Unilateral Melanoma-Associated Retinopathy Case Report.

In this report, we present a case of unilateral melanoma-associated retinopathy in a 72-year-old woman. The patient's main symptoms were decreased vision and positive dysphotopsia. Unilateral electronegative electroretinogram (ERG) was suggestive for melanoma retinopathy. PET-CT discovered metastatic disease, 3 years after the initial melanoma. A prompt treatment with corticosteroids was started, followed by immunotherapy. The central and peripheral vision of the patient improved, and the ERG showed normalization of the responses. This case highlights the importance of early recognition and individualized treatment strategies for melanoma-associated retinopathy.

RESOLUTION OF CHOROIDAL METASTASIS AND ASSOCIATED SUBRETINAL EXUDATION OF METASTATIC CUTANEOUS MELANOMA 15 DAYS AFTER TREATMENT WITH COMBINED TARGETED THERAPY.

PURPOSE: To report a case of metastatic cutaneous melanoma to the choroid with rapid and complete resolution of associated choroidal elevation and subretinal fluid after initiation of combined targeted therapy. METHODS: We describe a case of a 41-year-old man diagnosed with a metastatic cutaneous melanoma to the choroid of his right eye, for which treatment with dabrafenib/trametinib was initiated. RESULTS: A 41-year-old man with a past medical history of a BRAF V600E/V600E2/V600D mutated invasive superficial spreading cutaneous melanoma presented with acute metamorphopsia and blurred vision in his right eye. Examination revealed a best-corrected visual acuity (BCVA) of 20/22 and 2 elevated choroidal lesions temporal to the fovea with subretinal exudation to the fovea on fundoscopy. On repeat examination 3 days later, his vision had further decreased to 20/50 with an increase of subretinal fluid. Treatment with BRAF/MEK-inhibitor dabrafenib/trametinib was initiated, with complete resolution of the choroidal masses and subretinal exudation and improvement of the BCVA to 20/22 after only 15 days. Follow-up 8 weeks after start of therapy showed stable fundoscopic and tomographic findings, with further improvement of BCVA to 20/17 and no ocular side effects. CONCLUSION: A case of metastatic cutaneous melanoma to the choroid with choroidal elevation and subretinal exudation to the fovea, for which treatment with dabrafenib/trametinib was initiated. Rapid and complete resolution of choroidal metastasis and the associated subretinal exudation after initiation of combined targeted therapy was seen, without any ocular side effects.

VOGT-KOYANAGI-HARADA DISEASE-LIKE UVEITIS IN A PATIENT WITH ADVANCED MELANOMA TREATED BY SEQUENTIAL ADMINISTRATION OF NIVOLUMAB AND DABRAFENIB/TRAMETINIB THERAPY.

PURPOSE: To describe a case of bilateral Vogt-Koyanagi-Harada (VKH)-like uveitis during treatment with dabrafenib and trametinib and three months after discontinuation of nivolumab for malignant melanoma, and discuss the possible (synergistic) role(s) of mitogen-activated protein kinase (MAPK) inhibitors and immune checkpoint inhibitors in its pathophysiology. METHODS: Retrospective case report with fluorescein angiography and optical coherence tomography. RESULTS: A 55-year old patient with metastatic melanoma presented with a complaint of gradually worsening blurry vision in the right eye during treatment with dabrafenib and trametinib, three months after discontinuation of nivolumab. Based on the clinical examination, optical coherence tomography and fluorescein angiography findings, and a thorough laboratory work-up, he was diagnosed with a bilateral VKH-like uveitis without extraocular manifestations. The uveitis responded well to oral corticosteroids. CONCLUSION: Vogt-Koyanagi-Harada-like uveitis is a rare adverse effect of MAPK inhibitors and immune checkpoint inhibitors. Similar pathogenetic mechanisms including a drug-induced autoimmunity targeted against benign and malignant melanocytes may underlie MAPK inhibitor-induced and immune checkpoint inhibitors-induced VKH-like uveitis. In our report, the patient developed a VKH-like uveitis during MAPK inhibition therapy, four months after discontinuation of nivolumab. It is difficult to delineate whether MAPK inhibition alone was responsible for this adverse effect, or whether, on the contrary, potentiation occurred as a result of immune modulation by previous treatment with an immune checkpoint inhibitor. Further cases are needed to further clarify this latter hypothesis.

Relation between ocular paraneoplastic syndromes and Immune Checkpoint Inhibitors (ICI): review of literature.

