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. Author manuscript; available in PMC: 2017 Oct 19.
Published in final edited form as: Ophthalmology. 2011 Apr 29;118(8):1653–1660. doi: 10.1016/j.ophtha.2011.01.028

Structural Grading of Foveal Hypoplasia Using Spectral Domain Optical Coherence Tomography; A Predictor of Visual Acuity?

Mervyn G Thomas 1,*, Anil Kumar 1,*, Sarim Mohammad, Frank A Proudlock 1, Elizabeth C Engle 2, Caroline Andrews 2, Wai-Man Chan 2, Shery Thomas 1, Irene Gottlob 1
PMCID: PMC5648335  NIHMSID: NIHMS912228  PMID: 21529956

Abstract

Purpose

We aimed to characterize and grade the spectrum of foveal hypoplasia based on different stages of arrested development of the fovea. Grading was performed using morphological findings obtained by ultrahigh resolution spectral domain optical coherence tomography (UHR-OCT). Best corrected visual acuity (BCVA) was calculated for different grades.

Design

Observational Case Series

Participants and Controls

Sixty-nine patients with foveal hypoplasia (albinism (n=34), PAX6 mutations (n=10), isolated cases (n=14), achromatopsia (n=11)) and 65 control subjects were examined.

Methods

A 7x7mm retinal area was sampled using a 3-dimensional scanning protocol (743x75; AxB scans) with UHR-OCT (SOCT Copernicus HR, 3μm axial resolution). Gross morphological abnormalities were documented. B-scans at the fovea were segmented using a longitudinal reflectivity profile. Logarithm of Minimum Angle of Resolution (LogMAR) BCVA was obtained.

Main Outcome Measures

Grading was based on presence or absence of foveal pit, widening of outer nuclear layer (ONL) and outer segment (OS) at the fovea. Quantitative measurements were performed for comparing atypical foveal hypoplasia in achromatopsia. BCVA was compared to the grade of foveal hypoplasia

Results

Four grades of foveal hypoplasia were distinguished grade 1: shallow foveal pit, presence of ONL widening, presence of OS lengthening; grade 2: grade 1 but absence of foveal pit, grade 3: grade 2 but absence of OS lengthening; grade 4: grade 3 but absence of ONL widening). There was significant difference in visual acuity (VA) associated with each grade (p<0.0001). Grade 1 was associated with the best VA (median VA = 0.2), while grade 2, 3 and 4 was associated with progressively poorer VA with a median VA of 0.44, 0.60 and 0.78 respectively. The atypical features seen with foveal hypoplasia associated with achromatopsia were characterized by decreased retinal (RT) and ONL thickness and deeper foveal depth (FD).

Conclusions

We have developed a structural grading system for foveal hypoplasia based on the stage at which foveal development was arrested, which helps to provide a prognostic indicator for VA and is applicable in a range of disorders associated with foveal hypoplasia. Atypical foveal hypoplasia in achromatopsia shows different characteristics.

Normal foveal development occurs in stages where the pit formation for the incipient fovea starts at fetal week 25 and the excavation is complete 15–45 months after birth.1 Disruption of this developmental process leads to foveal hypoplasia which is a characteristic morphological abnormality associated with conditions such as albinism, PAX6 mutations or it may occur in isolation.2–5 With the advent of optical coherence tomography (OCT) it is now possible to document the varying degrees of foveal hypoplasia which are likely to represent the different stages of arrested development of the fovea. This has introduced various terminologies such as fovea plana, foveal dysgenesis and foveal aplasia to describe the structural variability associated with arrested development of the fovea.6–8 Mietz and colleagues suggested that foveal hypoplasia is a more appropriate terminology rather than aplasia since hypoplasia encompasses both the partial and complete absence of a structure.9

