# Optic Coherence Tomography Angiography Findings of Bilateral Choroidal Neovascularization Associated with Optic Disc Drusen Treated with Intravitreal Aflibercept Injection

Authors: Melih Akıdan; Mehmet Bulut; Lütfiye Yaprak; Muhammet Kazım Erol; Elcin Suren
Journal: Case Reports in Ophthalmological Medicine
 (2020)

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## Abstract

Purpose. The purpose of this case report is to present the findings of optical coherence tomography angiography (OCTA) of a patient with bilateral choroidal neovascularization (CNV) associated with optic disc drusen (ODD), who was treated with intravitreal aflibercept injection. Case presentation. A 14-year-old girl presented with a complaint of visual loss and metamorphopsia in her both eyes. Best-corrected visual acuity (BCVA) was 20/32 and 20/25, respectively, in the right and left eyes. Intraocular pressure and anterior segment examination were normal. Dilated fundus examination revealed elevated optic discs with blurred margins in both eyes. In addition, slightly elevated yellow lesion extending from optic nerve head to the macula was observed bilaterally. The patient underwent imaging with colour fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), spectral-domain optic coherence tomography (SD-OCT), OCTA, orbital ultrasonography (USG), and computed tomography (CT). In particular, OCTA demonstrated clearly the large circular CNV complex in the right eye and the CNV structure in the left eye containing slightly activated main trunk and minimal vessel loops in the papillomacular region. CNV secondary to bilateral ODD was suspected. Intravitreal aflibercept injections were performed in 3 doses to the right eye and a single dose to the left eye. After the injections, BCVA reached its complete level in both eyes. SD-OCT revealed irregularity of RPE in the temporal region of the optic disc and complete regression of the subretinal fluid. Interestingly, the entire CNV complex including the main trunk completely disappeared in OCTA. CNV complex was not observed in OCTA during 1-year follow-up, and peripapillary and macular vascular density measurements did not show any significant change. BCVA was preserved, and no additional injections were needed. Conclusion. It is possible that OCTA can be used for detailed evaluation of CNV associated with ODD, response to anti-VEGF treatment, and peripapillary and macular vascular density. There is a need for further studies to confirm the changes such as disappearance of CNV in OCTA after injection as we observed in our patient.


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## Body

## 1. Introduction

Optic disc drusen (ODD) are calcified hyaline-like deposits in the optic nerve head that are mainly located in front of the lamina cribrosa. They are often bilateral (67%-91%), and their incidence is 0.4%-20.4% in general population while there is female preponderance in their prevalence. They are usually benign and vision sparing; however, they may rarely complicate with visual field defects, haemorrhages, choroidal neovascularization (CNV), serous maculopathy, vascular occlusion, and nonarteritic ischemic optic neuropathy (NAION) [1].Various imaging methods have been used in order to detect ODD accurately and reliably, which include ultrasonography (USG), enhanced depth imaging-OCT (EDI-OCT), fluorescein fundus angiography (FFA), and fundus autofluorescence (FAF), and the newest application is optical coherence tomography angiography (OCTA, Optovue, Inc., Fremont, CA, USA) [2].Noninvasive imaging of the retina, choroidal, and disc microvasculature is now possible with OCTA and without the use of exogenous intravenous dye injection. It can provide information for the evaluation of both structure and blood flow. It particularly allows the assessment of CNV morphology and features activity as well as the timing of and response to anti-VEGF treatment of CNV [3, 4]. It has been increasingly used for the diagnosis and imaging of paediatric retinal vascular disease and especially CNV as it is both reliable and noninvasive [5].The OCTA studies in the literature mainly focus on microvascular changes associated with optic disc drusen. To the best of our knowledge, only Ong et al. demonstrated inactivate CNV associated with ODD in 1 case with OCTA in a series of 8 paediatric patients with CNV. However, this is the first time to report an interesting change in CNV after injection and long-term follow-up findings.


