in a patient with CHARGE association. Am J Ophthalmol 2003;135(6): 919–920. 22. Naithani P, Vashisht N, Mandal S, Sankaran P, Garg S. Intravitreal bevacizumab in choroidal neovascularization associated with congenital choroidal and optic nerve coloboma in children: long-term improvement in visual acuity. J AAPOS 2010;14(3):288–290. 23. von Eicken J, Ho¨h H, Rehfeldt K. Photodynamic therapy for choroidal neovascularisation due to choroidal coloboma in a 5 1/2-year-old child [in German]. Klin Monbl Augenheilkd 2007;224(2):140–145. 24. Goodwin P, Shields CL, Ramasubramanian A, Brown GC, Shields JA. Ranibizumab for coloboma-related choroidal neovascular membrane in a child. J AAPOS 2009;13(6): 616–617. 25. Wong TY, Ohno-Matsui K, Leveziel N, et al. Myopic choroidal neovascularisation: current concepts and update on clinical management. Br J Ophthalmol 2015;99(3):289–296. 26. Avery RL. Extrapolating anti-vascular endothelial growth factor therapy into pediatric ophthalmology: promise and concern. J AAPOS 2009;13(4):329–331. 27. Shaikh S, Trese M. Infantile choroidal neovascularization associated with choroidal coloboma. Retina 2003;23(4): 585–586. 28. Nakamura KM, Diehl NN, Mohney BG. Incidence, ocular findings, and systemic associations of ocular coloboma: a population-based study. Arch Ophthalmol 2011;129(1): 69–74. 29. Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet 2006;43(4):306–314.
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To describe the characteristics of pediatric choroidal neovascular membranes (CNVs) associated with retinochoroidal and optic nerve coloboma using optical coherence tomography (OCT) and their response to treatment. DESIGN: Retrospective case series. METHODS: Retrospective review of children <16 years of age with CNV and retinochoroidal and optic nerve coloboma from 1995–2015 who underwent OCT imaging using either handheld (Bioptigen, Morrisville, NC) or tabletop OCT (Spectralis; Heidelberg, Carlsbad, CA). RESULTS: Eight eyes of 8 patients (3 males, 5 females) with a mean age of 4.1 ± 3.9 years (range 6 months–10 years) at diagnosis were included. Mean follow-up was 21.4 ± 12.1 months (range 7–38 months). An optic nerve coloboma was present in 2 eyes and combined optic nerve and retinochoroidal coloboma in 6 eyes. In all eyes, CNVs were located at the temporal margin of the coloboma closest to the macula. Fluorescein angiogram characteristics included staining without leakage suggesting inactivity (n [ 6) and leakage (n [ 2). OCT characteristics included subretinal fluid (n [ 5), intraretinal fluid and cysts (n [ 1), and subretinal hyperreflective material (n [ 7). Two eyes received intravitreal bevacizumab (range 3–6) injections, one of which also underwent focal peripapillary laser. Both eyes showed improvement in subretinal or intraretinal fluid on OCT. Vision at presentation among those quantified ranged from 20/200 to 20/40 and at final follow-up from 20/400 to 20/30. Genetic or systemic abnormalities were seen in 6 patients. CONCLUSIONS: Association of pediatric CNV occurrence at the temporal margin of retinochoroidal and optic nerve colobomas closest to the fovea has not been established before and careful OCT and angiographic assessment of this region is warranted. The CNV lesions exhibit a varied degree of response Supplemental Material available at AJO.com. Accepted for publication Oct 14, 2016. From the Department of Ophthalmology, Duke University, Durham, North Carolina. Inquiries to Dilraj Singh Grewal, Department of Ophthalmology, Duke University, 2351 Erwin Rd, Box 3802, Durham, NC 27710; e-mail: dilraj. [email protected]
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to treatment. (Am J Ophthalmol 2017;174: 104–112. Ó 2016 Elsevier Inc. All rights reserved.)
