Progressive, Symmetrical, Painless Visual Loss

A 75-year-old woman with a medical history of mixed connective tissue disease and breast adenocarcinoma sought care for subacute visual “haze” in both eyes characterized by light sensitivity, particularly with commercial fluorescent lighting, progressing over weeks. Visual acuity was 20/40 in each eye. The pupils were equal in size with no relative afferent pupillary defect but were sluggishly reactive to light. Automated perimetry documented peripheral constriction in both eyes. Ocular motility was normal. Ophthalmoscopy showed mild retinal pigment epithelial changes in both maculae with normal optic nerves. Optical coherence tomography showed macular thinning in both eyes. Findings of fundus autofluorescence were normal. Serum testing documented the presence of 3 retinal antibodies, against 30-, 36-, and 46-kDa proteins. A paraneoplastic panel was negative except for low-level ganglionic (alpha 3) acetylcholine receptor autoantibody positivity, which was interpreted as nonspecific autoimmunity. Electroretinography indicated severely decreased scotopic and photopic a and b waves. A diagnosis of paraneoplastic or nonparaneoplastic autoimmune retinopathy was made, consistent with the clinical presentation, optical coherence tomography and electroretinography findings, and the presence of retinal antibodies. There are no established evidence-based guidelines to assist treatment decisions in autoimmune retinopathy, although several lines of therapy have been advocated. No specific immunosuppressive therapy was undertaken in this case. However, if her vision had continued to rapidly worsen over time, empiric immunotherapy would have been instituted. Autoimmune retinopathy includes paraneoplastic and nonparaneoplastic forms. The best-characterized autoimmune retinopathy phenotype is cancer-associated retinopathy. Cancer-associated retinopathy typically presents with subacute, painless, bilateral (although asymmetry has been described) vision loss that is progressive over weeks to months, reflecting both rod and cone dysfunction in most patients. Visual symptoms precede recognition of an underlying cancer in approximately 50% of cases.

Intravitreal dexamethasone implant use as first-line therapy for cancer-associated retinopathy

We present a 65-year-old female smoker who presented with acute bilateral blurred vision. Investigations led to an endobronchial ultrasound-guided fine-needle aspiration resulting in an early diagnosis of limited stage small cell lung cancer. Positive recoverin antibodies supported the diagnosis of cancer-associated retinopathy (CAR). CAR was the first manifestation of systemic malignancy in our patient and early diagnosis enabled curative intent systemic treatment with chemotherapy and radiotherapy. Ocular-specific treatment is required in CAR, although no standardised treatment exists. Current treatment options include steroids and immunosuppressive agents. Our patient was administered bilateral intravitreal dexamethasone implants, resulting in significant visual field and electroretinogram improvement at 8 weeks post-intervention. To our knowledge, this represents the first reported successful use of intravitreal dexamethasone implants as first-line therapy, in conjunction with chemoradiotherapy. Intravitreal dexamethasone implants therefore may provide an effective and safe treatment for CAR by reducing intraocular inflammation without systemic effects.

Off-Label Use of 0.19 mg Fluocinolone Acetonide Intravitreal Implant: A Systematic Review

Corticosteroids are used in a variety of ophthalmological diseases. One challenge faced by ophthalmologists is to deliver corticosteroids to the posterior segment of the eye with efficacy and safety. Sustained-release corticosteroid implants may be the answer to this problem. The 0.19 mg fluocinolone acetonide (FAc) implant (Iluvien®) releases FAc for 36 months, and it is approved for the treatment of diabetic macular edema (DME) and noninfectious uveitis. We decided to do a systematic review to acknowledge in which other diseases FAc implant is being used off-label. A literature search was performed in the following three electronic databases: PubMed, Scopus, and Web of Science (from January 1st, 2000, to September 20th, 2020), using the following query: (“Fluocinolone Acetonide” OR Iluvien®) AND (“eye” OR “ocular” OR “intravitreal).” A total of 11 papers were included, and the use of FAc implant was analyzed in the following diseases: radiation-induced maculopathy (RM); paraneoplastic visual syndromes (melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR)); Sjogren’s syndrome-related keratopathy; retinal vein occlusion (RVO); cystoid macular edema (CME); diabetic retinal neurodegeneration (DRN); and retinitis pigmentosa (RP). FAc implant may be a potential treatment for these diseases; however, the level of scientific evidence of the included studies in this review is limited. Further studies with larger cohorts and longer follow-ups are needed to validate this data.

