Central, high-resolution vision corresponds to the highly specialized macula region of the retina.1 Cones are densely packed in the fovea centralis within the macula to achieve high visual acuity (VA), resulting in a very high metabolic demand that is supplied by surrounding capillary plexi.2 Vascuologenesis in the retina commences during the start of the second trimester of fetal development at around 14 weeks and continues on until 25 weeks post-conception.3 Blood vessels begin to form around the optic disc and spread peripherally into the outer perimeters of the retina.3,4 In normal development of the adult primate eye, anti-proliferative and anti-angiogenic factors in the foveal zone inhibit blood vessel growth, thus forming a foveal avascular zone (FAZ).4 Past imaging studies demonstrate an absence of vascularization in the fovea starting from 26 weeks' gestation that persists through birth and adulthood.3 Both the thinning and displacement of inner retinal tissues in the fovea,5 as well as the absence of foveal blood vessels minimize the impedance of light as it passes through the retina.6
It has been suggested that the formation of the FAZ is a necessary prerequisite for the development of the foveal pit, due to discrepant mechanical properties between the FAZ and surrounding areas of the retina.6 Retinal tissue is more rigid in the perifoveolar areas due to the presence of blood vessels in the superficial capillary plexus (SCP), compared to the relatively elastic FAZ.6 Therefore, intraocular pressure is able to depress the fovea at the FAZ and contribute to the formation of the foveal pit.6 Supporting these theories, several studies have established a correlation between FAZ area and foveal pit depth.1,7,8
Until the recent advent of optical coherence tomography angiography (OCTA), fundus fluorescein angiography has been the gold standard for imaging retinal vasculature.9 Fluorescein angiography requires the intravenous injection of fluorescein dye in order to visualize retinal vasculature, which may cause side effects such as nausea, vasovagal syncope, dye extravasation, and anaphylaxis.10 In comparison, OCTA is a noninvasive imaging modality that demonstrates a better sensitivity for detecting vascularization in specific retinal layers such as the superficial capillary plexus (SCP) and deep capillary plexus (DCP).9
Studies of fetal retina development in humans, as well as macaque and marmoset species, have determined that the FAZ is supposed to remain avascular through fetal and adult development.3 Since OCTA is a new technology and FAZ anomalies are relatively rare, these studies have not established a consensus on the impact of FAZ absence on foveal pit morphology and VA. Furthermore, little is known about the impact of different ophthalmological diagnoses on the FAZ, and how FAZ anomalies in one eye can affect the fellow eye. Our aim was to gain insight into the spectrum of clinical presentations that may be associated with anomalous FAZ presentations and determine the impact of foveal vascularization on VA and foveal pit morphology.
Patients and Methods
For this retrospective case series, we reviewed the clinical imaging from 1,000 consecutive patients who were screened from January 2016 to February 2016 at the Vitreous Retina Macular Specialists of Toronto clinic. All patients referred to the clinic during this period received retinal vasculature imaging with swept-source OCTA (SS-OCTA) (Triton; Topcon, Tokyo, Japan). A total of 22 eyes with anomalous (vascularized) FAZs from 14 patients were identified using this method. Patient age, sex, VA, and ophthalmological diagnosis information were collected as part of the study.
SCP, DCP, and choriocapillaris vascular layers were automatically segmented using the OCT system software, and cases with inaccurate autosegmentation were excluded from the study. Each of the vascular layers in the retina were evaluated for both the affected and unaffected eyes using the 3.0 mm × 3.0 mm strategy (Supplementary Video available below). Presence of the FAZ was visually determined and classified as absent, partial, or present. Cases where FAZ classification was not definitive and clear due to poor resolution or artifact were excluded from the study.
Swept-source OCT imaging was used to scan the macula and obtain imaging of the foveal contour. In order to classify the degree of hypoplasia in each eye, the authors used the Structural Grading of Foveal Hypoplasia scale published by Thomas et al.11 This grading system characterized foveal pit morphology on a spectrum from structurally normal foveal pits to progressively increasing degrees of foveal hypoplasia (Table 1).
Grading of Foveal Pit Structural Characteristics as Detected by OCT11
The age of the patients ranged from 11 years to 89 years, with a mean age of 50 years. Six out of 14 patients (43%) had an anomalous FAZ findings in only one eye, whereas the remaining eight patients (57%) had bilaterally anomalous FAZ presentations. With the exception of one patient who presented with an anomalous retinal macrovessel located over the FAZ (Figure 3), the FAZ was absent in 21 out of 22 eyes at the level of the superficial capillary plexus (SCP). Eight out of 22 eyes (36%) demonstrated complete vascularization of the FAZ at the DCP layer in addition to the SCP. Vasculature in the choriocapillaris was normal in all eyes. Foveal hypoplasia was more severe in patients with FAZ vascularization in both the SCP and DCP compared to patients with a vascularized SCP and an intact FAZ in the DCP.