R
ETINOCHOROIDAL AND OPTIC NERVE COLOBOMA
results from the abnormal closure of the embryonic fissure during weeks 5–7 of fetal life and may involve the iris, lens zonules, ciliary body, choroid, retina, and optic nerve.1,2 They may be associated with serous retinal detachments, lenticonus, persistent hyaloid arteries, and optic disk pits.2 Genetic and environmental causes have been suggested to cause an intrauterine insult with a defective embryonal fissure closure leading to coloboma of the fundus.3 Histologically, there is no normal choroid, retinal pigment epithelium, or retina overlying a retinochoroidal coloboma, and the overlying tissue is an extension of the neurosensory retina called the intercalary membrane.2 Colobomas can vary from small defects located in the equatorial region that do not interfere with vision to larger ones involving the disc and macula with severe impairment of vision. Vision impairment may also be caused by retinal detachment, which has been estimated to _40% of these eyes, or choroidal neovascular occur in < membranes (CNVs), which are a rare cause of decreased vision in children with retinochoroidal colobomas.4,5 Optical coherence tomography (OCT) findings across a spectrum of coloboma severity have been described.2 In cases with retinal detachment, OCT has allowed for identification of the precise site of communication between the subintercalary membrane space and subretinal space.6 In some cases, subclinical retinal detachments have been identified along the margin of the coloboma. OCT characteristics of CNVs associated with pediatric optic nerve and retinochoroidal colobomas and their response to treatment have, however, not been well described before and are limited to isolated case reports. In these patients, it has been suggested that discontinuities of Bruch membrane and retinal pigment epithelium (RPE) at the margin of the coloboma may allow choroidal vessels to enter the subretinal space, resulting in CNV formation at the margin. This region at the coloboma margin has not yet been studied using high-resolution OCT in children. In this report, we describe the largest series of pediatric CNV associated with optic nerve and retinochoroidal
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FIGURE 1. A 6-month-old boy with bilateral uveal coloboma involving the iris, retina/choroid, and optic nerve who developed a choroidal neovascular membrane at the temporal margin of the retinochoroidal coloboma with subretinal hemorrhage in the left eye (Top, first column, white arrow) with leakage on fluorescein angiography (Top, second and third column) and overlying subretinal fluid on optical coherence tomography (Top right, white star). After 2 bevacizumab injections there was resolution of the subretinal hemorrhage (Bottom, first column, black arrow), reduction of leakage on fluorescein angiography (Bottom, second and third columns), and resolution of subretinal fluid on optical coherence tomography (Bottom last column).
coloboma reviewed over a period of 20 years, and show the OCT characteristics of CNV and response to treatment.
RESULTS EIGHT EYES OF 8 PATIENTS (3 MALES, 5 FEMALES) WITH A
METHODS THIS WAS A RETROSPECTIVE ANALYSIS OF CLINICAL RE-
cords of patients <16 years of age with retinochoroidal or optic nerve coloboma and associated CNV from March 1995 to March 2015 who were examined at the Pediatric Retina Service, Duke Eye Center (Durham, NC). Imaging was performed under an institutional review board– approved prospective observational study for pediatric retina imaging. Images from this database were analyzed. The study was approved by the Duke University Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. The Duke Enterprise Data Unified Content Explorer (DEDUCE) database was searched for patients diagnosed with retinochoroidal coloboma or optic disc coloboma (based on receipt of International Classification of Diseases, 9th revision [ICD-9] codes 743.52 or 743.57) and who had an associated CNV (ICD-9 code 362.16) as identified by billing records.7 Imaging was performed using either handheld spectral domain OCT during examination under anesthesia (Envisu; Bioptigen Inc, Morrisville, NC) or a tabletop unit in clinic when the child was old enough to co-operate (Spectralis; Heidelberg, Carlsbad, CA). Fluorescein angiography was performed using RETCAM (Clarity Medical Systems, Pleasanton, CA) during examination under anesthesia. VOL. 174
