Outcomes Associated With Sustained-Release Intraocular Fluocinolone Implants in a Case of Melanoma-Associated Retinopathy Treated Without Systemic Immunosuppression

Key Points

Question

What is the outcome of a fluocinolone implant on melanoma-associated retinopathy without systemic immunosuppression?

Findings

In 1 patient with melanoma-associated retinopathy, marked improvement in symptoms and retinal function as measured by automated perimetry and electroretinography were noted after treatment with an intravitreal fluocinolone acetonide implant.

Meaning

While results from 1 case should be generalized with caution, this outcome suggests that sustained-release steroid intraocular implants may offer an alternative to systemic immunosuppression in the treatment of melanoma-associated retinopathy, although the precise safety and effectiveness over time cannot be determined from a single case.

This case study discusses a patient who experienced relief from melanoma-associated retinopathy through the use of intravitreal long-acting steroid implants.

Abstract

Importance

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome in which antiretinal antibodies crossreact with retinal ON-bipolar cells, resulting in night blindness and progressive visual field loss. Current therapeutic options include cytoreductive surgery in combination with immunoglobulin, corticosteroids, or plasmapheresis, but their effectiveness is limited and may be contraindicated, given the possible protective role of circulating autoantibodies against metastatic spread. We report 3-year follow-up of the first case (to our knowledge) of MAR treated with intravitreal long-acting steroid implants.

Objective

To report on a patient with MAR who was treated with intravitreal fluocinolone acetonide implants in the absence of systemic immunosuppression.

Design, Setting, and Participants

This is a 3-year follow-up of a 73-year-old woman with a history of surgical excision of a malignant melanoma of the left pinna who presented with visual symptoms of shimmering and nyctalopia. Fundus examination, fundus autofluorescence, and optical coherence tomography were normal, with no evidence of cystoid macular edema. Automated perimetry showed a reduction in visual field and full-field electroretinography (ERG) demonstrated findings consistent with generalized ON-bipolar cell dysfunction, typical of MAR. The patient was treated with bilateral fluocinolone acetonide intravitreal implants.

Main Outcomes and Measures

Visual acuity, visual field, and electroretinography testing for 3 years after treatment.

Results

Visual fields improved in this 73-year-old patient from 20/30 (Snellen measured as 6/9) OD and 20/16 (6/5) OS at baseline to 20/20 OU within 1 week of treatment. Detailed electroretinography monitoring indicated characteristic abnormalities that partly resolved after treatment, consistent with improved inner retinal ON-bipolar cell function. Bilateral cataracts developed approximately 2 years after injection; cataract surgery was performed uneventfully. At 3 years posttreatment, the patient remained visually stable and in systemic disease remission, with best-corrected visual acuity remaining at 20/20 OU.

Conclusions and Relevance

We report what is, to our knowledge, the first case of MAR treated with intravitreal slow-release corticosteroid implants, which shows improvements in visual symptoms, visual fields, and retinal function. Sustained-release intraocular steroid implants may offer an effective and safe alternative to systemic immunosuppression in MAR, although results from 1 case should be generalized with abundant caution.

Introduction

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic syndrome that occurs in patients with cutaneous melanoma. It is considered to be an autoimmune phenomenon in which antiretinal antibodies react with bipolar cells in the outer plexiform layer of the retina, resulting in tissue damage.¹ Patients with MAR typically experience persistent photopsia or shimmering together with night blindness and progressive loss of visual field.² There are characteristic changes in full-field electroretinography (ERG) consistent with generalized dysfunction of the retinal ON-bipolar cell system.

Cutaneous melanoma may be treated by cytoreduction, chemotherapy, and/or radiotherapy, but the treatment of MAR is controversial, with relatively few reports existing in the literature of successful therapeutic intervention. Treatment modalities have included systemic corticosteroids, plasmapheresis and intravenous immunoglobulin (IVIG), all with variable results^2,3,4; 1 case series of patients treated with IVIG, corticosteroids, or plasmapheresis showed that short-term symptom improvement improved in only 40% of patients.² Here, we report 3 years of follow-up data from what we believe to be the first patient with MAR to have been treated with intravitreal slow-release (0.25 μg/d) fluocinolone acetonide implants (Iluvien), who was monitored using visual field testing and detailed retinal electrophysiology.⁵

Case Report

A 73-year-old patient was referred with a 1-month history of photopsia and nyctalopia. She had a history of malignant melanoma of the left pinna with lymph node involvement, for which she had undergone initial surgical excision and chemotherapy followed by radiotherapy and further chemotherapy for pulmonary metastases 2 years prior to her current presentation. She reported no history of ocular problems nor any family history suggestive of heritable retinal disease.

On examination, her visual acuities were approximately 20/30 (Snellen; measured as 6/9) OD and 20/16 (6/5) OS. Slit lamp biomicroscopy was normal, as were spectral-domain optical coherence tomography of the macula, fundus autofluorescence, and fluorescein angiography. Specifically, there was no evidence of cystoid macular edema or vascular leakage. However, automated perimetry showed field defects in both eyes (eFigure 1 in the Supplement).

