Reassessment of hyperautofluorescent rings in retinitis pigmentosa using novel retinal imaging techniques

1. Case report

Two unrelated patients, a male in his early thirties (case 1) and a female in her mid-sixties (case 2), both with autosomal dominant retinitis pigmentosa (ADRP) and bilateral Robson-Holder Rings (RHRs) were enrolled. Visual acuity was 20/25 bilaterally in each case. Genetic testing was conducted through the Invitae Inherited Retinal Disease panel in a CLIA-certified lab using next-generation sequencing technology (Invitae Corp., San Francisco, CA). In case 1 genetic testing was inconclusive. In case 2 a pathogenic variant in SAG gene (c.178_181del) associated with ADRP was identified.¹ Comprehensive ophthalmologic examination and multimodal imaging included fundus autofluorescence (FAF), macular pigment optical density (MPOD), Spectral-domain optical coherence tomography (SD-OCT), and High-resolution OCT (High-Res OCT). Both FAF and MPOD were performed using the Spectralis HRA + OCT2 (Heidelberg Engineering, Heidelberg, Germany). Both SD-OCT and High-Res OCT showed no apparent retinal pigment epithelium (RPE) attenuation beneath or immediately adjacent to the RHRs. The hyperreflective bands representing the photoreceptor ellipsoid and interdigitation zones were intact centrally, thinned as they approached the RHR, and became undetectable at its inner border. The hyporeflective photoreceptor inner segment myoids thinned as they approached the RHR outer border where they were no longer visible. The hyporeflective band representing the outer nuclear layer (ONL) and Henle's fiber layer (HFL) showed progressive thinning as it approached the RHR with some preservation extending beyond its outer border. MPOD analysis registered with FAF demonstrated a correspondence between the loss of MPOD and increasing FAF within the region of the RHR (Fig. 1, Fig. 2).

Fig. 1.

High-Resolution optical coherence optical coherence tomography (High-Res OCT) and macular pigment density analysis (MPOD) in the Robson-Holder ring (RHR) area. (A) High-Res OCT B-scan spanning the foveal center in an eye with autosomal dominant retinitis pigmentosa (case 2). Inset from cross-sectional scan registered with FAF highlights the inner and outer limits of the RHR (stippled yellow dots). The internal edge of the ring (red curved line in mosaic B) corresponds with the collapse of the photoreceptors' ellipsoid and interdigitation zones. Inside the RHR, the outer nuclear layer/Henle's fiber layer band is attenuated, the photoreceptors outer segments are absent, and the inner segment myoid band is progressively reduced. The outer edge of the ring (purple curved line in mosaic B) corresponds with the collapse of the external limiting membrane. (B) Fundus autofluorescence (FAF) registered with High-Res OCT demonstrates a perifoveal ring of increased FAF (Robson-Holder ring, RHR). The green arrow indicates the location and orientation of the High-Res OCT B-scan in (A). The triangular shaped structure indicates the correspondence with macular pigment density analysis and the curved lines the inner (red) and outer (purple) limit of the RHR. (C). Macular pigment optical density (MPOD) graphical analysis (left, y-axis representing optical density values and the x-axis the distance (radius) from the foveal center). The left half of the image shows MPOD distribution in a normative dataset (the black stripe represents the mean value and the grey zones the standard deviation).⁹ The right half shows MPOD values obtained from case 1 registered with FAF image of the fundus (mosaic C). Foveal center (radius 0-1°) corresponds to increased optical density values followed by a steep decrease. The region between the red and violet lines (Robson-Holder ring) corresponds to very reduced values of MPOD values compared to the corresponding area in the normative dataset profile.⁹ Outside the green line, MPOD values are negligible.