mean age of 4.1 6 3.9 years (range 6 months-10 years) and with available OCT imaging at diagnosis were included. Mean follow-up was 21.4 6 12.1 months (range 7–38 months). An associated iris coloboma was present in 5 eyes. None of the eyes had a lens or lens zonule coloboma. One of the patients had microphthalmia. An optic nerve coloboma was present in 2 eyes and a combined optic nerve and retinochoroidal coloboma in 6 eyes. The fovea was involved within the coloboma in 4 eyes and spared in 4 eyes. In all 8 eyes, the CNV was located at the temporal margin of the coloboma: temporal to the colobomatous nerve (n ¼ 3) and at the temporal edge of the combined optic nerve–retinochoroidal coloboma closest to the fovea (n ¼ 5). Figures 1–4 provide representative examples and OCT characteristics. Fluorescein angiographic characteristics included window defects in the area of coloboma or staining but no leakage, suggesting inactivity (n ¼ 6; Figure 3), and leakage (n ¼ 2; Figures 1 and 2). Leakage was observed at the temporal edge of optic nerve (n ¼ 1; Figure 2) and retinochoroidal (n ¼ 1; Figure 1) coloboma. Seven patients underwent imaging with handheld spectral domain OCT during examination under anesthesia, while 1 patient could be imaged using the tabletop OCT unit in the clinic. OCT characteristics included subretinal fluid (n ¼ 5; Figures 1 and 2), intraretinal fluid and intraretinal cysts (n ¼ 1; Figure 3), and subretinal hyperreflective material consistent with a subretinal fibrovascular
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FIGURE 2. A 2-year-old boy with coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality (CHARGE) syndrome with bilateral optic nerve coloboma (top left) and associated active choroidal neovascular membrane at the temporal margin of the optic nerve coloboma (top, first column) with leakage on fluorescein angiogram in the left eye (top, second and third columns) and surrounding subretinal fluid on optical coherence tomography (top last column). After 4 injections of intravitreal bevacizumab (1.25 mg/0.05 mL; Middle, first column) there was a reduction in leakage on fluorescein angiogram (Middle, second and third columns) and subretinal fluid on optical coherence tomography (Middle, last column). After continued bevacizumab therapy (n [ 5) and focal peripapillary 532-nm green diode laser (n [ 1; Bottom, left column), there was further reduction in leakage on fluorescein angiogram (Bottom second and third columns) and reduction of retinal thickening and consolidation of subretinal hyperreflective material on optical coherence tomography (Bottom, last column).
membrane (n ¼ 6; Figures 1–4). Among patients in whom vision could be quantified, it ranged from 20/200 to 20/40 at presentation and at final follow-up ranged from 20/400 to 20/30. Individual vision for all patients is listed in Table 1. Among the fellow eyes, a coloboma was present in 7 eyes (retinochoroidal coloboma n ¼ 5, retinochoroidal and optic nerve coloboma n ¼ 2, iris coloboma n ¼ 2, and lens coloboma n ¼ 1). A retinal detachment associated with the coloboma was present in 3 fellow eyes, and 1 fellow eye had micro-ophthalmia. None of the patients had a family history of uveal colobomas. Genetic abnormalities were observed in 2 of 3 patients that underwent genetic testing. These included a 2-copy gain of chromosome 8q11.21 and chromosome 4 (4q35.2) microdeletion. However, neither of these abnormalities has been shown to be associated as a cause of retinochoroidal or optic nerve coloboma. There was a syndromic association of coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality (CHARGE) syndrome 106
with the optic nerve and retinochoroidal coloboma in 2 patients. An additional 4 patients had associated systemic abnormalities but did not undergo formal genetic testing. These included cardiac anomalies (e.g., double outlet right ventricular hypertrophy, ventricular septal defect, patent foramen ovale, coarctation of aorta, tricuspid regurgitation, or bicuspid aortic valve), pulmonary anomalies (e.g., tracheoesophageal fistula, tracheomalacia, or pulmonary atresia), cerebral ventriculomegaly, facial hemangioma, cleft lip, hip dysplasia, and hydronephrosis. TREATMENT:
Two eyes with active leakage on angiogram underwent intravitreal bevacizumab (1.25 mg/0.05 mL Avastin; Genentech, South San Francisco, CA) (range 3–6 injections). One of these eyes also underwent focal peripapillary laser (532-nm green diode laser). Among these 2 eyes that underwent bevacizumab treatment, OCT response included resolution of subretinal fluid (n ¼ 2) and improvement in intraretinal cysts and intraretinal fluid
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FIGURE 3. A 5-year-old boy with an optic disc, inferior retinochoroidal and iris coloboma in the right eye with a gray choroidal neovascular membrane at the temporal margin of the coloboma (Left) with leakage on fluorescein angiogram (Middle) and subretinal hyerreflective material with overlying intraretinal cystic fluid on optical coherence tomography (Right). Given absence of subretinal fluid, the choroidal neovascular membrane was observed.