All 22 eyes with vascularized foveae demonstrated some degree of foveal hypoplasia according to the Thomas et al. grading scale.11 The different grades of foveal hypoplasia were not associated with significantly different mean Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected VA (BCVA) values (Table 2). In addition, higher grades of foveal hypoplasia (grades 3 and 4) were detected in younger patients (Table 2), and these patients were found to have better BCVA compared to patients with milder foveal hypoplasia (grades 1 and 2). Eight of the 14 patients had anomalous FAZ presentations bilaterally, whereas among the remaining six patients with unilateral presentations, two patients had a partial FAZ in their uninvolved eye and four patients had anomalous FAZ presence in only one eye. Mean ETDRS BCVA was 0.16 logMAR ± 0.15 logMAR for anomalous FAZ eyes, and 0.16 logMAR ± 0.18 logMAR for uninvolved eyes for patients with single-eye involvement.
Mean ETDRS BCVA for Different Grades of Foveal Hypoplasia
Four patient cases are described to highlight the spectrum of anomalous FAZ presentations that were detected using OCT and OCTA.
An 11-year-old girl with no previous history of any eye conditions or diseases was referred for foveal hypoplasia. OCTA showed a fully vascularized FAZ in both the right and left eyes (Figure 1). Her OCT B-scan was evaluated to be grade 3 hypoplasia, with the absence of plexiform layer extrusion, foveal pit shallowing, and outer segment lengthening (Figure 1). The patient had no features of albinism, and all other retinal exam findings were normal. Her BCVA was 20/25 in both eyes.
Swept-source optical coherence tomography angiography (SS-OCTA) of the superficial capillary plexus (SCP) (A) and deep capillary plexus (DCP) (B) of the right eye showing complete vascularization of the foveal avascular zone (FAZ) over both retinal vascular plexuses. The SS-OCT of the patient's right eye foveal pit, showing a grade 3 foveal hypoplasia (C). The SCP (D) and DCP (E) of the left eye were also completely vascularized over the FAZ, and the foveal pit was also classified as grade 3 on the foveal hypoplasia scale (F).
A 56-year-old male was referred for a retinal tuft. He was a high myope with 20/20 BCVA in both eyes and had a history of cataract surgery in both eyes. Both eyes were found to have a fully vascularized FAZ in the SCP layer, with an intact FAZ in the DCP layer, and were classified as grade 3 on the foveal pit hypoplasia scale (Figure 2).
Swept-source optical coherence tomography angiography (SS-OCTA) of the right superficial capillary plexus (SCP) (A) showing complete vascularization of the SCP and right deep capillary plexus (DCP) (B) showing an intact foveal avascular zone (FAZ). The SS-OCT of the patient's right eye foveal pit showing a grade 3 foveal hypoplasia (C). For the left eye, the SCP (D) was fully vascularized (E), whereas the DCP had an intact foveal avascular zone (F), and the foveal pit was classified as grade 3 on the foveal hypoplasia scale (F).
A 60-year-old male was referred for central serous retinopathy in the left eye. He was found to have an anomalous retinal macrovessel penetrating into both the SCP and DCP of the left eye (Figure 3). The FAZ was still found to be intact in both the SCP and DCP. The right eye showed normal retinal vasculature, and all the other retinal exams findings were within normal limits. His BCVA was 20/20 for the right eye, and 20/50 for the left eye due to central serous retinopathy.
Swept-source optical coherence tomography angiography of the left eye showing an anomalous retinal macrovessel penetrating the superficial capillary plexus (A) and deep capillary plexus (B).
A 65-year-old female was referred for wet age-related macular degeneration in both eyes. Her VA was 20/40 in the right eye and 20/50 in the left eye, whereas OCTA showed a fully vascularized FAZ SCP in the left eye only. The DCP FAZ was intact in both eyes. Her OCT B-scan showed a pigment epithelial detachment in the left eye (Figure 4); thus, it was classified as “atypical” in the foveal pit hypoplasia grading scale.
Swept-source optical coherence tomography of the left eye showing a pigment epithelial detachment (A). The superficial capillary plexus was vascularized (B), whereas the deep capillary plexus had an intact foveal avascular zone (C).