Recent studies have shown that OCT can be used as a diagnostic aid and prognostic indicator for the foveal hypoplasia.4, 10, 11 In addition structural-functional correlation studies have been performed to document OCT findings in foveal hypoplasia although most of them were disease specific for albinism. Harvey et al. showed a weak but significant correlation between macular thickness and visual acuity.12 In contrast, Holmstrom et al. did not find significant correlation between central macular thickness and visual acuity (VA).10 Seo et al. proposed a grading system for foveal hypoplasia in albinism, this was based on: (1) foveal hyporeflectivity, (2) choroidal transillumination, (3) tram tract sign and (4) foveal depression. They showed in 13 patients that visual acuity correlates well with degree of foveal hypoplasia.11 Although subsequently they suggested that the role of foveal depression as prognostic indicator remains unclear due to the small sample size.13 Chong et al. also characterized the foveal morphological abnormalities in 2 patients with ocular albinism and 5 patients with suspected ocular albinism and reported that there were no foveal hyporeflectivity or tram tract sign in their study population.14 Marmor et al. noted a spectrum of different visual acuities in four patients that all lacked a foveal pit. Furthermore they showed that foveal cone specialisation, represented on OCT by the lengthening of the outer segment (OS) at the fovea, can be preserved even in the absence of a foveal pit. 7 However it still remains unclear how the morphological variability associated with foveal hypoplasia relates to visual prognosis and what specific features at the fovea may be more important in determining visual performance.

In this study we aim to characterize the spectrum of foveal hypoplasia and develop a structural grading system for foveal hypoplasia based on foveal development which can be applied to various disorders associated with foveal hypoplasia. The purpose for establishing a grading system was three fold: (1) to document the stage at which foveal development was arrested, (2) to provide a prognostic indicator for visual acuity and (3) to ensure applicability in a range of disorders associated with foveal hypoplasia. We used a high speed UHR-OCT (axial resolution, 3μm) to image the foveal region in patients with foveal hypoplasia associated with different diseases and controls.

Patients and methods

Patients

The study population consisted of 69 patients with foveal hypoplasia (defined as incursion or continuation of inner retinal layers) and 65 controls with a mean age of 28.5 years (standard deviation [SD] = 15.7; range = 5 – 64) and 33.5 years (SD = 14.3; range = 8 – 62) respectively. The patient cohort consisted of 58 Caucasians (84%) and 11 Asians (16%); similarly the control cohort consisted of 48 Caucasians (74%) and 17 Asians (26%). In the patient group there were 38 males (55%) and 31 females (45%); in the control group there were 31 males (48%) and 34 females (52%). All patients underwent ophthalmological examination which included slit lamp examination, fundus examination and measuring binocular best corrected visual acuity (BCVA) using standardized Logarithm of the Minimum Angle of Resolution (LogMAR) charts. BCVA with both eyes open was used for comparison with OCT grading as it represents the best achievable VA and would for example reduce other causes of decreased VA such as amblyopia or latent nystagmus. Full field electoretinogram (ERG) response and visually evoked potentials (VEPs) were recorded based on International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients were diagnosed with albinism (n = 34), PAX6 mutations (n = 10), isolated foveal hypoplasia (n = 14) and achromatopsia (n = 11). The diagnosis of albinism and achromatopsia were based on the clinical findings and on electrodiagnostic tests. All patients diagnosed with albinism had asymmetric VEPs and transillumination defects of the iris. Patients with achromatopsia had extinguished photopic ERGs. All other patients with normal VEPs and ERGs underwent bidirectional sequence analysis for PAX6 mutations. PAX6 mutations were detected in 10 patients of whom 3 had aniridia. One patient with PAX6 mutation had to be excluded due to poor scan quality due to corneal opacity. All patients in the study population had nystagmus. There was no history of premature birth among the patients evaluated. All other patients and controls chosen for this study had clear media. None of the controls had nystagmus or a history of premature birth.

Informed consent was obtained from all volunteers participating in this study. The study adhered to the tenets of the Declaration of Helsinki and was approved by the local Ethics Committee.