FIGURE 4. A 3.5-year-old boy with an optic disc and inferior retinochoroidal coloboma in the right eye (Top) with a choroidal neovascular membrane at the temporal margin of the coloboma visualized as a grayish membrane (white arrow). Optical coherence tomography shows sub retinal hyerreflective material without overlying intraretinal cystic fluid or associated subretinal fluid (Bottom). Given absence of associated fluid, the choroidal neovascular membrane was observed.
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TABLE 1. Clinical and Anatomic Characteristics of Study Population and Response to Treatment Age at Diagnosis (months)
Case No.
Eye
1
OD
30
M
2
OS
25
M
3
OS
6
4
OS
5
Sex
Coloboma
Fellow Eye
Initial VA
Final VA
Follow-Up Duration (months)
Treatment
Retinochoroidal and ON ON
Normal
Unable
LP
30
None
Retinochoroidal coloboma not involving macula
LP
20/400
14
M
Retinochoroidal and ON
F&F
F&F
32
13
M
LP
LP
13
OS
120
F
20/100
20/300
38
6
OS
114
F
Retinochoroidal and ON Retinochoroidal and ON ON
20/40
20/30
29
7
OD
5
M
F&F
F&F
7
None
8
OD
47
M
Retinochoroidal and ON coloboma–associated RD, microphthalmia, iris coloboma Retinochoroidal and ON coloboma–associated RD Retinochoroidal and ON coloboma–associated RD Retinochoroidal coloboma–associated RD Retinochoroidal and ON coloboma Retinochoroidal coloboma
IB (36), focal 532-nm green diode laser (31) IB (33)
20/50
20/50
8
None
Retinochoroidal and ON Retinochoroidal and ON
Retinal detachment repair Retinal detachment repair None
F ¼ Female; F&F ¼ fix and follow; IB ¼ intravitreal bevacizumab (1.25 mg/0.05 mL); LP ¼ light perception; M ¼ male; OD ¼ oculus dexter; ON ¼ optic nerve; OS ¼ oculus sinister; RD ¼ retinal detachment; VA ¼ visual acuity.
overlying the subreretinal hyperreflective material (n ¼ 1) (Figures 1 and 2). There was reduction of leakage on angiogram in both eyes. Vision was stable in 1 eye (fix and follow) and improved in the second eye (from wince to light to count fingers). Patients were also concurrently treated for amblyopia. Clinical and anatomic characteristics for the patients in the series and their response to treatment are summarized in Table 1. Two patients progressed to develop a retinal detachment associated with the coloboma during the followup period with an associated reduction in vision and required surgical intervention. Neither of these patients had received intravitreal bevacizumab or laser. One patient underwent a scleral buckle, lensectomy, vitrectomy with laser to the coloboma margin, and silicone oil tamponade, while the other patient underwent vitrectomy with fibrin glue, laser to the coloboma margin, and gas tamponade. The retina remained reattached in both eyes during the follow-up period; however, vision remained poor because it was limited by the coloboma, CNV, and ambylopia.
