Optical Coherence Tomography Angiography and Macular Vessel Density Analysis of Cystoid Macular Edema in Gyrate Atrophy

Introduction

Gyrate atrophy of the choroid is a rare, autosomal recessive, chorioretinal degeneration characterized by a deficiency of the enzyme ornithine-delta-aminotransferase (OAT), which results in a 10- to 20-fold increase in plasma ornithine concentrations.¹ Hyperornithinemia is the primary biochemical manifestation of OAT deficiency, with a 10- to 20-fold higher systemic level of ornithine in plasma, urine, spinal fluid, and aqueous humor. The complementary DNA and genomic locus for OAT is assigned to chromosome 10.² The vision loss in patients with gyrate atrophy is either due to progressive atrophy of the choroid and retinal pigment epithelium (RPE) cells or due to development of myopia, posterior subcapsular cataract, and cystoid macular edema (CME), either alone or in combination.³ The pathophysiologic mechanism in development of this progressive retinal degeneration is unknown.⁴ Fundus fluorescein angiography (FFA) does not show classical leakage pattern in macular area and hence does not add much to understanding of the pathophysiology.⁵ We investigated the role of optical coherence tomography (OCT), OCT angiography (OCTA), and en face OCT of the RPE and photoreceptor layer to see whether these modalities could shed further insight into pathogenesis of gyrate atrophy and associated CME.

Patients and Methods

We included four consecutive patients (eight eyes) between July 2015 and September 2017. The informed consent was taken from all the subjects as per the institutional practice. A complete and comprehensive ophthalmologic examination including fundus autofluorescence (FA), spectral-domain OCT, en face OCT, and OCTA was performed.

The OCTA was performed using a DRI-OCT Triton swept-source OCT (Topcon, Tokyo, Japan). For each eye, a 3 mm × 3 mm scan centered on the fovea was acquired. The superficial capillary plexus (SCP) en face image was segmented with an inner boundary at 3 μm beneath the internal limiting membrane and an outer boundary set at 15 μm beneath the inner plexiform layer (IPL), whereas the deep capillary plexus (DCP) en face image was segmented with an inner boundary 15 μm beneath the IPL and an outer boundary at 70 μm beneath the IPL. The instrument automatically generated vascular density of the SCP and DCP in the foveal and parafoveal areas. Vessel density was calculated as the proportion of the measured area occupied by blood vessels with flow, defined as pixels having decorrelation values above the threshold level. The fovea was defined as the area within the central 1-mm ring of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, and the parafovea was considered as the area between the central 1- and the 3-mm ring of the ETDRS grid.⁶ Two experienced investigators (SN, AK) independently graded the FAZ area in the SCP and DCP. The graders manually outlined the inner border of foveal capillaries in the FAZ using the color vessel density map analysis. The total number of pixels in the FAZ area was converted to square millimeters for analysis.

Results

The mean age of all four female patients was 20 years (range: 13 years to 32 years). All patients had high myopia; the mean refractive error was −6.5 diopters (D) (range: −1 D to −11 D). The mean follow-up period was 24.25 months (range: 12 months to 40 months). The demographic details are seen in Table 1.

Table 1: Demographic Details and OCT Parameters

OCT in all eight eyes showed CME involving the outer retinal layers (ORLs), with macular schisis present in both the inner retinal layer (IRL) and ORL in the parafoveal region in six eyes (75%). There was disruption of inner segment-outer segment junction with distorted or absent ellipsoid zone (EZ) in six eyes (75%). The average central macular thickness was 509 μm (range: 291 μm to 752 μm). In all eight eyes, OCTA demonstrated enlarged FAZ area with petaloid hyporeflective cyst-like areas in the DCP in six eyes (75%).

Table 2 shows macular capillary density in the SCP and DCP in 1-mm foveal and 3-mm parafoveal areas, along with measurement of the FAZ area in SCP and DCP. All eyes were compared with normal values reported by Coscas et al.⁷

Table 2: OCTA Analysis of FAZ Area and Macular Vessel Density

The mean (standard deviation [SD]) FAZ area in patients with gyrate atrophy in the DCP layer was enlarged as compared to the SCP layer (P = .04). When comparing with normal subjects, the mean FAZ area in both the SCP and DCP layers was enlarged and was statistically significant (SCP: P = .01; DCP: P = .001). The mean (±2 SD) macular vessel density percentage was decreased; this was statistically significant when compared with normal subjects in both the foveal SCP and DCP layers (P = .001 and P = .002, respectively) and parafoveal SCP and DCP layers (P = .001 and P = .001, respectively).

Representative images of one patient (Case No. 3) are shown in Figure 1.