Optical Coherence Tomography Image Acquisition

We used an ultrahigh resolution spectral domain optical coherence tomography (UHR-OCT) (SOCT Copernicus HR, OPTOPOL Technology S.A., Zawiercie, Poland) to acquire tomograms from the patient and control cohorts. A 3-D scan program (743x75: Ascans x Bscans) was used to obtain a 7x7mm retinal area centered at the fovea. The effective axial and transverse resolution for our machine was ~3 and 12μm respectively. Since our OCT machine achieves quite a high scanning speed (52,000 A-scans/second) we are able to achieve reproducible quantitative OCT measurements with no associated motion artefact. OCT images were obtained from both eyes in the study population. The tomograms were viewed using SOCT software (version 4.10) and subsequently graded. Intra-retinal thickness measurements were obtained using reflectivity profiles as described elsewhere.15 The thickness measurements derived from both eyes were averaged and subsequently analysed similar to a one-eye study design as described by Ray et al. 16

Grading foveal hypoplasia

The rationale behind the grading system we adopted was based on the unique developmental processes occurring at the fovea (figure 1). During development of the fovea there is (i) centrifugal displacement of cells of the inner retina towards the periphery, (ii) centripetal migration of cone photoreceptors towards the location of the incipient fovea and (iii) cone specialization of the foveolar cones. 1, 17 Due to the centrifugal displacement of the inner retinal cells the foveal depression continues to deepen until 15 months after birth, this is seen as complete extrusion of the inner nuclear and plexiform layers posterior to the foveola (see example of normal OCT in figure 2). 18 The centripetal migration of the cone photoreceptors is represented by the ONL widening. The cone outer segment undergoes both a decrease in diameter and increase in length (i.e., cone specialization); this allows an increase in foveolar cone packing density.17 The change in cone diameter continues up to 45 months postpartum. The cone specialization is represented on OCT by the OS lengthening.7 The grading system we have used takes into account each of these developmental steps.

Figure 1.

Figure 1

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Chart showing the 3 developmental processes involved information of a structural and functional fovea. In grade 1 foveal hypoplasia, all processes occur to a certain extent. However, in grade 4 foveal hypoplasia, none of these processes occur; thus, the retina resembles that of the parafovea. In grade 2 and 3 foveal hypoplasia, there is outer nuclear layer widening, but no foveal pit. The difference between grade 2 and 3 foveal hypoplasia is occurrence of cone photoreceptor specialization. Identifying these specific features on optical coherence tomography (OCT) enables us to understand whether the respective developmental process has occurred.

Figure 2.

Figure 2

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A, Optical coherence tomography scan showing a normal fovea with description of the normal foveal elements. Optical coherence tomography scans showing the spectrum of foveal hypoplasia seen in various conditions, including: (B, C) albinism, (D, E) associated with PAX6 mutations, (F, G) isolated cases, and (H, I) an atypical form of foveal hypoplasia seen in achromatopsia. A hyporeflective zone (cavitation) is also seen (I) that is a sign of cone photoreceptor degeneration. Both foveal hypoplasia and fovea plana were seen in all disorders except the achromatopsia, which results in an atypical form of foveal hypoplasia with a shallower pit, incursion of the plexiform layers, and disruption of the inner segment (IS)/outer segment (OS) junction. INL = inner nuclear layer; NFL = nerve fiber layer; ONL = outer nuclear layer.

Statistical Methods

Normality of the visual acuity (VA) and intra retinal thickness measurements data was tested using Shapiro-Wilk test. Non-parametric tests (Kruskal-Wallis) were used (due to non-normality) to test difference in (i) LogMAR VA between the different grades of foveal hypoplasia (ii) retinal thickness, (iv) outer nuclear layer thickness and (iv) foveal depth at the fovea between controls and patients with typical and atypical forms of foveal hypoplasia. Multiple comparisons were performed with Bonferroni correction. Mann-Whitney test was used to test the difference in VA between typical and atypical forms of foveal hypoplasia.

Results

Gross morphological features associated with foveal hypoplasia

Examples of the gross features of foveal hypoplasia detectable on UHR-OCT are shown in figure 2. The hallmark of foveal hypoplasia detectable on OCT is the incursion of the inner retinal layers posterior to the foveola. In addition to this other features seen on OCT included: shallower or absent foveal pit, diminished ONL widening, decreased OS lengthening and overall thickening of the retina. However there is considerable phenotypic variability associated with foveal hypoplasia. Figure 2 shows examples of foveal hypoplasia and the degree of variability seen.

