DIAGNOSTIC YIELD OF AN INHERITED RETINAL DISEASE GENE PANEL IN RETINOPATHY OF UNKNOWN ORIGIN.

PURPOSE: Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). METHODS: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy. RESULTS: The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. CONCLUSION: Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.

Unilateral cancer-associated retinopathy: diagnosis, serology and treatment.

PURPOSE: To report a case of unilateral cancer-associated retinopathy (CAR) with clinical, serological and electroretinogram (ERG) normalization after aggressive cancer treatment combined with steroids and rituximab. METHODS: Work-up included extensive clinical and electrophysiological testing. Also, serological work-up for antiretinal antibodies and oncological screening was organized. RESULTS: A 45-year-old female presented with progressive photopsias, photophobia and relative central scotoma in the right eye since 6 weeks prior. BCVA was 1.0 in both eyes. Biomicroscopy, IOP and fundus exam were unremarkable. Also, colour vision, autofluorescence imaging, OCT and EOG were normal. Visual fields showed decreased central sensitivity in the right eye. ERG showed a unilateral, electronegative combined and ON-bipolar response. A diagnosis of CAR was suspected. After a diagnosis of an adenocarcinoma of the right ovary, radical ovariectomy and hysterectomy were performed, followed by adjuvant chemotherapy. A whole-body PET scan revealed no metastasis. Treatment with rituximab monoclonal antibodies in combination with corticosteroids was initiated. The patient tested positive for serum autoantibodies against TRPM1, a transient receptor potential cation channel expressed in ON-bipolar cells. During treatment, there was progressive improvement in symptoms and the ERG normalized. Serology confirmed complete clearance of autoantibodies. CONCLUSIONS: Although rare, unilateral CAR does occur and in cases with high clinical suspicion an oncological work-up is mandatory. Aggressive cancer treatment combined with steroids and rituximab can lead to normalization of the clinical and ERG phenotype, with clearing of antiretinal antibodies.

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.

Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines.

The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNγ, TNFα and IL-17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNγ (150ng/ml), TNFα (30ng/ml) or IL-17 (100ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IκBα expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNγ-induced SOCS1 mRNA increase and IFNγ-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNγ-induced decrease of IL-8 secretion and prevents IFNγ-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFα-induced IκBα degradation nor block TNFα-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17-induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNγ-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFα and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression.

Severe bilateral panuveitis during melanoma treatment by Dabrafenib and Trametinib.

BACKGROUND: We report a case of severe bilateral panuveitis during melanoma therapy with a combination of Dabrafenib, a B-raf (BRAF) inhibitor, and Trametinib, a mitogen/extracellular signal-regulated kinase (MEK) inhibitor. Both of these drugs are effectors in the mitogen-activated protein kinase (MAPK) pathway, which plays an important role in the physiopathology of melanoma. Dabrafenib and Trametinib have shown improved survival of patients with metastatic melanoma but they have also been associated with the development of uveitis. FINDINGS: Our patient was a 55-year-old woman with metastatic melanoma who presented with sudden onset of bilateral painless visual loss. She had been treated with Dabrafenib and Trametinib. Trametinib was discontinued at the onset of symptoms but there was no improvement. Ophthalmological examination revealed severe bilateral non-granulomatous panuveitis, with choroidal thickening, chorio-retinal folds, and multiple serous retinal detachments (SRDs). Topical corticosteroid treatment was initiated, and Dabrafenib was discontinued. A good response was obtained with a recovery of visual acuity of 20/25 on both eyes and an almost complete resolution of the SRDs. CONCLUSIONS: This case highly suggests that MAPK pathway inhibition can lead to severe uveitis. Dabrafenib and Trametinib could have both played a role in inducing the disease. Further studies are needed to evaluate the possible role of the combination of these drugs in inducing uveitis and SRD.