Paraneoplastic vitelliform retinopathy successfully treated with intravitreal dexamethasone implants

Abstract

Purpose

To report a rare case of paraneoplastic vitelliform retinopathy, characterized by detachments of the retinal pigment epithelium and neurosensory retina manifesting as vitelliform lesions, successfully managed with a sustained-release intravitreal dexamethasone implant in a patient receiving systemic immunotherapy for metastatic cutaneous melanoma.

Observations

A 79-year-old man presented with progressive bilateral visual loss and serous retinal detachment. Multimodal retinal imaging revealed bilateral vitelliform lesions, choroidal thickening, and subretinal fluid. Electroretinography demonstrated an electronegative waveform, supporting the diagnosis of a condition in the spectrum of MAR. Systemic evaluation revealed axillary melanoma metastasis confirmed by fine-needle aspiration. Despite treatment with systemic pembrolizumab and a trial of intravitreal anti-VEGF injections, visual symptoms and subretinal fluid persisted. Bilateral intravitreal dexamethasone implants led to marked anatomical and functional improvement within one month, with sustained benefits observed over a two-year follow-up.

Conclusions and importance

This case highlights the potential role of local corticosteroid therapy in paraneoplastic vitelliform lesions secondary to metastatic melanoma, particularly when systemic immunosuppression is contraindicated.

1. Introduction

Ocular paraneoplastic syndromes are a group of rare, often immune-mediated disorders in which remote effects of systemic malignancy result in retinal or optic nerve dysfunction. Among the paraneoplastic syndromes are paraneoplastic optic neuropathy, cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), bilateral diffuse uveal melanocytic proliferation (BDUMP), paraneoplastic vitelliform maculopathy/retinopathy (PVM), and the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. 1, 2, 3, 4, 5, 6^,7,8.

PVM is characterized by vitelliform retinal deposits or serous retinal detachments resembling other vitelliform retinopathies, such as acute exudative polymorphous vitelliform maculopathy or the multifocal variant of Best disease. 7, 9, 10 Although PVM was initially considered an atypical form of MAR, subsequent evidence suggests that distinct immune-mediated mechanisms may contribute to its pathogenesis.^7,11 raising the discussion on whether PVM should be classified as a MAR-like syndrome or as a distinct immune-mediated entity. Rahimy and Sarraf, for instance, reviewed 23 cases of PVM and found that while most were associated with melanoma (cutaneous or uveal), three occurred in patients with non-melanoma malignancies.⁷

Clinical presentation varies, but the most common symptom is central visual loss. Patients may also report nyctalopia, metamorphopsia and shimmering photopsias.11, 12 Multimodal imaging findings in PVM are relatively consistent. Fluorescein angiography typically shows blockage of choroidal fluorescence with late staining or, alternatively, mild early hyperfluorescence. The lesions are usually hyperautofluorescent.^7,9,13,8 Optical coherence tomography localizes the vitelliform material and associated fluid to the subretinal space. Electrophysiological testing (electroretinogram and electrooculogram) yields variable results. 7, 8, 9, 11, 14, 15.

Treatment remains controversial, however, intravitreal corticosteroids may offer an effective alternative, with isolated reports demonstrating promising outcomes using dexamethasone or fluocinolone implants in paraneoplastic ocular syndromes, particularly MAR.16, 17, 18, 19 In this article, we report the case of a patient with melanoma-associated PVM treated with pembrolizumab combined with a sustained-release intravitreal dexamethasone implant, resulting in a marked and long-lasting ophthalmologic improvement maintained over a two-year follow-up.

2. Case report

A 79-year-old male was referred to our service for investigation of yellowish-white lesions in the posterior pole accompanied by bilateral serous retinal detachment. His medical history included vitiligo and systemic arterial hypertension. Ocular history was notable for recent bilateral cataract surgery. At the initial visit, the patient reported progressive bilateral visual acuity decline over the previous six months. On review of systems, the patient mentioned a palpable, painless right axillary mass, with no other associated systemic symptoms.