DISCUSSION WE DESCRIBE THE CLINICAL AND ANATOMIC CHARACTERIS-
tics of 8 eyes of 8 patients with CNV associated with 108
varying sizes of retinochoroidal and optic nerve coloboma and demonstrate the occurrence of CNV at the junction of the normal and abnormal retina at the temporal margin of the coloboma in all eyes. Natural history data for pediatric CNV associated with coloboma is scarce, and such an association of CNV occurrence at the temporal margin of the coloboma has not been categorically recognized before. In addition, OCT characteristics of coloboma-associated pediatric CNV along with serial OCT imaging to monitor the treatment response of fluid exudation have not been well described before. We found that CNV appeared in eyes that were often at risk to progress to a retinal detachment, and while some colobomas were isolated, most were associated with genetic abnormalities or multisystem syndromes. To the best of our knowledge, this is the largest series of pediatric CNVs associated with retinochoroidal and optic nerve coloboma. We hypothesize separate anatomic explanations for the occurrence of CNV at the coloboma margin and specifically at the temporal margin of the coloboma closest to the fovea. Histologic studies can help to partially explain the predisposition of CNV occurrence at the margin of retinochoroidal colobomas. The coloboma margin has a thickened and folded RPE with a point of reversal and disorganization of the photoreceptor layer.8 There is possibly a schisis-like split of the neurosensory retina at the level of the inner nuclear layer, outer plexiform layer, or both to form the locus minoris resistentiae (junction of
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FIGURE 5. Diagram demonstrating the occurrence of choroidal neovascular membrane at the coloboma margin and specifically at the temporal margin of the coloboma closest to the fovea (Top). Cross sectional view of the margin (inset, Below) showing the anomalies with a thickened and folded retinal pigment epithelium with a point of reversal of the photoreceptor layer which becomes disorganized, and possibly a schisis-like split of the neurosensory retina to form the locus minoris resistentiae and the transition zone prior to merging with the intercalary membrane. The termination of the choriocapillaris, retinal pigment epithelium, and Bruch membrane in the area of duplication of the retina disrupts the barrier function of the Bruch membrane and is postulated to allow aberrant growth of retinal pigment epithelium and nearby choroidal vessels into the subretinal space at the margin of the coloboma, predisposing to choroidal neovascular membrane formation at the margin location.
reversal and duplication of the outer layers of retina) (Figure 5).7 Gopal and associates7 described 2 forms of the transition zone between undifferentiated and differentiated retina using OCT: an abrupt transition or a more gradual transition with relative preservation of the layers or merging with the intercalary membrane.8,9 The termination of the choriocapillaris, RPE, and Bruch membrane in the area of duplication of the retina disrupts the barrier function of the Bruch membrane and is postulated to allow aberrant growth of RPE and nearby choroidal vessels into the subretinal space at the margin of the coloboma, predisposing to CNV formation at the margin location (Figure 5).6,7,10 CNV can occur in ocular disorders associated with discontinuities in the Bruch membrane and RPE, including lacquer cracks, pathologic myopia, angioid streaks, choroidal rupture, excessively strong laser burns, and age-related macular degeneration (AMD).11 It is not unreasonable to expect that the choriocapillaris could enter the subretinal pigment epithelial space through defects in the Bruch membrane within the coloboma, resulting in the development of subretinal neovascularization at VOL. 174