Grading and functional implications of foveal hypoplasia

In order to derive a structural grading system for foveal hypoplasia we subdivided the foveal region according to foveal development into the structural elements which represent the unique features of the fovea detectable using OCT (see figure 3A). Progressive loss of the foveal elements is represented as increasing grades.

Figure 3.

Figure 3

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A, Illustration showing the unique features of a normal fovea detectable on optical coherence tomography. B, Illustration of typical and atypical grades of foveal hypoplasia. All grades of foveal hypoplasia had incursion of inner retinal layers. Atypical foveal hypoplasia also had incursion of the inner retinal layers. Grade 1 foveal hypoplasia is associated with a shallow foveal pit, outer nuclear layer (ONL) widening, and outer segment (OS) lengthening relative to the parafoveal ONL and OS length, respectively. In Grade 2 foveal hypoplasia, all features of grade 1 are present except the presence of a foveal pit. Grade 3 foveal hypoplasia consists of all features of grade 2 foveal hypoplasia except the widening of the cone outer segment. Grade 4 foveal hypoplasia represents all the features seen in grade 3 except there is no widening of the ONL at the fovea. Finally, an atypical form of foveal hypoplasia also is described in which there is a shallower pit with disruption of the inner segment/outer segment (IS/OS) junction, possibly a sign of photoreceptor degeneration. The atypical form of foveal hypoplasia is seen with achromatopsia, whereas grades 1 through 4 are seen with albinism, PAX-6 mutations, and isolated cases. ELM = external limiting membrane; GCL = ganglion cell layer; INL = inner nuclear layer; IPL = inner plexiform layer; OPL = outer plexiform layer; RNFL = retinal nerve fibre layer; RPE = retinal pigment epithelium.

Incursion of the plexiform layers was present in all types of foveal hypoplasia as it was our criteria to diagnose foveal hypoplasia. Subsequently our grading system gives most importance to the integrity of the outer segment OS (i.e., is this region disrupted or not; to rule out atypical forms of foveal hypoplasia). Then importance is given to the development of this region (detected on OCT by the lengthening of the outer segment; this feature is present in grade 1 and 2 but not present in grade 3 and 4). Subsequently we assessed the features of foveal development anterior to the inner-outer segments. Widening of the ONL differentiated between grade 3 and 4 and foveal pit formation, between grade 1 and 2. The features of each grade are illustrated in figure 3B. An algorithm was devised to structurally grade foveal hypoplasia (figure 4).

Figure 4.

Figure 4

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Algorithm used for grading foveal hypoplasia based on optical coherence tomography findings. The hallmark of foveal hypoplasia is incursion of the inner retinal layers. Based on disruption of the inner segment/outer segment (IS/OS) junction of the photoreceptor, the foveal hypoplasia is classified into either typical or atypical foveal hypoplasia. The grade of foveal hypoplasia can be determined based on whether the following features are present or absent: outer segment (OS) lengthening, foveal pit, and outer nuclear layer (ONL) widening.

We assessed whether the grade of foveal hypoplasia significantly predicted the best corrected visual acuity. We found that there was a significant difference in BCVA between the grades of foveal hypoplasia (p < 0.0001) (see figure 5). Grade 1 foveal hypoplasia was associated with the best visual acuity (median BCVA = 0.2 LogMAR), while grade 2, 3 and 4 was associated with progressively poorer VA with a median BCVA of 0.44, 0.60 and 0.78 LogMAR respectively (figure 5B). The results of the multiple comparisons of VA between the grades are shown in figure 5B. We did not find a significant effect of gender, age or ethinicity on the grade of foveal hypoplasia.

Figure 5.