PURPOSE: To describe different ocular paraneoplastic syndromes in patients treated with Immune Checkpoint Inhibitors (ICI), its relation with different types of ICI and different types of tumors, and its implications for treatment. METHODS: A comprehensive review of the literature was performed. RESULTS: Patients treated with ICI can present with different ocular paraneoplastic syndromes, such as Carcinoma Associated Retinopathy (CAR), Melanoma Associated Retinopathy (MAR) and paraneoplastic Acute Exudative Polymorphous Vitelliform Maculopathy (pAEPVM). In literature, the different types of paraneoplastic retinopathy are mostly related to different types of primary tumors, with MAR and pAEPVM seen in melanoma, and CAR in carcinoma. Visual prognosis is limited in MAR and CAR. CONCLUSION: Paraneoplastic disorders result from an antitumor immune response against a shared autoantigen between the tumor and ocular tissue. ICI enhance the antitumor immune response, which can lead to increased cross-reaction against ocular structures and unmasking of a predisposed paraneoplastic syndrome. Different types of primary tumors are related to different cross-reactive antibodies. Therefore, the different types of paraneoplastic syndromes are related to different types of primary tumors and are probably unrelated to the type of ICI. ICI-related paraneoplastic syndromes often lead to an ethical dilemma. Continuation of ICI treatment can lead to irreversible visual loss in MAR and CAR. In these cases overall survival must be weighed against quality of life. In pAEPVM however, the vitelliform lesions can disappear with tumor control, which may involve continuation of ICI.

Brentuximab vedotin induced uveitis.

PURPOSE: To report a case of bilateral Vogt-Koyanagi-Harada (VKH)-like granulomatous pan uveitis secondary to brentuximab vedotin (BV) administration to treat for classical Hodgkin lymphoma (CHL). OBSERVATIONS: A case of bilateral pan uveitis is described, following administration of BV, with features of VKH-like uveitis: presence of inflammatory cells in the anterior and posterior segment, multiple small serous detachments around the optic disc and retinal pigment epithelium (RPE) folds confirmed by optical coherence tomography (OCT) as well as hypocyanesent dark dots, disc hyperfluorescence and fuzzy vascular patterns seen on indocyanine green and fluorescein angiography. There were no systemic features of VKH disease. Further etiological investigation showed no clear infectious or inflammatory cause. The uveitis responded well to treatment with corticosteroids and cessation of BV. A relapse occurred a few months later when BV treatment was reinitiated, suggesting a probable adverse event to this drug, according to the Naranjo algorithm. CONCLUSIONS: We hypothesize that administration of BV can induce a VKH-like uveitis, caused by loss of function of protective CD30+ cells present in the uveal tract, possibly aggravated by collateral damage to surrounding CD30-cells and melanocytes, leading to a uveal immune reaction. It is therefore important for the clinicians using BV to be aware of this adverse event. Growing experience with immunotherapy will provide more clinical insights in these complex immune mechanisms in the future.

THE ROLE OF CHECKPOINT INHIBITORS IN PARANEOPLASTIC ACUTE EXUDATIVE POLYMORPHOUS VITELLIFORM MACULOPATHY: REPORT OF TWO CASES.

PURPOSE: To report on two cases with paraneoplastic acute exudative polymorphous vitelliform maculopathy within one month after the initiation of nivolumab. METHODS: Case report. RESULTS: Two patients with metastatic mucosal melanoma were diagnosed with acute exudative polymorphous vitelliform maculopathy within one month after the initiation of the checkpoint inhibitor nivolumab. Both cases showed a neurosensory retinal detachment and subretinal hyperautofluorescent material, which persisted after discontinuation of nivolumab and treatment with local and/or systemic corticosteroids. In one case, nivolumab was introduced again in a later stage in combination with surgical reduction of the tumor, eventually leading to resolution of the subretinal lipofuscin-rich fluid. CONCLUSION: The development of paraneoplastic acute exudative polymorphous vitelliform maculopathy in melanoma patients can be triggered by treatment with nivolumab. However, achieving tumor control, which may involve continuation of nivolumab, could be the key to success.

Two siblings with Heimler syndrome caused by PEX1 variants: follow-up of ophthalmologic findings.

BACKGROUND: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype. MATERIALS AND METHODS: The medical records of the siblings were reviewed retrospectively. RESULTS: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant. CONCLUSION: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.

Optical Coherence Tomography Angiography of Retinal Microvascular Changes Overlying Choroidal Nodules in Neurofibromatosis Type 1.