On ophthalmologic examination, best corrected visual acuity (BCVA) was 20/200 in the right eye (OD) and 20/160 in the left eye (OS). Anterior segment slit-lamp biomicroscopy was unremarkable in both eyes. Indirect binocular ophthalmoscopy revealed mild vitreous inflammation graded as 1+/4 cells, well-defined optic discs, macular edema, multiple yellowish-white punctate lesions along the superior temporal arcade, and serous retinal detachment in the posterior pole of both eyes (Fig. 1A and B). Fundus autofluorescence revealed punctate areas of hyperautofluorescence corresponding to the lesions seen on fundoscopy, with sparse areas of hypoautofluorescence along the superior and inferior arcades (Fig. 1C and D). Optical coherence tomography (OCT) showed outer retinal lesions, subretinal fluid accumulation, and vitreous inflammation (Fig. 2A–D).

Fig. 1.

Color fundus photographs of the right (A) and left (B) eyes at presentation demonstrate yellowish subretinal dotted and blotted lesions (vitelliform deposits) along the superior vascular arcade (blue arrows), associated with serous retinal detachment involving the posterior pole. Corresponding fundus autofluorescence images (C, D) reveal dotted hyperautofluorescent foci corresponding to the vitelliform lesions, along with scattered hypoautofluorescent areas along the arcades (red arrows). Following intravitreal dexamethasone implant therapy, the yellowish subretinal deposits are attenuated in both the right (E) and left (F) eyes. Follow-up fundus autofluorescence (G, H) shows residual lipofuscin-related hyperautofluorescence inferior to the fovea after resolution of the serous detachment (yellow arrows), with overall improvement of the vitelliform hyperautofluorescent lesions and reduction of the hypoautofluorescent areas.

Fig. 2.

Optical coherence tomography B-scans through the superior arcade and macula of the right (A, B) and left (C, D) eyes at presentation show subretinal fluid with a hyperreflective outer retinal band along the superior arcade (A, C) (examples pointed out by the red arrowheads) and exudative retinal detachment (B, D). After treatment (E–H), the hyperreflective outer retinal changes and detachment have resolved, with minimal subretinal fluid (blue arrow) remaining in the macula of the left eye (H).

Given the ocular findings, the differential diagnosis included intraocular lymphoma and paraneoplastic syndromes, prompting comprehensive systemic and local investigations. The patient underwent vitreous biopsy via pars plana vitrectomy, which revealed negative cytology. Fine-needle aspiration of the right axillary lymph node was performed, and histopathological and immunohistochemical analysis confirmed a diagnosis of metastatic cutaneous melanoma.

Following the diagnosis, the patient began systemic treatment with pembrolizumab. However, visual symptoms persisted. Given the negative vitreous cytology and confirmed melanoma in the axillary lesion, the differential diagnosis favored paraneoplastic etiologies, with BDUMP, MAR or PVM considered as the main possibilities. A full-field electroretinogram (ERG) demonstrated a distinctly electronegative configuration, with marked depression of the b-wave with relative preservation of the a-wave in all scotopic responses, consistent with post-photoreceptor dysfunction involving ON-bipolar cells. Photopic responses were similarly reduced, including attenuation of the 30-Hz flicker amplitude, reflecting superimposed cone pathway involvement and corroborating with the diagnosis of a paraneoplastic retinopathy (Fig. 3A). Anti-retinal antibody testing was not available at the institution.

Fig. 3.

(A) Pre-treatment full-field electroretinography (ffERG) showing an electronegative scotopic response with marked b-wave reduction and relative preservation of the a-wave, consistent with ON-bipolar cell dysfunction. Photopic responses, including the 30-Hz flicker, were diffusely reduced. (B) Post-treatment ffERG demonstrating improvement in cone-mediated photopic responses and mild increase in scotopic b-wave amplitude following intravitreal dexamethasone implant therapy.