## 2. Case Report

A 14-year-old girl was referred to us with complaints of visual loss and metamorphopsia in both eyes that had persisted for 1 week. Her best-corrected visual acuity (BCVA) was 20/32 in the right eye and 20/25 in the left eye. Her ocular and systemic history was unremarkable. Her intraocular pressure and anterior segment examination were normal. Dilated fundus examination revealed elevated optic discs with blurred margins in both eyes. In addition, slightly elevated yellow lesion extending from optic nerve head to the macula was observed bilaterally (Figures1(a) and 1(d)). The patient underwent imaging with colour fundus photography, FAF, FFA, spectral-domain optic coherence tomography (SD-OCT, Cirrus HD OCT 5000, Carl Zeiss Meditec Inc., Dublin, CA, USA), OCTA, orbital USG, and computed tomography (CT). FAF showed bilateral aspect of white refractile and hyperautofluorescence bodies on the surface of the optic nerve linked with the drusen and a hypoautofluorescent and hyperautofluorescent lesion in the papillomacular region (Figures 1(b) and 1(e)). FFA showed no hyperfluorescence or leakage with blurred borders of the optic disc, and early hyperfluorescence and intense leakage that might be associated with CNV were observed in both eyes with the right eye predominance (Figures 1(c) and 1(f)). The peripheral retina was normal. B-mode USG showed hyperechogenic appearance, and orbital CT revealed papilla as bright spots which might be associated with optic disc drusen (Figure 1(g)). SD-OCT showed retinal thickening, subretinal hyperreflectivity in the papillomacular region bilaterally, and subfoveal fluid in the right eye (Figures 1(h) and 1(i)). Furthermore, macular and retinal nerve fiber layer (RNFL) thickness measurements were recorded (Table 1).Figure 1
On the first day. (a and d) Fundus image of the right and left eyes; elevated optic disc with blurred margin and slightly elevated yellow lesion extending from optic nerve head to the macula. (b and e) FAF image of the right and left eyes; hyperautofluorescence bodies on the surface of the optic nerve linked with the drusen and hyperautofluorescent lesion in the papillomacular region. (c and f) FFA image of the right and left eyes; hyperfluorescence and intense leakage that might be associated with CNV. (g) Orbital CT image of the right and left eyes; bright spot on papilla associated with optic disc drusen. (h) SD-OCT image of the right eye; retinal thickening, subretinal hyperreflectivity, and subfoveal fluid in the papillomacular region. (i) SD-OCT image of the left eye; retinal thickening and subretinal hyperreflectivity in the papillomacular region.
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)Table 1
On the first day, 3rd month, and 12th month; OCT and RNFL thickness measurements.
Thickness (μm)
Day 1
Month 3
Month 12
Macular
Fovea
232
250
236
248
239
251
Parafovea
337
340
339
335
338
348
Superior-hemi
339
342
340
338
339
350
Inferior-hemi
335
337
337
333
336
