Melanoma associated retinopathy: A new dimension using adaptive optics.

We report a 56-year-old male patient, complaining of metamorphopsia in his left eye nevertheless visual acuity, slit lamp, and fundus examinations were within normal limits. Microperimetry (MAIA, Centervue, Italy) revealed central field loss and spectral domain optical coherence tomography (Spectralis, Heidelberg, Germany) showed disrupted cone outer segment tip layer. The patient had a diagnosis of cutaneous melanoma in his foot for which an excision biopsy with lymph node dissection was performed 5 months earlier. Our clinical diagnosis was melanoma-associated retinopathy. Electrophysiology confirmed the diagnosis. Adaptive optics retinal imaging (Imagine eyes, Orsay) was performed to assess the cone mosaic integrity across the central retina. This is the first report on the investigation of autoimmune retinopathy using adaptive optics ophthalmoscopy. This case highlights the viability of innovative diagnostic modalities that aid early detection and subsequent management of vision threatening retinal.

Introduction

Autoimmune retinopathy is a spectrum of immune-mediated degenerations of the retina that occurs in patients, including cancer-associated retinopathy, melanoma-associated retinopathy (MAR) and presumed nonparaneoplastic autoimmune retinopathy.

Most commonly, these patients present with night blindness, photopsia and painless, progressive vision loss. Clinically, ocular findings are often unremarkable; nevertheless they include optic nerve pallor, retinal pigment epithelial alterations across the macular area and vascular attenuation.[1] In the absence of clinical findings, high-resolution imaging tools might be of great value to detect pathological alterations of ocular microstructures, even in patients with a history of systemic neoplasm.

We discuss a case of a patient with history of cutaneous melanoma in the foot where combined imaging and functional tools aided in assessment of early pathological retinal alterations.

Case Report

A 56-year-old man complained of metamorphopsia in his left eye since 1 month. On examination, his best-corrected visual acuity was 20/20 and N6 in both eyes. The anterior segment was normal. Intraocular pressure was 10 and 12 mmHg using applanation tonometry in the right and left eye respectively. The pupils were quickly reacting to light without any relative afferent pupillary defect. Fundus examination was normal as shown in Figure 1.

Figure 1

Fundus montage of the right (a) and (b) left eye showing normal fundus with normal spectral domain optical coherence tomography and the decreased cone count using adaptive optics at 1.5° eccentricity in all four quadrants

He subsequently underwent a few investigations including a 30-2 Humphreys perimetry (Humphrey Field Analyzer; Carl Zeiss Meditec, Dublin, CA), spectral domain optical coherence tomography (SD-OCT; Spectralis, Heidelberg, Germany) and microperimetry (MAIA, Centervue, Italy).

The 30-2 field of vision showed a central scotoma in both eyes, larger in the left eye than right eye. The SD-OCT of the macula was normal. Foveal contour and central foveal thickness were 204 microns in both eyes as shown in Figure 1.

The microperimetry showed abnormal macular integrity index, 100, in both eyes (normal values = 0-40, suspect = 40-60, abnormal = 60-100). Average threshold was 22.1 decibels (dB) and 0 dB in the right and left eye respectively (normal = 36-25 dB, suspect = 25-24 dB and abnormal <24 dB). Fixation was stable in the right eye and relatively unstable in the left eye as shown in Figure 2.

Figure 2

Sensitivity map of the right (a) and left eye (b) showing unstable fixation and decreased sensitivity in the left eye only

Detailed systemic history elicited that the patient had a diagnosis of cutaneous melanoma of the foot 5 months earlier for which he had undergone a wide excision of the lesion with block dissection of the ilio-inguinal lymph nodes. The histopathology report clarified it was a histiocytoid variant with tumor-free margins. Positron emission tomography showed metastasis to right iliac, inguinal and popliteal lymph nodes. The patient was free from pulmonary or distant metastasis.

With a provisional diagnosis of MAR, the patient underwent full field and multifocal electroretinogram (Full-field electroretinography [ff ERG] and multifocal electroretinography [mf ERG]; Visual Evoked Response Imaging System Science™ 5) for confirmation. The ff ERG showed a central cone photoreceptor dysfunction in the right eye and a reduced scotopic response, with a negative ERG in the combined maximal response in the left eye as shown in Figure 3. The mf ERG showed reduced responses across the central 0-15° in both eyes.

Figure 3

Full-field electroretinography (ff ERG) of the right eye (a) shows normal response in scotopic ERG and subnormal response in photopic ERG; (b) ff ERG Left shows an unrecordable b wave in the dark-adapted 0.01 ERG and a negative ‘b’ wave in dark-adapted 3.0 ERG; the photopic response is also subnormal

Adaptive optics retinal imaging was done using the rt × 1 instrument (Imagine Eyes, France) and its automated software was used to assess the cone density and their spacing across the central retina as seen in Figure 1. The central 4° × 4° of the retina were evaluated. His axial length was 24 mm in both eyes. A mean (±standard deviation [SD]) density of 12.923 ± 4218 cones/mm2 at 1.5° temporal and 18.485 ± 5825 cones/mm2 at 1.5° nasal from the foveal fixation was detected in the right and left eye respectively (mean cone density of emmetropes with no ocular pathology at 1.5° from the fovea is 31.707 ± 7149 cones/mm2 as calculated on 25 age-matched healthy subjects). The mean cone spacing (±SD) was of 9.61 ± 1.75 μm and 8.16 ± 1.52 μm in the right eye and left eye respectively (cone spacing of emmetropes, as seen in 25 age-matched healthy subjects was an average of 6.21 ± 0.85 μm at 1.5° from the fovea.

The patient was then sent to his primary oncologist for metastatic work up. All the reports were negative. He was then started on a tapering oral prednisolone 1 mg/kg body weight by the immunologist. At 3 months followup, he remains clinically stable.

Discussion

The diagnosis of MAR is always a clinical dilemma since most of the patients have very subtle clinical findings. Hence, the use of highly accurate investigative modalities plays a main role in the management of these patients. Identification of antiretinal antibodies might not be often feasible because of the costs and the reagents availability in the laboratory in developing countries. There is no definitive treatment of MAR.[1] Audemard et al. discuss a rare case of melanoma and MAR treated with ipilimumab, taking into account the fact that it can be effective on tumor burden, but can also increase autoimmunity.[2]

Pepple et al. have evaluated the use of SD-OCT and auto fluorescence in patients with autoimmune retinopathy and reported the presence of a hyperautofluorescence ring that corresponded with disruptive changes seen in outer retinal layers on SD-OCT.[3] ERGI changes were inconclusive of the diagnosis too. In our patient the structural damage was not severe enough to be picked up on SD OCT, but was easily detected on the adaptive optics camera where the cone density was reduced. Furthermore, functional changes were appreciated on Humphrey fields and microperimetry.

With the advent of new technology such as adaptive optics, we can image as near-histology as possible with the high resolution scans, allowing us to quantify the extent of cone degeneration. Thus far, adaptive optics has been used to study eyes with early retinal degenerations and dystrophies and were proving to be a good tool to study early onset of subtle pathology.[45]

This new imaging modality may be useful in establishing the diagnosis of this rare disease, monitoring disease progression and evaluating response to therapy. This may help in monitoring the patient's response to immunotherapy by quantifying the cone density and hence revolutionize the way these patients are managed in the future.