Given the prominent subretinal fluid accumulation, initial ophthalmic management included a cycle of bilateral intravitreal bevacizumab injections every month for three months to help exclude a component of increased vascular permeability. This approach resulted in slight anatomical improvement on OCT but no visual acuity gains. Two months after completing this treatment cycle, despite ongoing systemic immunotherapy, the patient experienced a significant worsening of visual acuity and serous retinal detachment. At that point, bilateral intravitreal dexamethasone implants were placed.

At one-month follow-up, the patient showed significant improvement in ocular symptoms, with a BCVA of 20/80 OD and 20/50 OS. Fundus photography demonstrated marked regression of multiple yellowish-white punctate lesions and resolution of the serous retinal detachment (Fig. 1E–H). OCT revealed a substantial reduction in macular edema and subretinal fluid, with subsequent scans demonstrating complete resolution of subretinal fluid and preservation of retinal anatomy throughout two years of follow-up, following a second implant administered eight months after the first (Fig. 2E–H). Retinal function was partially restored, as evidenced by improved retinal sensitivity on computerized microperimetry, which demonstrated focal gains in the macular region (Fig. 4). A repeat full-field ERG confirmed modest functional improvement, most prominently within the photopic responses, with partial recovery of cone-driven signals and a mild increase in scotopic b-wave amplitude (Fig. 3B). The patient currently maintains stable visual acuity (20/40 OU), performs daily activities independently, and remains under joint follow-up with the clinical oncology team for systemic treatment.

Fig. 4.

Fundus-guided microperimetry overlay on color fundus photographs of the right (A) and left (B) eyes after treatment. Colored test points indicate retinal sensitivity in decibels (dB), with values shown at each locus and corresponding to the color scale (bottom). The right eye (A) demonstrates patchy central and paracentral reductions in sensitivity, whereas the left eye (B) shows generally preserved macular sensitivity with most points ≥15 dB.

3. Discussion

This case illustrates the diagnostic and therapeutic challenges of a MAR-like syndrome in a patient with no prior history of malignancy, whose initial complaint was bilateral visual decline following cataract surgery. The fundus appearance, characterized by punctate yellowish lesions and serous retinal detachment, coupled with OCT findings of choroidal thickening and subretinal fluid, initially raised suspicion for intraocular lymphoma. However, the diagnosis of cutaneous melanoma with axillary lymph node metastasis confirmed by fine-needle aspiration and the electronegative ERG pattern supported the diagnosis of MAR or a MAR-like entity.

The mechanism underlying vitelliform lesion formation remains incompletely understood. 7, 9, 10, 20^,8, 11, 15 Several autoantibodies have been identified, including those directed against bipolar cells, rod outer segment protein (ROS, 120 kDa), peroxiredoxin 3 (PRDX3, 26 kDa), bestrophin-1 (68 kDa), carbonic anhydrase II (CAII, 30 kDa), interphotoreceptor retinoid-binding protein (IRBP, 145 kDa), as well as uncharacterized 35-kDa and 68-kDa proteins. 7, 9, 10, 21^,13,8,11 Although PVM is classically attributed to primary RPE dysfunction, the electronegative ERG observed in this case suggests that the autoimmune process extended to the inner retina, as can occur in some paraneoplastic presentations. This pattern may be explained by mechanisms such as epitope spreading and molecular mimicry, in which the immune reaction initially directed against the RPE expands to include newly exposed bipolar cell antigens; notably, epitopes such as TRPM1²² are expressed in both RPE cells and ON-bipolar cells. ERG findings in PVM have been reported to vary widely, from normal responses^23,24 to selective a- or b-wave reductions and fully electronegative waveforms,^11,25 reflecting the heterogeneity of immune targets triggered by the underlying tumor. These observations suggest that the vitelliform phenotype may occur in isolation or in combination with paraneoplastic bipolar cell dysfunction, resulting in overlapping features of PVM and MAR.

Importantly, structural and clinical improvement in paraneoplastic retinopathies does not necessarily translate into parallel normalization of electrophysiologic findings. In many cases, ERG abnormalities reflect persistent bipolar cell dysfunction or synaptic injury that may be only partially reversible.²⁶ In the present case, post-treatment ERG demonstrated only partial recovery, predominantly affecting photopic responses, while scotopic abnormalities largely persisted. This dissociation underscores the concept that ERG findings in MAR-like syndromes may lag behind or incompletely reflect clinical recovery and should be interpreted in conjunction with multimodal structural imaging and functional assessments rather than as a sole marker of treatment response.