345
Temporal
323
319
328
316
327
328
Superior
348
349
349
344
349
358
Nasal
335
350
335
347
332
354
Inferior
343
340
344
334
343
350
Perifovea
318
322
316
316
316
325
Superior-hemi
322
328
317
322
315
330
Inferior-hemi
315
316
314
310
316
320
Temporal
293
296
299
292
297
302
Superior
322
330
320
323
318
333
Nasal
341
349
330
342
329
346
Inferior
317
313
314
307
318
320
Retinal nerve fiber layer
Whole
129
126
126
125
129
134
Superior-hemi
123
130
121
129
122
142
Inferior-hemi
137
122
131
121
136
126
Nasal superior
111
107
116
102
117
110
Nasal inferior
107
97
100
91
108
98
Inferior nasal
145
146
142
141
149
147
Inferior temporal
195
173
202
182
211
184
Temporal inferior
108
74
87
78
82
80
Temporal superior
100
97
88
100
91
107
Superior temporal
176
179
173
185
174
201
Superior nasal
118
157
119
150
117
174
Cells are divided into two to show the results of the right and left eyes separately.OCTA revealed superficial and deep capillary density, foveal avascular zone, flow, and en face images in the macula (Table2). A large circular CNV complex with main trunk, multiple dense thin capillaries branching from the main trunk in a tree-like manner, and frequent anastomoses was observed in the papillomacular region of the right eye in the outer retina and choriocapillaris cross-sections (Figures 2(a) and 2(b)). In the left eye, CNV with main trunk, minimal vessel loops, and capillaries was observed, which was considered as slightly activated (Figures 2(c) and 2(d)). Moreover, radial papillary capillary density was measured with OCTA (Table 2). Density was lower in the areas associated with nasal quadrant compared to the other quadrants.Table 2
On the first day, 3rd month, and 12th month; OCTA macula and disc vascular density, FAZ, and flow measurements.
Day 1
Month 3
Month 12
Disc-capillary density
Radial peripapillary (%)
Whole
49.1
48.6
49.2
48.1
48.2
48.5
Inside disc
46.9
45.3
45.9
43.3
40.6
45.9
Peripapillary
51.7
51.0
51.1
49.5
50.7
50.4
Superior-hemi
50.7
50.8
51.2
49.9
50.7
50.5
Inferior-hemi
52.8
51.2
50.9
49
50.7
50.2
Nasal superior
45.8
47.8
46
47.1
46.1
46.3
Nasal inferior
49.1
46.6
48.4
46.6
49.6
46.3
Inferior nasal
53.1
50.9
52.3
45.4
51.8
48.3
Inferior temporal
53.8
57.2
52.3
53.1
49.7
57.2
Temporal inferior
56
51.5
51.4
52.2
51.7
51.1
Temporal superior
57.3
55.3
57.1
56
56.7
58.2
Superior temporal
56.1
53.2
55.9
53.3
52.4
50.9
Superior nasal
45.7
47.9
47.2
43.9
48.2
47.7
Macula-capillary density
Superficial (%)
Whole
52.4
53.2
54.5
54.1
53.5
51.9
Superior-hemi
53.5
53
54.8
53.7
53.3
51.9
Inferior-hemi
54.6
50.8
54.2
54.5
53.6
51.9
Fovea
15.2
17.1
14.6
17.7
15.7
15.3
Parafovea
55.3
53.6
58.2
58.1
56.8
55
Superior-hemi
57.1
53.5
57.8
56.6
55.9
54.1
Inferior-hemi
56.8
56.8
58.6
59.6
57.7
56
Temporal
56.2
52.8
55.5
56.5
56.1
54.1
Superior
58.5
55.6
58.8
57.4
57.2
53.6
Nasal
56.7
59.3
57.5
57.9
55.4
55.6
Inferior
60
55.9
61
60.5
58.4
56.8
Perifovea
52.8
51.8
54.3
54.5
53.3
52.9
Superior-hemi
53.1
53.5
54.7
54.3
52.9
53.2
Inferior-hemi
53.6