ELM: external limiting membrane; ISm: Inner segment myoid; EZ: ellipsoid zone; IZ: interdigitation zone; RPE: retinal pigment epithelium. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

Macula pigment optical density (MPOD) in the Robson-Holder Ring (RHR) area. (A) Spectral-domain optical coherence optical coherence tomography (SD-OCT) B-scan spanning the foveal center in an eye with autosomal dominant retinitis pigmentosa (case 1). Inset from cross-sectional scan registered with FAF highlights the area of RHR (stippled yellow dots). (B) Fundus autofluorescence (FAF) registered with SD-OCT acquisition highlights the position of the B-scan (green arrow) and an area of the hyperfluorescence ring with a triangular-shaped structure registered with MPOD analysis. (C) MPOD graphical analysis (left, y-axis representing MPOD values and the x-axis the distance (radius) from the foveal center) shows a first optical density peak corresponding to the fovea, followed by a steep decrease that is most noticeable within the RHR area (between red and violet lines). MPOD values inside the RHR are similar to those from the corresponding area in a normative dataset.⁹ Outside the green circle, MPOD values are negligible.

ELM: external limiting membrane; ISm: Inner segment myoid; EZ: ellipsoid zone; IZ: interdigitation zone; RPE: retinal pigment epithelium. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

2. Discussion

A RHR is seen in >50% of eyes with retinitis pigmentosa as increased perifoveal FAF surrounding centrally preserved retinal structure and function.² SD-OCT of the RHR shows decreased outer retinal thickness with ellipsoid and interdigitation zone disruption. Prior descriptions have attributed RHR FAF to elevated RPE lipofuscin and changes in photoreceptor pigment³; however, reduced macular pigment overlying the RPE enhances its intrinsic FAF through an unmasking effect.⁴ To the best of our knowledge, the distribution of macular pigment has not previously been linked to the pattern of RHR FAF. MPOD can be quantified using 2 wavelengths (blue and green) FAF. Macular pigment (lutein, zeaxanthin and meso-zeaxanthin) absorbs blue light more than green light and the difference in FAF values measured with each of the 2 wavelengths at a specific location is proportional to the density of macular pigment masking the underlying RPE FAF in that region.⁵ In normal subjects, MPOD follows a monotonic decline from the center to the periphery that is believed to be created by macular pigment-containing structures in Henle's Fiber layer and photoreceptors' outer segment membranes.^6,7 We used HighRes-OCT and MPOD maps to demonstrate how the altered outer retinal structure associated with reduced MPOD might contribute to increased FAF within the RHR by unmasking underlying RPE FAF.² Loss of luteal pigment within an attenuated Henle Fiber layer and reduced macular pigment in disrupted photoreceptor outer segments would account for the reduction in MPOD within the RHR. Further photoreceptor loss during disease progression can help explain the constriction of the RHR seen in follow-up studies.⁸ The MPOD density profiles herein reported in the RHR area show values inferior to normal subjects in one of the two cases.⁹

Reduced macular pigment at greater eccentricities from the foveal center is likely just one of several mechanisms accounting for the hyperautofluorescent rings. We agree with prior authors who suggested that the relative hypoautofluorescence at the outer edge of the hyperautofluorescence ring may be related to the absence of photoreceptor outer segments as indicated on OCT by the loss of a visible ellipsoid zone and interdigitation zone in this region. RPE lipofuscin originates from the daily phagocytosis of shed photoreceptor outer segments, and photoreceptor outer segments are required for a normal continuous increase in RPE FAF intensity due to aging.¹⁰ Presumably, in this more eccentric region of higher rod density and greater disease-related photoreceptor depletion, there would be reduced RPE FAF. Our methods could not assess the relative contribution of altered RPE FAF within the RHR. We also acknowledge that increased perifoveal FAF can be found in other disorders including acute zonal occult outer retinopathy, autoimmune retinopathy, central serous chorioretinopathy and syphilitic outer retinopathy in which unmasking of RPE FAF is more likely related to reduced photopigment density than to MPOD and is due to photoreceptor outer segment damage and/or dysfunction.^{4 2}

3. Conclusion

Reassessment of the RHR using High-Res OCT and MPOD analysis shows altered outer retinal structure and reduced pigment density within the RHR area. Unmasking the underlying RPE autofluorescence within the RHR area might be one of the mechanisms accounting for the observed hyperautofluorescence.

Patient consent

Consent to publish this case report has been obtained from the patient in writing.

Funding

This work was supported by The Macula Foundation, Inc., New York, NY, USA. Diogo Cabral was supported in part by a studentship from Fundação Luso-Americana para o Desenvolvimento (FLAD, USA R&D@PhD – Proj 2020/0140). Prithvi Ramtohul is supported by The Philippe Foundation.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.