Due to recent advances in retinal imaging technology, the development and function of the FAZ and foveal pit have been increasingly studied. The formation of the fovea is influenced by a complex interplay between molecular factors that guide the development of macular axons and the balance between angiogenesis and anti-angiogenesis.6 The first step of FAZ development is defined by a gradient of ephrin-A6 expression in the ganglion cell layer, which regulates the migration of astrocytes in the retina.6 As the astrocytes invade the retina at around 15 weeks' gestation, they express vascular endothelial growth factor and lead a trail of proliferating endothelial cells. Provis et al.6 postulated that to the gradient of ephrin-A6 expression at the macula inhibits astrocyte migration into the fovea, and therefore reduces the formation of blood vessels over the fovea. Anti-angiogenesis in the macula is regulated by the release of pigment epithelium derived factor (PEDF), released by ganglion cells in a gradient following the initial gradient of ephrin-A6 expression.6 Since foveal anti-angiogenesis occurs at an early stage in development, it is reasonable that the anomalous FAZ presentations were found across a wide age range of patients, who demonstrated a spectrum of different associated ophthalmological findings. Mutations and alterations in the ephrin-A6 and PEDF pathways likely contributed to complete foveal vascularization in the SCP layer and limited presence of the FAZ in the DCP.
Although the literature establishes that FAZ size and foveal pit depth are correlated,1,7,8 the influence of both morphological features on VA is not as clear. OCTA analyses in patients with macular diseases such as diabetic retinopathy and retinal vein occlusion have found a correlation between larger FAZ sizes with worse VA.12,13 In contrast, foveal cones are able to elongate and pack in the absence of an FAZ, and it has been suggested that FAZ size has minimal influence on VA.5,6,14 These findings suggest that foveal cone cells can adapt to anomalies in FAZ structure and foveal pit hypoplasia in fetal development, but diseases in later life that are associated with retinal vasculature pathology have a more profound impact on cone function and VA. In this study, patients with higher grades of foveal hypoplasia were actually measured to have better BCVA, at 0.10 logMAR ± 0.11 logMAR and 0 logMAR for grades 3 and 4, respectively, compared to patients with milder foveal hypoplasia, at 0.14 logMAR ± 0.15 logMAR and 0.20 log-MAR ± 0.19 logMAR for grades 1 and 2, respectively. However, this association is likely confounded by the age differences between the different grade classifications, with a mean age of 57.8 years and 63.0 years for grades 1 and 2 foveal pit hypoplasia, respectively, compared to 36.8 years and 15.0 years for grades 3 and 4, respectively.
In healthy adults, OCTA measurements of FAZ size are generally found to be statistically equal between both eyes.8,12 However, in retinal vein occlusion, the FAZ was found to be significantly larger in diseased eyes compared to the healthy fellow eye.15 For the six patients in this study who presented with unilaterally anomalous FAZ, the diagnoses were: retinitis pigmentosa, optic pit, wet age-related macular degeneration with pigment epithelial detachment, epiretinal membrane, adult vitelliform dystrophy, and anomalous venular branching. In comparison, five out of eight patients with bilaterally anomalous FAZ had normal retinal exam findings, and the other three patients also presented with glucose-6-dehydrogenase deficiency, a peripheral retinal hole, and hypertensive retinopathy in one eye and dry macular degeneration in the other eye.
SS-OCTA is a new imaging modality which offers several benefits over conventional spectral-domain OCTA, including faster imaging speeds, higher detection efficiency, and uniform sensitivity over the entire scan window.16,17 Currently, there have been no reported cases of a fully developed foveal pit in a patient with an absent FAZ. Using the Thomas et al.11 grading scale and high-sensitivity OCTA imaging, we were able to stratify different foveal pit morphologies and examine the link between foveal pit hypoplasia and FAZ anomalies.
Limitations of this study include its small sample size of 22 eyes. It is, however, important to note that foveal hypoplasia is an uncommon finding on clinical examination and OCT. As a result of this smaller sample in the study, the association between degree of hypoplasia and vascular plexus could not be statistically powered. Although the SS-OCTA images acquired were high quality and we could definitively assess the SCP, our study did not differentiate between the two DCP layers,18 and as such, further segmentation with third-party software could assist in analyzing any differences.
This case series demonstrates that anomalies of the FAZ and foveal pit can present in a spectrum, in patients with a wide range of ages and ocular diagnoses. Visual acuity was not correlated to the presence or absence of the FAZ, or the degree of foveal pit hypoplasia. Swept-source OCTA has allowed for an expansion of the knowledge in understanding vascularization of the fovea, which is an uncommon finding that is often associated with foveal hypoplasia.