54.1
53.9
54.7
53.6
52.7
Temporal
50.3
52
51.8
52.2
50.8
52.5
Superior
54.2
54.7
54.7
53.9
52.4
53.1
Nasal
57.5
53.4
57.7
58.2
57.4
55.2
Inferior
53.4
52.4
52.6
53.8
52.2
50.9
Deep (%)
Whole
48.1
47.6
48.3
48.4
48
46.9
Superior-hemi
49.9
47.9
50.3
47.9
49.7
47.4
Inferior-hemi
46.4
48.5
46.4
49
46
46.4
Fovea
32.3
30.1
30.6
29.1
32.7
29.2
Parafovea
55.8
53.9
56.4
55.1
55.5
55.7
Superior-hemi
56.7
55.7
56.7
55.2
56.2
55.9
Inferior-hemi
55.6
56.2
56
54.9
54.8
55.5
Temporal
55.8
57.5
55
57.4
55.6
57.8
Superior
56.5
53.4
57.8
53.7
55.5
55.3
Nasal
57.9
55.2
58.3
55.9
58.1
55.8
Inferior
52.3
51.8
54.4
53.4
52.8
53.9
Perifovea
50.1
48.3
50.7
50.1
48.1
46.3
Superior-hemi
50.2
48.6
52.8
49.8
49
46.7
Inferior-hemi
48.5
47.4
48.6
50.4
47.2
45.8
Temporal
54.8
54.3
56.1
54.6
55.5
49.5
Superior
49.4
49.2
53.3
49.4
47.3
47.4
Nasal
43.9
43.4
46.4
46.5
44.6
42.8
Inferior
46.7
48.1
47.8
50
45.8
45.3
Foveal avascular zone (mm2)
Retina
352
376
347
389
358
386
Foveal flow
Outer retina
0.558
0.732
0.346
0.846
0.602
0.665
Choriocapillaris
2.101
2.068
2.087
2.091
2.195
2.058
Cells are divided into two to show the results of the right and left eyes separately.Figure 2
On the first day. (a) Unified and coloured OCTA image of the right eye; circular CNV complex with main trunk, multiple dense thin capillaries branching from the main trunk and frequent anastomoses (yellow). (b) Outer retina cross-section and en face OCTA image of the right eye. (c) Unified and coloured OCTA image of the left eye; CNV with main trunk, minimal vessel loops, and capillaries (yellow). (d) Outer retina cross-section and en face OCTA image of the left eye.
(a)
(b)
(c)
(d)All evaluations suggested CNV secondary to ODD, and intravitreal aflibercept was injected in 3 doses to the right eye and a single dose to the left eye. Three doses were injected to the right eye every other month. After the first injection, BCVA remained as 20/32 and increased to 20/25 after the second one. After the third dose of injection to the right eye and the first one to the left eye, BCVA was 20/20 in both eyes. After the injections in both eyes, SD-OCT revealed RPE irregularity in the temporal region of the optic disc and complete regression of the subretinal fluid. OCTA interestingly showed that the entire CNV compete including the main trunk disappeared (Figures3(a) to 3(d)). CNV complex was not observed with OCTA, and no significant change was observed in the peripapillary and macular vascular density measurements, and findings which might be correlated with RNFL measurements were not detected in 1-year follow-up. BCVA was preserved, and no additional injections were needed.Figure 3
At 3 months. (a and b) Outer retina, choriocapillaris cross-sections, and en face OCTA image of the right eye; CNV complex including the main trunk disappearance. (c and d) Outer retina, choriocapillaris cross-sections, and en face OCTA image of the left eye; entire CNV compete of including the main trunk disappearance.
(a)
(b)
(c)
(d)