Figure 5

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A, Bar graph showing the number of patients within each grade of foveal hypoplasia; the proportion of different disorders within each grade are shown with different shades. B, Box plots of visual acuity (VA) for each grade of foveal hypoplasia. The results of multiple comparisons of how grade of foveal hypoplasia affects VA are shown with the respective P values and median difference (d) in VA measured in logarithm of the minimum angle of resolution (logMAR) units. C, Box plot showing that similarly, there was a significant difference in visual acuity between the typical forms of foveal hypoplasia and atypical foveal hypoplasia. The other features that were significantly different between the controls and typical and atypical forms of foveal hypoplasia were: (D) retinal thickness at the fovea, (E) outer nuclear layer thickness, and (F) foveal depth. For all box plots, the whiskers represents the maximum and minimum range of observations, whereas the box represents the interquartile range and the line dividing the box represents the median. All multiple comparisons are shown with the box plots with the significance values and median differences (d), units for which are logMAR (for B and C) or micrometers (for D, E, and F).

Comparison of typical and atypical foveal hypoplasia

The number of patients within each grade and their diagnosis is shown in figure 5A. Most patients with albinism had grade 3 foveal hypoplasia while most isolated cases and PAX6 patients had grade 1 foveal hypoplasia. Overall, patients with albinism were associated with the worst BCVA (median BCVA = 0.6 LogMAR; interquartile range (IQR) = 0.30) followed by patients with PAX6 mutations (median BCVA = 0.4 LogMAR; IQR = 0.35) and then isolated cases (median BCVA = 0.2 LogMAR; SD = 0.30). However if the grade of foveal hypoplasia was considered there was no significant difference in BCVA between the three disorders for grade 1 foveal hypoplasia (p = 0.83)(Only grade 1 had sufficient sample numbers within each diagnosis to make multiple comparisons).

As shown in figure 2 achromatopsia is associated with disruption of the inner-outer segment (IS/OS) junction however it can also be associated with a shallower pit and incursion of the plexiform layers posterior to the foveola. This results in an atypical foveal hypoplasia since it is associated with photoreceptor degeneration. The other atypical features associated with achromatopsia which does not follow the pattern seen with the typical forms of foveal hypoplasia include: a significantly decreased retinal thickness in comparison to both controls (p < 0.0001) and the patients with typical foveal hypoplasia (p < 0.0001) (grade 1–4) (figure 5D). Similarly there is a significantly thinner outer nuclear layer in comparison to both controls (p < 0.0001) and patients with typical foveal hypoplasia (p < 0.0001) (figure 5E). Although achromatopsia is associated with significantly shallower pit in comparison to the controls (p < 0.0001), the foveal pit in achromatopsia is significantly deeper in comparison to the patients with grade 1 foveal hypoplasia (p = 0.005) (only grade 1 foveal hypoplasia was used for this comparison since only these patients have a rudimentary foveal pit) (see figure 5F).

Discussion

In this study we propose a structural grading system for foveal hypoplasia based on loss of unique elements that form the normal fovea which have likely been arrested during early development. The proposed grading system has three advantages: (1) it gives insight into the degree of development of the fovea, (2) provides a prognostic indicator from a morphological OCT scan and (3) it can be applied to most disorders associated with foveal hypoplasia. We also show that achromatopsia can be associated with foveal hypoplasia although it is associated with atypical features such as IS/OS disruption, ONL thinning which are signs of photoreceptor degeneration reduced RT and a deeper foveal pit in comparison to the typical forms of foveal hypoplasia.

From a developmental perspective each grade suggests developmental arrest of the three key events to varying degrees as shown in figure 1. All patients with foveal hypoplasia in this study had incursion of the plexiform layer posterior to the foveola, suggesting that pit formation was incomplete in all patients. A partial displacement of the inner retinal layers results in a rudimentary pit as encountered with grade 1 foveal hypoplasia and atypical foveal hypoplasia. This process has failed to occur in grades 2, 3 and 4 of foveal hypoplasia. Lengthening of the OS is a sign of cone photoreceptor specialization and this occurs to some extent in grade 1 and 2, but not grade 3 and 4. It is interesting to note that lengthening of OS can occur in the absence of a foveal pit as seen in grade 2 foveal hypoplasia as also suggested by Marmor et al.7 However we did not encounter any cases where a foveal pit was present with no OS lengthening (i.e., all patients with a foveal pit had OS lengthening), this suggests that pit formation maybe partly dependent on OS lengthening. Successful centripetal migration of cone photoreceptors is represented by ONL widening (seen in Grade 1, 2 and 3). However in grade 4 foveal hypoplasia this developmental process is completed arrested and has failed to occur.

