Ancillary imaging was obtained including optical coherence tomography (Fig. 2), fundus autofluorescence imaging (Fig. 3A, B), and fluorescein angiography (Fig. 3C, D). OCT confirmed the presence of subretinal fluid and debris with a predominance in the fovea and inferior macula; both eyes also showed smaller areas of retinal detachment near the superior vascular arcades. The subretinal debris appeared as an irregular thickening of the photoreceptor layer, as well as a lining on the inner surface of the RPE. The inner retinal layers up to the ellipsoid zone revealed preserved architecture. The choroid appeared to be of normal thickness and vascularity. FAF showed “boat-shaped” areas of hyperautofluorescence corresponding to the vitelliform lesions observed on fundus examination, suggestive of lipofuscin accumulation. IVFA revealed trace hypofluorescence at the site of the lipofuscin debris.
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| Figure 2. Foveal optical coherence tomography through the right (A) and left (B) eyes. The presence of subretinal fluid and debris is confirmed. |
The differential diagnosis for this patient with a history of metastatic cutaneous melanoma and new-onset subretinal fluid with vitelliform material included acute exudative paraneoplastic polymorphous vitelliform maculopathy (AEPPVM), choroidal metastasis, medication-associated retinopathy related to dabrafenib or pembrolizumab and adult-onset vitelliform macular dystrophy. Given the patient’s melanoma history and clinical and imaging findings, a diagnosis of AEPPVM was considered. Options for management of this paraneoplastic retinopathy included observation for spontaneous resolution, plasmapheresis, intravenous immunoglobulin and corticosteroids. Per patient choice, observation was rendered.
Discussion
Paraneoplastic syndromes are a complex of signs and symptoms that result from damage to an organ or tissue remote from the site of a malignant neoplasm or related metastases.1 The typical paraneoplastic retinopathies include cancer-associated retinopathy, melanoma-associated retinopathy, acute exudative paraneoplastic polymorphous vitelliform maculopathy, paraneoplastic optic neuropathy and others.2 CAR is the most common of the intraocular paraneoplastic syndromes, and often manifests with symptoms of rod and cone photoreceptor dysfunction. In cases of CAR, fundus examination may be normal; characteristic electroretinogram and visual field changes help establish the diagnosis. The most frequently associated malignancy is small-cell lung carcinoma, followed by gynecologic and breast carcinomas. MAR presents with rod-mediated symptoms and visual loss to a lesser degree than CAR. Similar to CAR, the fundus examination is frequently normal initially; additional diagnostic testing such as ERG, visual fields and serum anti-retinal antibody testing support the diagnosis. MAR is most often associated with metastatic cutaneous melanoma but has also been reported with uveal melanoma.2
AEPPVM is a paraneoplastic retinopathy demonstrating bilateral multifocal pockets of subretinal fluid and subretinal vitelliform deposits documented on fundus examination and confirmed with hyperautofluorescence on FAF. This condition is usually found in patients with cutaneous melanoma or choroidal melanoma and can appear before or after detection of the primary malignancy and/or metastasis. Initially thought to be an unusual presentation of MAR, AEPPVM seems to demonstrate a different spectrum of findings from MAR and is now classified as a separate entity.3,4 AEPPVM has subsequently been identified in cases of metastatic lung and breast adenocarcinoma, as well as a single case of metastatic clear cell sarcoma of the toe.5,6,7 The vitelliform fundus lesions are a classic distinction of AEPPVM and are different from the features of MAR, which typically presents with a normal fundus picture but occasionally with optic nerve pallor, vascular attenuation and, rarely, retinal pigment epithelial changes.8
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| Figure 3. Fundus autofluorescence imaging of the right (A) and left (B) eyes showing areas of hyperautofluorescence corresponding to the location of the vitelliform debris. Fluorescein angiography of the right (C) and left (D) eyes revealed trace hypofluorescence in corresponding areas. |
The pathogenesis of AEPPVM is poorly understood, but several studies have revealed serum autoantibodies against various retinal and retinal pigment epithelial antigens. These include antibodies against bipolar cells,3 rod outer segment protein,9 bestrophin 1,10 interphotoreceptor retinal-binding protein,11 peroxiredoxin 312 and carbonic anhydrase II.6,13 While autoantibody testing by Western blot and immunohistochemistry is commercially available, the patient often incurs an out-of-pocket expense, and this may not be essential for establishing the diagnosis.
Treatment of AEPPVM includes observation for ill patients, reducing the underlying malignancy burden, or reducing the presumed autoimmune etiology. Our patient chose observation, and we anticipate little change in the fundus appearance over time. Reduction of tumor burden has been found successful in a patient with AEPPVM discovered four months before a diagnosis of cutaneous metastatic melanoma.12 Initially not responding to prednisone, the patient received temozolomide, an alkylating agent, for treatment of the underlying melanoma and regained 20/20 visual acuity OU following resolution of the subretinal fluid at one year follow-up. Reduction of autoimmune factors is accomplished with plasmapheresis and IVIg, although evidence for their use is sparse.8 Most important in the management of affected patients is a careful and thorough evaluation for systemic metastatic disease performed by an oncologist, even if the patient is believed to be in remission.
Other considerations in the differential diagnosis of our patient included choroidal metastases and medication-associated retinopathies, especially medications for metastatic melanoma. Subretinal vitelliform debris is not generally seen with choroidal metastases, and the OCT did not demonstrate any choroidal tumor.
Regarding medication, this patient was currently taking or had taken three medications used in the treatment of metastatic melanoma, including ipilimumab, pembrolizumab and dabrafenib, all of which have been associated with retinopathies. Ipilimumab and pembrolizumab are two monoclonal antibodies that upregulate the immune response to tumor cells by inhibiting the checkpoint sites of CTLA-4 and PD-1, respectively, on the T cell surface. In many instances, patients with AEPPVM are on medication for melanoma control, and it’s challenging to sort out if the features are truly autoimmune or medication related. In the literature, there are two reports describing serous retinal detachment with and without vitelliform subretinal material suggested to be related to ipilimumab, and both patients demonstrated reduction in fundus features upon discontinuation of the medication.14,15 Regarding pembrolizumab, there is a single report of a patient with multiple bilateral peripheral chorioretinal scars with RPE atrophy and pigment clumping after starting pembrolizumab.16 Our patient didn’t report taking ipilimumab at the time of presentation, and the lesions on fundus examination didn’t resemble those reported with pembrolizumab. Finally, dabrafenib is a B-Raf inhibitor, which targets a protein in the MAP Kinase pathway, frequently dysregulated in neoplasms. While dabrafenib has not been implicated directly in retinopathy, the related family of MEK inhibitors has been associated with the presence of subretinal fluid and vitelliform lesions in some patients.17 Although our patient was taking dabrafenib when she presented to us, she reports that the symptoms started while she was off the medication, making it unlikely to be the underlying cause.
In summary, AEPPVM must be considered in the differential diagnosis of patients with subretinal fluid demonstrating vitelliform lesions, whether or not a known history of malignancy exists. When present, close coordination of care with an oncologist must be undertaken to perform a thorough investigation for metastases. REVIEW
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