## 3. Discussion

CNV associated with ODD is a very rare complication, which has been reported in both adults and children [6]. In most of the patients, CNV membranes associated with ODD occur nasally; however, they may also occur temporally resulting in serous haemorrhagic maculopathy, cystoid macular edema, and macular scarring [7]. Its pathogenesis is unknown. Possible mechanisms involved in this complication include the compressive effect of drusen on the surrounding blood vessels, which leads to mechanical impairment of peripapillary vascular integrity, vascular congestion, or ischemia. Retinal ischemia and the release of VEGF may be the factors that trigger the development of CNV [8, 9]. Treatment must be provided if vision is jeopardized. The modern antivascular endothelial growth factor (VEGF) medications, photodynamic therapy, and surgical removal have each been demonstrated to be successful [10]. Anti-VEGF agents have been increasingly preferred as the first-line treatment because they ensure high visual acuity and disease stabilization usually with fewer intravitreal injections especially in paediatric cases, and recurrence is almost never observed. Gan and Long reported complete resolution after 3 doses of injection in cases for whom aflibercept was injected for the first time [11]. Knape et al. reported rapid and atraumatic resolution with the combination of bevacizumab and focal laser photocoagulation [12]. Alkın et al. emphasized that CNV secondary to ODD might be more sensitive than CNV secondary to age-related macular degeneration (AMD) in cases injected with a single dose of ranibizumab [13]. We achieved rapid response and did not observe recurrence in cases injected with 3 doses of aflibercept in the right eye and a single dose of aflibercept in the left eye and whom we followed for 12 months with OCTA.4 different CNV patterns associated with exudative age-related macular degeneration can be detected with OCTA: Medusa pattern: central feeder vessel, circular peripheral anastomosis, thin branches, and hypointense halo; seafan pattern: eccentric feeder vessel, thin branches, and hypointense halo; indistinct network pattern: thin branches and hypointense halo; and pruned vascular tree pattern: persistence of main vascular trunks [14]. Pruned vascular tree pattern is considered as inactivate and usually followed up. The morphology of CNV and structural response to anti-VEGF treatment are strongly correlated. Anti-VEGF is ineffective for the vascular trunk while it is effective for especially the newly formed capillaries from preexisting vascular trunks while there is a correlation between better functional outcomes an increased vascularity of the CNV [15]. Spaide demonstrates reprofileration 20-50 days after the injection [16]. However, long-term inactivation can be ensured with fewer anti-VEGF injections in cases of CNV associated with high myopia, punctate inner choroidopathy (PIC), choroidal osteoma, optic nerve drusen like our patient, and idiopathic with lower activity than AMD [17–20]. The literature does not contain wide range of data which can be used to assess why stabilization can be achieved with fewer injections and make comparisons with CNV patterns of AMD with OCTA as highlighted above and assess reproliferation.The most striking finding after injection in our case was the absence of CNV visualization in OCTA. The absence of CNV visualization in OCTA was associated with clinical and SD-OCT exudative inactivity [14]. In fact, inactive lesions are visualized as pruned vascular tree pattern, presence of large linear vessel with no or minimal anastomosis in OCTA. This may be due to other reasons such as the masking effect generated by a high PED, media opacities, or the presence of haemorrhages [21]. However, they were not observed in the follow-up of our patient. Hua and Ning demonstrated the development of atrophy in the CNV complex after 3 doses of anti-VEGF injections in PIC cases with high myopia and round dark region visualization due to no-perfusion/hypopefusion zone in the choriocapillaris [22]. This situation which was also observed in our case can be interpreted as decreased signal due to inactivity, but the absence of pruned vascular tree pattern may at least contribute to explaining why atrophy/shrinkage can develop in the main vascular trunk and why non-AMD CNV causes are more benign and can be stabilized longer with fewer injections.In the literature, only Ong et al. demonstrated inactive CNV associated with ODD in 1 case with OCTA in a series of 8 paediatric patients with CNV. A 12-year-old female patient first underwent injection and photodynamic therapy in the left eye; however, OCTA revealed two large calibre vessels and a lack of fine capillaries, anastomoses, and vessel loops, which was considered as inactive sub-RPE CNV lesion [23]. This is the first paper to report a case with an interesting change in CNV visualization after injection and followed up for a long term for both CNV and vascular density. On the other hand, studies on OCTA for ODD mainly focus on microvascular changes. Biçer and Atilla showed that macular vascular density located in different regions decreased both at the superficial and deep capillary layer in cases with bilateral ODD, and there was a density loss in the peripapillary area especially the nasal region. They reported that ODD findings could be used to demonstrate that enlarged ODD might cause acute or chronic ischemia by compressing nerve fibers or surrounding vessel [24]. Aghdam et al. compared patients with ODD, NAION, and normal individuals and reported that optic nerve head vessel density was lower in the NAION group than in the other groups [25]. Cennamo et al. reported that flow rate measurements were correlated with ganglion cell layer thickness and OCTA examination can be an early marker to show the axonal damage in patients with ODD [26]. Similarly, Engelke et al. demonstrated the correlation between vascular density and RNFL and ganglion cell complex (GCC) and peripapillary capillary density loss compared to the normal group [27]. In our case, however, peripapillary capillary density evaluation revealed that the vascular density in the nasal quadrants was lower than those in the other quadrants, which was an interesting finding. However, changes that might be correlated in both RNFL and disc and macular vascular density measurements were not detected contrary to the abovementioned reports.In conclusion, it is possible to evaluate vascular density, presence of associated CNV, and response to injection with OCTA in patients with optic nerve diseases such as ODD. Nonetheless, there is a need for further studies to confirm the changes in CNV visualization like in our case with OCTA that has been increasingly used.



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