- Dubis AM, Hansen BR, Cooper RF, Beringer J, Dubra A, Carroll J. Relationship between the foveal avascular zone and foveal pit morphology. Invest Ophthalmol Vis Sci. 2012;53(3):1628–1636. doi:10.1167/iovs.11-8488 [CrossRef]
- Iafe NA, Phasukkijwatana N, Chen X, Sarraf D. Retinal capillary density and foveal avascular zone area are age-dependent: Quantitative analysis using optical coherence tomography angiography. Invest Opthalmol Vis Sci. 2016;57(13):5780. doi:10.1167/iovs.16-20045 [CrossRef]
- Provis JM, Hendrickson AE. The foveal avascular region of developing human retina. Arch Ophthalmol. 2008;126(4):507–511. doi:10.1001/archopht.126.4.507 [CrossRef]
- Yanni SE, Wang J, Chan M, et al. Foveal avascular zone and foveal pit formation after preterm birth. Br J Ophthalmol. 2012;96(7):961–966. doi:10.1136/bjophthalmol-2012-301612 [CrossRef]
- Noval S, Freedman SF, Asrani S, El-Dairi MA. Incidence of fovea plana in normal children. J AAPOS. 2014;18(5):471–475. doi:10.1016/j.jaapos.2014.07.157 [CrossRef]
- Provis JM, Dubis AM, Maddess T, Carroll J. Adaptation of the central retina for high acuity vision: Cones, the fovea and the avascular zone. Prog Retin Eye Res. 2013;35:63–81. doi:10.1016/j.preteyeres.2013.01.005 [CrossRef]
- Chui TYP, Zhong Z, Song H, Burns SA. Foveal avascular zone and its relationship to foveal pit shape. Optom Vis Sci. 2012;89(5):602–610. doi:10.1097/OPX.0b013e3182504227 [CrossRef]
- Chui TYP, VanNasdale DA, Elsner AE, Burns SA. The association between the foveal avascular zone and retinal thickness. Invest Ophthalmol Vis Sci. 2014;55(10):6870–6877. doi:10.1167/iovs.14-15446 [CrossRef]
- Magrath G, Ferenczy S, Shields CL. Correlation of foveal avascular zone size with foveal morphology in normal eyes using optical coherence. Retina. 2015;35(11):2188–2195. doi:10.1097/IAE.0000000000000847 [CrossRef]
- Yu S, Lu J, Cao D, et al. The role of optical coherence tomography angiography in fundus vascular abnormalities. BMC Ophthalmol. 2016;16(1):107. doi:10.1186/s12886-016-0277-2 [CrossRef]
- Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography: A predictor of visual acuity?Ophthalmology. 2011;118(8):1653–1660. doi:10.1016/j.ophtha.2011.01.028 [CrossRef]
- Magrath GN, Say EAT, Sioufi K, Ferenczy S, Samara WA, Shields CL. Variability in foveal avascular zone and capillary density using optical coherence tomography angiography machines in healthy eyes. Retina. 2017;37(11):2102–2111. doi:10.1097/IAE.0000000000001458 [CrossRef]
- Balaratnasingam C, Inoue M, Ahn S, et al. Visual acuity is correlated with the area of the foveal avascular zone in diabetic retinopathy and retinal vein occlusion. Ophthalmology. 2016;123(11):2352–2367. doi:10.1016/j.ophtha.2016.07.008 [CrossRef]
- Marmor MF, Choi SS, Zawadzki RJ, Werner JS. Visual insignificance of the foveal pit: Hypoplasia, foveal plana. Arch Ophthalmol. 2008;126(7):907–913. doi:10.1001/archopht.126.7.907 [CrossRef]
- Kang JW, Yoo R, Jo YH, Kim HC. Correlation of microvascular structures on optical coherence tomography angiography with visual acuity in retinal vein occlusion. Retina. 2017;37(9):1700–1709 doi:10.1097/IAE.0000000000001403 [CrossRef]
- Tatham AJ. Clinical advantages of swept-source OCT and new non-damaging laser treatments. Review of Ophthalmology. 2014.
- Ferrara D, Mohler KJ, Waheed N, et al. En face enhanced-depth swept-source optical coherence tomography features of chronic central serous chorioretinopathy. Ophthalmology. 2014;121(3):719–726. doi:10.1016/j.ophtha.2013.10.014 [CrossRef]
- Campbell JP, Zhang M, Hwang TS, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep. 2017;7:42201. doi:10.1038/srep42201 [CrossRef]
Grading of Foveal Pit Structural Characteristics as Detected by OCT11
|Foveal Hypoplasia Grade||Extrusion of Plexiform Layers||Foveal Pit Shallowing||Outer Segment Lengthening||Outer Nuclear Layer Lengthening|
Mean ETDRS BCVA for Different Grades of Foveal Hypoplasia
|Number of Presentations||Age (Years)||Mean BCVA (logMAR)||BCVA Standard Deviation (logMAR)|
|Normal Fovea Contour||0||*||*||*|
|Grade 1 Foveal Hypoplasia||5||57.8||0.14||0.15|
|Grade 2 Foveal Hypoplasia||6||63.0||0.20||0.19|
|Grade 3 Foveal Hypoplasia||9||36.8||0.10||0.11|
|Grade 4 Foveal Hypoplasia||1||15.0||0||*|
|Atypical Foveal Hypoplasia||1||65.0||0.40||*|