Treatment of MAR-like syndromes remains controversial. Systemic immunosuppressive agents, such as corticosteroids, intravenous immunoglobulin, or plasmapheresis, have shown limited efficacy, with partial response rates around 40% according to a case series.⁵ Moreover, the use of systemic immunosuppression in patients receiving immune checkpoint inhibitors, such as pembrolizumab, raises concern about potential antagonism of anti-tumor immune responses.27, 28, 29 These concerns have led to growing interest in local therapies that may mitigate retinal inflammation without compromising systemic oncologic control.

In our patient, the initial use of intravitreal bevacizumab yielded only transient and modest anatomical improvement, without functional gains. The introduction of a sustained-release dexamethasone intravitreal implant led to significant visual and anatomical improvement within one month, with resolution of subretinal fluid and regression of vitelliform lesions. A second implant, administered eight months later, contributed to sustained remission, with preserved retinal structure on OCT and improved retinal sensitivity confirmed by computerized microperimetry over a two-year follow-up period. The subretinal fluid in this case was likely attributable to an inflammatory outer retinal response inherent to the immune-mediated nature of MAR-like syndromes, rather than to pigment epithelial detachment or choroidal neovascularization. This mechanism helps explain the limited response to anti-VEGF therapy and the favorable anatomical and functional improvement observed after intravitreal corticosteroid treatment.

These findings align with isolated reports supporting the use of local corticosteroid therapy in MAR-like syndromes. Karatsai et al. described a patient treated with bilateral intravitreal fluocinolone acetonide implants, showing visual and ERG improvement over three years.³⁰ Similarly, Poujade et al. reported clinical benefit from repeated intravitreal dexamethasone injections in a patient undergoing pembrolizumab therapy.¹⁸ Most PVM cases reported in the literature, however, did not receive targeted ocular therapy, as management focused primarily on treating the underlying malignancy, and many patients died of systemic disease before ocular-directed treatment could be considered. Other localized ocular treatments have been proposed. A report of two cases described the use of intravitreal aflibercept³¹ and, in a refractory case, intravitreal methotrexate.³² Our case adds further evidence that although systemic therapy is the cornerstone of management, local immunomodulatory and anti-exudative strategies may be valuable in controlling the progressive or recurrent retinal dysfunction in PVM. Local corticosteroid therapy, particularly using a slow-release implant, can provide long-term control of inflammation and functional preservation in MAR-like syndromes, even in patients under systemic immunotherapy.

Importantly, this case also highlights the potential utility of this approach in resource-limited settings. Intravitreal corticosteroids offer a more accessible and sustainable treatment alternative when compared to systemic immunosuppression or long-term biologics. Furthermore, the success of this approach reinforces the critical role of ophthalmologic evaluation in unveiling systemic malignancies through paraneoplastic manifestations and underscores the importance of multidisciplinary care in optimizing outcomes.

4. Conclusion

In summary, this report emphasizes the diagnostic complexity of MAR and other ocular paraneoplastic syndromes and supports the efficacy of intravitreal dexamethasone as a safe and effective local therapy. The sustained anatomical and functional recovery documented over a two-year period reinforces the value of this strategy in the management of melanoma-associated retinopathy spectrum and opens avenues for broader application in similar clinical contexts.

CRediT authorship contribution statement

Mariel S. Natividade: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Victor Bellanda: Writing – review & editing, Visualization, Validation, Investigation, Formal analysis, Data curation. Gabriela M. Carvalho: Writing – original draft, Investigation, Formal analysis. Henrique B. Trad Souza: Writing – original draft, Investigation, Formal analysis. João Marcello F. Furtado: Writing – review & editing, Validation, Methodology, Investigation, Formal analysis. Rodrigo Jorge: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Patient Consent

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

Authorship

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

Funding

This study received no financial support.

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.