Our grading system provides a prognostic visual function indicator as we have shown that the grade of foveal hypoplasia is significantly related to visual acuity. It can be easily performed in a clinical setting and does not require thickness measurements in order to predict and provide a likely visual prognosis for the patient with foveal hypoplasia. The grading system we propose accounts for the retinal structural basis for the decreased VA but not for additional causes reducing VA such as nystagmus, amblyopia, anterior segment disorder or refractive error. Hence morphological grading of foveal hypoplasia can help in deciding whether further investigation or treatment are necessary to improve the patients VA. For instance if a patient presents with grade 1 foveal hypoplasia and a VA of 0.7 LogMAR factors other than the foveal hypoplasia are likely to contribute to the poor VA. Similarly if a patient presents with a VA of 0.6 LogMAR and has a grade 3 foveal hypoplasia, one would not expect the vision to improve past 0.5 LogMAR as the structural development of the fovea is the limiting factor. We have also developed an algorithm which is easy to follow which can be utilized to derive the structural grade for foveal hypoplasia. Although we have included four representative disorders associated with foveal hypoplasia we have not applied our grading system in patients with other forms of foveal hypoplasia such as nanophthalmos 19 and retinopathy of prematurity.20 In our study population we find that VA correlates well with the grade of foveal hypoplasia, however validation of the grading scheme in larger cohorts is necessary.

The previous study by Seo et al. used OCT signs in albinism which are dependent on reflectivity of structures in the tomogram such as foveal hyporeflectivity, choroidal transillumination and tram tract sign.11 Presence or absence of foveal depression was also used to grade the foveal hypoplasia. Determining reflectivity features can be subjective especially when using a spectral domain OCT since they are associated with a sensitivity roll off, i.e., the decrease in reflectivity values as the image moves away from the zero delay line. Hence foveal hyporeflectivity could potentially be difficult to interpret between an image which is close to the zero delay line (which would be associated with higher reflectivity) and one which is further away (which would be less reflective).21 In our study we avoided using reflectivity values due to this inherent difficulty in standardizing these values with a spectral domain OCT and since these signs might be specific for albinism. We also show that atypical foveal hypoplasia (seen in achromatopsia) is associated with worse visual prognosis in comparison to the typical disorders associated with foveal hypoplasia, this is due to the photoreceptor degeneration, visualized on OCT as IS/OS disruption.22, 23 Interestingly in achromatopsia there is also a reduction in RT while in typical foveal hypoplasia there is an increase in RT compared to controls. This paradoxical reduction in RT in achromats is due to the ONL thinning due to photoreceptor degeneration.22 However in achromatopsia there is still a significantly shallower foveal pit compared to controls and incursion of the inner retinal layers. This suggests that the centrifugal displacement of the inner retinal layers is not complete in some patients with achromatopsia.

In summary, we outline a structural grading system for foveal hypoplasia that relates to developmental stages, visual prognosis and which can be applied to most disorders associated with foveal hypoplasia. We also investigated atypical forms of foveal hypoplasia seen with achromatopsia which are associated with worse visual prognosis due to photoreceptor degeneration. This grading is especially suitable for clinical use as it qualitative and fast, does not need measurements or specialized analytical sofware and can hence be used just by visualizing the OCT.

Acknowledgments

Financial Support: The study was supported by the National Eye Research Centre (Grant no: RM61G0124 and RM61G0216) and Ulverscroft foundation

Footnotes

Conflict of Interest: No authors have any financial/conflicting interests to disclose

References

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