the coloboma margin, an area that has been shown to be very vascular.8 These aberrant vessels then tend to grow toward the fovea at the temporal edge of the coloboma, which may in part be attributable to an angiogenic signaling response because the macular vascularization proceeds by vascular endothelial growth factor–dependent angiogenesis. This is in contrast to the peripapillary vessels, which are formed by vasculogenesis from the vascular precursor cells proceeding from disc anteriorly.8,10,12–16 Baer and associates17 reported that 86% of recurrences of CNV after 360-degree macular translocation surgery for neovascular AMD involved the margin of the bed closest to the fovea. They proposed a ‘‘foveal signaling hypothesis,’’ wherein angiogenic signaling from the fovea was the impetus for recurrent CNV, possibly because of an increased concentration of proangiogenic factors under the more metabolically active fovea.17 The influence of this effect was inversely proportional to the distance of the translocated fovea from the original lesion. The recurrent CNV almost always involved the temporal edge of the bed closest to the repositioned fovea. An ischemic stimulus has also been suggested to
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TABLE 2. Review of Prior Reports of Pediatric Choroidal Neovascularization Associated With Optic Nerve and Retinochoroidal Colobomas and Their Response to Treatment
Report
Age at Examination,
Systemic
Location of
Sex
Association
Coloboma
Guirgis and 21 months, M CHARGE Optic nerve Leuder (2003)21 coloboma Shaikh and Trese (2003)27
1 year, F
None
Goodwin et al. (2009)24
19 months, M None
Naithani et al. (2010)22
5 years, F
None
8 years, F von Eicken et al. (2007)23
5.5 years, F
None
Brodsky et al. (1991)5
1 year, F
None
Bondalapati et al. 2 years, F (2016)20
None
Bilateral inferonasal iris coloboma, optic nerve and inferior retinochoroidal coloboma Optic nerve and retinochoroidal coloboma
Location of CNV
Treatment
Temporal margin of Transpupillary diode optic nerve laser coloboma Temporal margin of Argon laser optic disc and photocoagulation inferior retinochoroidal coloboma in both eyes
Pre-VA
NA
20/100a
CSM
CSM
Temporal margin of Intravitreal ranibizumab NAb retinochoroidal (0.25 mg/0.025 mL) 3 coloboma 2, and focal argon laser photocoagulation Temporal margin of Intravitreal bevazicumab 20/400 optic nerve and (1.25 mg/0.05 mL) 3 2 retinochoroidal coloboma
Inferior retinochoroidal coloboma and optic nerve coloboma Bilateral optic nerve coloboma Retinochoroidal Supero-temporal coloboma margin of retinochoroidal coloboma (subfoveal location) Inferior Temporal edge of retinochoroidal coloboma and optic nerve coloboma Retinochoroidal No photographic coloboma in documentation macula
Intravitreal bevazicumab 20/60 (1.25 mg/0.05 mL) 31 PDT with veteporfin 20/500 (2.46 mL verteporfin, 4500 mm spot size, 83 sec treatment time)
Focal argon green laser photocoagulation
Bevacizumab (1.25 mg/0.05 mL) 3 1
Post-VA
NA
20/400
20/40 20/100
Did not Followed follow optikinetic optikinetic stimuli stimuli 20/540 20/310
CHARGE ¼ Coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality; CSM ¼ central steady and maintained; F ¼ female; M ¼ male; PDT ¼ photodynamic therapy; VA ¼ visual acuity. a Visual acuity was not measured at the baseline visit. Follow-up vision was assessed at 7 years of age. b Visual acuity was not measured because of the patient’s age.
explain the growth of the vessels toward the intercalary membrane.8,18 The observations made in the current series lend further support to an angiogenesis-dependent signaling mechanism directing development of CNV at the foveal margin in eyes with abnormal macular anatomy. In all 8 eyes in our report, the CNV was visualized as a grayish membrane sometimes associated with subretinal fluid, and subretinal hemorrhage at the temporal edge of the coloboma. A review of previous reports of 7 pediatric eyes identified in literature with available photographic documentation of CNV associated with coloboma revealed 110
that CNV occurred as a grayish membrane at the temporal margin of the coloboma in all eyes (Table 2). It is important to recognize this focal grayish subretinal membrane and differentiate it from the choroidal thickening and retinal pigment epithelial hyperplasia that often also occurs as a gray fibroglial membrane at the coloboma margin.17 Clinicians should consider screening with OCT and fluorescein angiography for signs of CNV at the temporal edge of the coloboma closest to the fovea (or in setting of vision changes) or if anomalous pigmentary changes are seen at the edge of the coloboma.