Pattern ERG and full-field ERG were performed to incorporate the standards of the International Society for Clinical Electrophysiology of Vision,^6,7 and extended protocols for photopic on-off ERG^6,7,8 and additional short-wavelength flash (S-cone) ERG. The dark-adapted (DA) dim flash (DA 0.01 cd • s/m²) ERG was undetectable, in keeping with a severe loss of rod system function. The strong flash (DA 10.0 cd • s/m²) ERG a-wave was normal, but the waveform was electronegative (ie, with a b:a ratio <1), indicating severe dysfunction occurring after rod phototransduction (eFigure 2 in the Supplement). The light-adapted (LA) flicker (LA 3.0 cd • s/m²; 30 Hz) ERG was of normal timing and borderline amplitude for age and the single-flash cone (LA 3.0 cd • s/m²) ERG had an abnormally broadened bifid trough and a reduced b-wave with a sharply rising peak that had a lack of oscillatory potentials. The on-off ERG revealed an electronegative on response and preserved off response, and there was a reduced S-cone ERG (eFigure 2 in the Supplement). The pattern ERG P50 was reduced in both eyes, in keeping with macular dysfunction. In summary, the ERG findings were consistent with bilateral generalized retinal ON-bipolar cell dysfunction of rod and cone systems.

A diagnosis of MAR was made on the basis of the clinical picture and ERG findings. Within 6 months of presentation, the patient's visual acuities had declined to 20/80 OD and 20/40 OS, and her night blindness had worsened. Clinical examination remained unchanged. Treatment options were discussed, including standard systemic therapy in the form of oral corticosteroids, IVIG, or plasmapheresis or local immunosuppression in the form of intraocular corticosteroid implants. The patient chose local therapy to avoid systemic treatment and thus minimize any risk of melanoma reactivation; a fluocinolone acetonide implant was placed in the right eye, followed by one in the left eye 4 months later.

Within 1 week of treatment to each eye, the patient’s visual acuity improved to 20/20 OU, and her visual symptoms resolved with concurrent improvement in visual fields (eFigure 1 in the Supplement). A repeated ERG 1 year after treatment of the right eye revealed partial recovery of the DA 0.01 ERG and DA 10 ERG b:a ratio (eFigure 2 in the Supplement). The LA ERGs, including on-off ERGs and S-cone ERGs, also improved in amplitude and waveform shape, suggesting significant recovery of ON-bipolar pathway function. However, the pattern ERG P50 remained subnormal in keeping with persistent mild macular dysfunction on the right. The recordings of the left eye, obtained 8 months after treatment of that eye, failed to show improvement, but improvement was seen in the ERG obtained 2 years after treatment.

Bilateral cataracts developed approximately 2 years after injection; cataract surgery was performed uneventfully. Neither eye developed elevated intraocular pressure at any stage. Full-field ERGs at further follow-up were stable on the right side and showed continuing improvement on the left side (eFigure 2 in the Supplement). The pattern ERG P50 components also improved bilaterally compared with baseline, indicating that macular function and automated perimetry showed improvement over time.

At the patient’s most recent examination, 3 years after treatment initiation, her best-corrected visual acuities remain 20/20 OU. She is clinically stable and in systemic remission.

Discussion

This report describes a case of MAR with improvement in visual symptoms, perimetry, and retinal function after intravitreal slow-release corticosteroid implants. The sustained improvement observed in this difficult-to-treat condition is encouraging and suggests potential advantages over systemic therapies such as IVIG or systemic corticosteroids.

Melanoma-associated retinopathy is an uncommon autoimmune condition, and its rarity has restricted the emergence of controlled, prospective studies to evaluate different treatment methods. Therapy is often based on systemic immunosuppression, yet treatment with IVIG (either alone or in combination with cytoreductive surgery, plasmapheresis, or corticosteroids) has been reported to be relatively ineffective and is hampered by a lack of evidence for any particular dosage regimen.^2,9 There may also be a protective role of autoimmunity (including antiretinal antibodies) in countering metastatic spread,¹⁰ rendering systemic immunosuppression relatively contraindicated. This would limit treatment to IVIG as the only nonimmunosuppressive immunomodulatory agent available.

Local intraocular immunosuppression provides an alternative therapeutic approach and the fluocinolone acetonide implant has been shown to be effective against non-infectious intermediate, posterior uveitis or panuveitis.¹¹ Here, we report notable improvements in the classic symptoms of MAR in association with significant improvement in retinal function as measured by ERG and perimetry and in the absence of cystoid macular edema. Cataracts developed bilaterally and were treated surgically without complication; intraocular pressures remained normal throughout. This patient remains in remission at 3 years posttreatment, with a plan to repeat fluocinolone acetonide injections in the event of ocular relapse.

These treatment-induced changes in ERG findings most likely represent direct inhibition of the pathological effects of antiretinal antibodies. The ERG abnormalities detected are characteristic of reduced postreceptoral on-pathway function, and there is evidence that the antigen in typical cases of MAR is transient receptor potential cation channel subfamily M member 1 (TRPM1).¹² Notably, pretreatment ERGs were identical to those associated with complete congenital stationary night blindness, a form of which can be caused by biallelic mutations in the gene TRPM1.¹³ Improvements in ERG findings have been reported previously after various systemic and surgical interventions in MAR.^14,15 This report documents comprehensive electrophysiological assessments and demonstrates improvements of pattern ERG and full-field ERGs, including recovery of both on-off and S-cone ERG on-pathway components.

Limitations

This study is limited by being confined to a retrospective report of 1 case. This finding should be generalized with abundant caution.

Conclusions

This report describes a case of MAR treated with slow-release intravitreal corticosteroid implants and demonstrates dramatic and long-lasting improvements in visual symptoms and retinal function. These findings suggest intravitreal corticosteroids may be effective in MAR.

Supplement.

eFigure 1. Automated Humphrey perimetry visual fields showing progressive improvement following FAc implant insertion.

eFigure 2. Full-field and pattern ERGs from both eyes before and after FAc implant insertion.