Structural Grading of Foveal Hypoplasia Using Spectral-Domain ...

Figure 1. Chart showing the 3 developmental processes involved in
formation 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.
Statistical Methods
Normality of the VA and intraretinal thickness measurements data
were tested using the Shapiro-Wilk test. Nonparametric tests
(Kruskal-Wallis) were used (because of nonnormality) to test the
difference in (1) logMAR VA between the different grades of
foveal hypoplasia, (2) retinal thickness, (3) ONL thickness, and (4)
foveal depth at the fovea between controls and patients with
typical and atypical forms of foveal hypoplasia. Multiple comparisons
were performed with Bonferroni correction. The Mann–
Whitney U test was used to test the differences in VA between
typical and atypical forms of foveal hypoplasia.
Results
Gross Morphologic Features Associated with
Foveal Hypoplasia
Examples of the gross features of foveal hypoplasia detectable on
ultra high-resolution spectral-domain 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
To derive a structural grading system for foveal hypoplasia, the
foveal region was subdivided according to foveal development
into the structural elements that represent the unique features of the
fovea detectable using OCT (see Fig 3A). Progressive loss of the
foveal elements is represented as increasing grades.
Incursion of the plexiform layers was present in all types of
foveal hypoplasia because it was the criteria used to diagnose
foveal hypoplasia. Subsequently, the grading system gives most
importance to the integrity of the outer segment (OS; i.e., whether
this region disrupted to rule out atypical forms of foveal hypopla-
Thomas et al Structural Grading of Foveal Hypoplasia
sia). Then, importance is given to the development of this region
(detected on OCT by the lengthening of the OS; this feature is
present in grades 1 and 2 but not in grades 3 and 4). Subsequently,
the features of foveal development anterior to the inner segment
(IS) and OS were assessed. Widening of the ONL differentiated
between grades 3 and 4, and foveal pit formation differentiated
between grades 1 and 2. The features of each grade are illustrated
in Figure 3B. An algorithm was devised to grade foveal hypoplasia
structurally (Fig 4).
Whether the grade of foveal hypoplasia significantly predicted
the BCVA was assessed. There was a significant difference in
BCVA between the grades of foveal hypoplasia (P0.0001; see
Fig 5). Grade 1 foveal hypoplasia was associated with the best VA
(median BCVA, 0.2 logMAR), whereas grades 2, 3, and 4 were
associated with progressively poorer VA with a median BCVA of
0.44, 0.60, and 0.78 logMAR, respectively (Fig 5B). The results of
the multiple comparisons of VA between the grades are shown in
Figure 5B. A significant effect of gender, age, or ethnicity on the
grade of foveal hypoplasia was not found.
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, whereas 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, 0.30), followed by patients with
PAX6 mutations (median BCVA, 0.4 logMAR; interquartile range,
0.35), and then isolated cases (median BCVA, 0.2 logMAR; standard
deviation, 0.30). However, if the grade of foveal hypoplasia
was considered, there was no significant difference in BCVA
between the 3 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 IS/OS junction; however, it also can be associated
with a shallower pit and incursion of the plexiform layers posterior
to the foveola. This results in an atypical foveal hypoplasia because
it is associated with photoreceptor degeneration. The other
atypical features associated with achromatopsia that do not follow
the pattern seen with the typical forms of foveal hypoplasia include:
a significantly decreased retinal thickness in comparison
with both controls (P0.0001) and the patients with typical foveal
hypoplasia (P0.0001; grades 1 through 4; Fig 5D). Similarly,
there is a significantly thinner outer nuclear layer in comparison
with both controls (P0.0001) and patients with typical foveal
hypoplasia (P0.0001; Fig 5E). Although achromatopsia is associated
with significantly shallower pit in comparison with the
controls (P0.0001), the foveal pit in achromatopsia is significantly
deeper in comparison with the patients with grade 1 foveal
hypoplasia (P 0.005; only grade 1 foveal hypoplasia was used
for this comparison because only these patients have a rudimentary
foveal pit; see Fig 5F).
Discussion
This study proposed a structural grading system for foveal
hypoplasia based on loss of unique elements that form the
normal fovea that likely have been arrested during early
development. The proposed grading system has 3 advantages:
(1) it gives insight into the degree of development of
the fovea, (2) it provides a prognostic indicator from a
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