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Colobomas are commonly associated with visual loss attributable to the abnormalities in retinal architecture for which there is little treatment other than amblyopia management. However, treatment of retinal detachment and subretinal fluid associated with CNV can potentially improve vision.17 CNV associated with coloboma is a rare cause of vision loss, with few reports describing CNV associated with retinochoroidal coloboma in children and their treatment with focal laser photocoagulation, photodynamic therapy, or anti-VEGF therapy.8 Surgical removal of CNV associated with coloboma has not been reported in children. OCT is helpful in the diagnosis of CNV and determining its location, which can help guide treatment options and monitor treatment response. Argon and diode laser photocoagulation have been demonstrated to be effective in ablating extrafoveal CNV, despite the inherent sequelae of scarring and potential scotoma.19,20 Photodynamic therapy has been described for subfoveal CNVs.5,21 More recent reports have described the use of intravitreal anti-VEGF therapy, and the long-term side effects of anti-VEGF therapy in children—especially in infant populations—are still being investigated.21–23 Previous cases of pediatric CNV associated with coloboma and their treatment are summarized in Table 2. The literature and also our series do not report any recurrence of CNV in pediatric cases associated with a retinochoroidal coloboma, suggesting that once involuted, it may not require long-term treatment, which is different from other causes of pediatric CNV.24 In this regard, it may be similar to myopic CNV, which often involutes
and requires a substantially lower number of injections compared to neovascular AMD.25 Retinochoroidal colobomas may be associated with other ocular disorders, such as microphthalmia, with multisystem syndromes, such as CHARGE syndrome, or they may be found in isolation.26 Upon review of medical records over a 40-year period, Nakamura and associates described a prevalence of ocular coloboma of approximately 1 in 2077 live births, and reported that CHARGE syndrome was diagnosed in 1 in 8 study patients.22,27,28 Patients with CHARGE syndrome association may develop CNV with serous retinal detachments in association with optic nerve colobomas.29 We found a syndromic association (CHARGE) in 2 patients in our series, suggesting the need for a careful systemic evaluation in such cases. The genetic abnormalities found in 2 patients in our series were of unknown significance, suggesting that the utility of genetic screening in such eyes has yet to be fully established. All patients with syndromic association and genetic abnormalities had bilateral disease. In conclusion, we describe the largest series of pediatric eyes with CNV associated with optic nerve and retinochoroidal coloboma and report the occurrence of CNV at the temporal margin of the coloboma closest to the fovea in all cases. OCT imaging of this margin allowed for diagnosis of CNV and serial imaging permitted treatment response monitoring. Careful attention should be paid to this area with OCT surveillance and fluorescein angiography during examination. The lesions exhibited a varied degree of anatomic response to treatment and visual acuity improvement was noted.
FUNDING/SUPPORT: PUBLICATION OF THIS ARTICLE WAS SUPPORTED BY THE HEED OPHTHALMIC FOUNDATION, SAN FRANcisco, California (D.S.G.) and the Ronald G. Michels Fellowship (D.S.G.), The Hartwell Foundation (C.A.T.), and an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, Inc, New York, New York. Financial Disclosures: The following authors have no financial disclosures: Dilraj Singh Grewal, Du Tran-Viet, Lejla Vajzovic, Prithvi Mruthyunjaya, and Cynthia A. Toth. All authors attest that they meet the current ICMJE criteria for authorship. Design of the study (D.S.G., P.M., L.V., C.A.T.); conduct of the study (D.S.G., D.T.V., P.M., L.V., C.A.T); data collection and management, analysis, and interpretation of data (D.S.G., D.T.V., P.M., L.V., C.A.T); preparation, review, and approval of the manuscript (D.S.G., P.M., L.V., C.A.T.).
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