Figure 1. A 17-year-old girl with gyrate atrophy of the retina (Case No. 3). (a) Color fundus photograph (montage) of the left eye showing classical scalloped areas of chorioretinal degeneration advancing from the periphery toward the posterior pole. (b) Fundus autofluorescence image showing area of decreased autofluorescence corresponding to areas of chorioretinal degeneration. (c) A spectral-domain optical coherence tomography (OCT) vertical line scan (12 mm) passing through the fovea showing cystoid macular edema (CME) involving both the inner and outer retinal layers (ORLs), with macular schisis in the ORLs. Disruption of the ellipsoid zone was noted in the subfoveal area, with areas of retinal and choroidal atrophy seen in the periphery. (d, e, f) OCT angiography scan (3 mm × 3 mm) of the macular area depicting the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris layer. In both the SCP (d) and DCP (e), the foveal avascular zone (FAZ) was enlarged, and a parafoveal honeycomb pattern-like hyporeflective cyst and surrounding microvascular abnormalities were present in the deep capillary layer (e). The choriocapillaris layer (f) showed few hyporeflective areas, most likely caused by artifacts from larger retinal vessels. The color-coded macular vessel density map (g) in the DCP showed the percentage of vessel density in the central 1-mm fovea and surrounding 3-mm parafoveal area, which after centration was calculated automatically by inbuilt software. (h) En face OCT image in the SCP showed parafoveal structural changes with enlarged FAZ, whereas (i) in the DCP, OCT showed numerous petalloid like configuration of hyporeflective cysts corresponding to CME and macular schisis. (j) Corresponding B-scan OCT image with the segmentation boundaries (two red lines) extending from inner plexiform to outer plexiform layer depicting the DCP layer.

Discussion

OCTA provided additional information over the clinical and fluorescein angiographic features in gyrate atrophy. In this disease, the symptoms such as night blindness associated with high myopia start in early childhood. Clinically, sharply demarcated, scalloped areas of chorioretinal degeneration start at the periphery and advance toward the posterior pole. With time, these lesions coalesce and enlarge, involving the entire fundus. The vision loss is progressive with advancing age and leads to gross constriction of peripheral fields. In late stages of disease, patients develop cataracts and macular complications such as cystoid macular edema,^3,5 macular schisis, or rarely epiretinal membrane;⁸ these developments decrease the central visual acuity and the quality of life.

The deficiency of the enzyme, OAT, is known in gyrate atrophy. OAT is expressed in most tissues, including kidney, small intestine, liver, and retina. Even though high activity of OAT is known in RPE,⁹ its role in the metabolic function of the RPE is poorly understood. A direct ornithine toxicity to the RPE cells that leads to photoreceptor degeneration and ultimate choriocapillaries atrophy is postulated.¹⁰ In our series, six of eight eyes had gross CME with schistic changes involving both IRLs and ORLs. The causes could be possible photoreceptor damage as a result of direct ornithine toxicity, damage from toxic debris resulting from degenerating RPE cells, failure of the RPE cells to provide their normal nutritive functions, reduced nutrition as the result of choriocapillaries atrophy,¹¹ and failure to maintain the protected microenvironment required for optimal photoreceptor function secondary to the breakdown of the blood-retina barrier. Because of close association between RPE, choriocapillaries and retinal capillaries, it is still not clear whether retinal capillary bed is primarily affected due to disease per se or is secondary to photoreceptor and RPE degeneration.

A marked reduction in macular vessel density is seen in most of the inherited retinal dystrophies like retinitis pigmentosa (RP),¹² Stargardt disease,¹³ Best disease,¹⁴ choroideremia,¹⁵ and X-linked juvenile retinoschisis (XLJR),¹⁶ thereby helping to understand the pathogenesis of these diseases. As per these reports, the FAZ in the DCP is significantly enlarged in RP, Best disease, and XLJR, whereas it remains unchanged in choroideremia. Macular microvasculature changes are significantly reduced in both the SCP and DCP in RP and Stargardt disease, whereas in choroideremia and XLJR, there is reduction in vascular density in only DCP.

Meyer et al.¹⁷ have described OCT features in gyrate atrophy as areas of chorioretinal atrophy correlating with a loss of reflectivity in the RPE-choriocapillaries complex and thinning of the nerve fiber layer. In our series, OCT and en face OCTA showed loss of integrity of the photoreceptor layers as well as a distorted or absent EZ (six of eight eyes). In the DCP, there was loss of capillary bed in the foveal and parafoveal areas, with presence of classical perifoveal hyporeflective cysts extending from the IPL to the outer plexiform layer. These findings are in accordance with the postulated hypothesis of RPE degeneration along with loss of photoreceptors as the earliest changes in pathogenesis of gyrate atrophy and other inherited retinal dystrophies. The presence of perifoveal cysts in the DCP also explains the pathogenesis for the formation of macular schisis and associated macular edema.

In our series, all of the patients were ordered arginine-restricted diet along with vitamin B-6 supplementation for 6 months. The rationale was to increase the activity of residual OAT enzyme to decrease the accumulation of ornithine in the plasma and subsequently in the RPE.^18,19 There is only one report with positive results.²⁰ However, we did not notice either an improvement in vision or reduction of macular edema in any of these patients in 12 months' time. Sandos et al.²¹ have reported transient resolution of macular edema with intravitreal triamcinolone acetonide injection; we did not observe similar effect in our patient (Case No. 3).

The limitations of our study include low number of patients, no normative database for OCTA in healthy individuals, and shorter duration of treatment and follow-up. The strength of the study was using multimodal imaging to quantify the macular vessel density in patients of gyrate atrophy with CME.

In conclusion, multimodal imaging like OCT, OCTA, and en face OCT helped us in better understanding the pathogenesis of gyrate atrophy of the choroid. These imaging procedures also provided further insights into etiology of macular edema and macular schisis in this series of patients.