Alpha-Enolase: Emerging Tumor-Associated Antigen, Cancer Biomarker, and Oncotherapeutic Target

Alpha-enolase, also known as enolase-1 (ENO1), is a glycolytic enzyme that “moonlights” as a plasminogen receptor in the cell surface, particularly in tumors, contributing to cancer cell proliferation, migration, invasion, and metastasis. ENO1 also promotes other oncogenic events, including protein-protein interactions that regulate glycolysis, activation of signaling pathways, and resistance to chemotherapy. ENO1 overexpression has been established in a broad range of human cancers and is often associated with poor prognosis. This increased expression is usually accompanied by the generation of anti-ENO1 autoantibodies in some cancer patients, making this protein a tumor associated antigen. These autoantibodies are common in patients with cancer associated retinopathy, where they exert pathogenic effects, and may be triggered by immunodominant peptides within the ENO1 sequence or by posttranslational modifications. ENO1 overexpression in multiple cancer types, localization in the tumor cell surface, and demonstrated targetability make this protein a promising cancer biomarker and therapeutic target. This mini-review summarizes our current knowledge of ENO1 functions in cancer and its growing potential as a cancer biomarker and guide for the development of novel anti-tumor treatments.

Cancer-Associated Retinopathy due to Clear Cell Renal Carcinoma

An 84-year-old female presented with bilateral scotomas and progressive nyctalopia over 1 year. Best-corrected visual acuity was 20/50 in both eyes with reduced color vision. Goldmann visual field showed bilateral cecocentral scotomas and generalized constriction of the visual fields. This led to an electroretinogram showing an electronegative pattern consistent with autoimmune retinopathies. Infectious workup was negative. Anti-retinal antibodies were positive, leading to a presumed diagnosis of cancer-associated retinopathy (CAR). Imaging showed a previously unknown left renal lower pole mass, and she underwent a radical nephrectomy. Biopsy showed nuclear grade-3 clear cell renal carcinoma staged T1. The patient was treated with oral prednisone with no ocular improvement. We report on a rare case of clear cell renal carcinoma causing CAR. CAR is an important paraneoplastic syndrome to diagnose since the majority of ocular cases precede other manifestations of malignancy. Therefore, a timely diagnosis of CAR can be lifesaving or at least life-extending.

Ocular Paraneoplastic Syndromes

Ocular-involving paraneoplastic syndromes present a wide variety of clinical symptoms. Understanding the background pathophysiological and immunopathological factors can help make a more refined differential diagnosis consistent with the signs and symptoms presented by patients. There are two main pathophysiology arms: (1) autoimmune pathomechanism, which is presented with cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), cancer-associated cone dysfunction (CACD), paraneoplastic vitelliform maculopathy (PVM), and paraneoplastic optic neuritis (PON), and (2) ectopic peptides, which is often caused by tumor-expressed growth factors (T-exGF) and presented with bilateral diffuse uveal melanocytic proliferation (BDUMP). Meticulous systematic analysis of patient symptoms is a critical diagnostic step, complemented by multimodal imaging, which includes fundus photography, optical coherent tomography, fundus autofluorescence, fundus fluorescein angiography, electrophysiological examination, and sometimes fundus indocyjanin green angiography if prescribed by the clinician. Assessment of the presence of circulating antibodies is required for diagnosis. Antiretinal autoantibodies are highly associated with visual paraneoplastic syndromes and may guide diagnosis by classifying clinical manifestations in addition to monitoring treatment.

Cancer-associated retinopathy preceding the diagnosis of a pulmonary carcinoid tumour

Cancer-associated retinopathy (CAR) belongs to the paraneoplastic retinopathy syndromes and manifests itself by rapidly progressive vision loss, scotoma and photopsia. We herein reported the case of a 77-year-old woman without a cancer history who presents typical CAR symptoms. A complete workup followed by lung biopsy enabled the detection of a pulmonary carcinoid tumour. Treatment of oral cortisone was then initiated with dramatic improvements in the symptoms.