PURPOSE: To report 3 cases of neurofibromatosis type 1 (NF1) with choroidal nodules associated with retinal microvascular changes imaged with optical coherence tomography angiography (OCTA). METHODS: Small case series in 3 NF1 patients. OCTA examinations were performed by a trained examiner (J.J.) after pupillary dilation. A standard scan, centered over the macula measuring 6 × 6 mm and 3 × 3 mm was obtained according to the findings on standard color photography. Additional scans were obtained in the zones with microvascular abnormalities. The segmentation provided by the machine software was used. RESULTS: Corkscrew retinal vessels were observed in association with "placoid"-type choroidal nodules as shown by near-infrared reflectance imaging. In all cases, multiple lesions were found. They were second- or third-order tortuous vessels originating from the superior or inferior temporal veins. OCTA demonstrated that the tortuous venules were located in the superficial capillary plexus, and no abnormalities were found in the deep capillary plexus. DISCUSSION: Corkscrew retinal vessels are part of a spectrum of retinal microvascular alterations seen in association, sometimes overlying choroidal nodules in patients with NF1 and are visualized in the superficial capillary plexus on OCTA. We demonstrated with OCTA that they are not associated with flow loss or ischemia in the superficial and deep capillary plexus. The link between the underlying nodule remains unclear. Since neovascularization was described in choroidal ganglioneuroma, we hypothesize that corresponding secretory substances from Schwann cells, ganglion cells, or melanocytes in choroidal nodules might alter the retinal vasculature. CONCLUSION: We report on 3 cases of NF1 with choroidal nodules in association with retinal microvascular changes imaged with OCTA. OCTA demonstrated preservation of the blood flow in the deep and superficial capillary plexus of the retina. We hypothesize that angiogenic factors secreted by the underlying choroidal nodules could have an effect on the retinal vasculature. Further immunohistological studies in NF1 patients with choroidal nodules to detect angiogenic factors (such as VEGF) are necessary to confirm this hypothesis.

Comparing Parafoveal Cone Photoreceptor Mosaic Metrics in Younger and Older Age Groups Using an Adaptive Optics Retinal Camera.

BACKGROUND AND OBJECTIVE: To analyze cone mosaic metrics on adaptive optics (AO) images as a function of retinal eccentricity in two different age groups using a commercial flood illumination AO device. PATIENTS AND METHODS: Fifty-three eyes of 28 healthy subjects divided into two age groups were imaged using an AO flood-illumination camera (rtx1; Imagine Eyes, Orsay, France). A 16° × 4° field was obtained horizontally. Cone-packing metrics were determined in five neighboring 50 µm × 50 µm regions. Both retinal (cones/mm2 and µm) and visual (cones/degrees2 and arcmin) units were computed. RESULTS: Results for cone mosaic metrics at 2°, 2.5°, 3°, 4°, and 5° eccentricity were compatible with previous AO scanning laser ophthalmoscopy and histology data. No significant difference was observed between the two age groups. CONCLUSIONS: The rtx1 camera enabled reproducible measurements of cone-packing metrics across the extrafoveal retina. These findings may contribute to the development of normative data and act as a reference for future research. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:45-50.].

Laser Photocoagulation for Peripheral Retinal Capillary Hemangioblastoma in von Hippel-Lindau Disease.

PURPOSE: To study the efficacy and limits of laser photocoagulation for retinal capillary hemangioblastoma (RCH) of various sizes in von Hippel-Lindau disease. DESIGN: Retrospective study. PATIENTS: The records of 176 patients with von Hippel-Lindau were reviewed retrospectively. Seventy-four patients with 304 RCHs in 100 eyes were treated primarily with laser photocoagulation. Eyes with concomitant rhegmatogenous or tractional retinal detachment or with papillary RCH were excluded. METHODS: The treatment consisted of inactivating RCH using direct green laser photocoagulation with long-duration laser burns (0.1-0.7 seconds). MAIN OUTCOME MEASURES: The number of RCH lesions per eye, RCH size in disc diameter (DD) at diagnosis, the presence of retinal lipid exudation or subretinal fluid, and visual acuity were recorded. Final outcomes included RCH inactivation, posttreatment complications, and final visual acuity. RESULTS: Patient mean age was 28 years (range, 8-62). Mean follow-up duration after treatment was 4.5 years (range, 0.4-17.5). Median RCH size was 0.25 DD (range, 0.25-3.00). Laser alone inactivated 97% of RCHs. A mean number of 1.6 laser sessions (range, 1-8) were needed to achieve RCH inactivation. A single laser session allowed coagulating 77% of RCHs. Their median size was 0.50 DD (range, 0.25-1.50). More than 1 laser session was needed to inactivate 23% of RCHs. Their median size was 1 DD (range, 0.25-3.00). Among them, 29 (10% of all RCHs) needed additional laser session during the first 48 hours. Their median size was 1.5 DD (range, 0.5-3). Subretinal fluid transiently increased in 7 eyes after the first laser session and was controlled promptly by additional photocoagulation. Additional cryotherapy was needed only in 7 eyes with large RCH partially inactivated by laser. In all eyes, visual acuity remained stable during the follow-up. CONCLUSIONS: In the absence of tractional retinal detachment, laser photocoagulation allowed inactivating most RCHs up to 3 DD, even when they were associated with subretinal fluid. Laser photocoagulation alone inactivated 100% of RCHs up to 1 DD, and 73% of larger RCHs. In such cases, additional cryotherapy increased RCH inactivation to 94% so that 99% of all treated RCHs were finally inactivated.