Diagnosis and treatment of autoimmune retinopathy: review of current approaches

Abstract

Purpose: To provide a comprehensive overview of the existing understanding regarding the clinical characteristics, diagnostic investigation, and treatment strategies for autoimmune retinopathy (AIR). To emphasize the lack of consensus in the field and the ongoing controversies regarding best practices.

Methods: Narrative review of the literature on PubMed and Google Scholar databases.

Results: AIR comprises a group of rare autoimmune disorders causing retinal degeneration, characterized by rapid vision deterioration linked to circulating anti-retinal autoantibodies (ARAs). The spectrum includes primary autoimmune diseases and associations with retinitis pigmentosa or various malignancies, raising questions about the causative role of antibodies. Non-paraneoplastic AIR patients may be younger on average than paraneoplastic AIR patients and may have a higher likelihood of being female and having a history of autoimmune disease. Diagnosing AIR is challenging due to its complex pathophysiology, overlapping phenotypes, the absence of standardized diagnostic criteria, and the limited availability of specialized serological testing for ARAs. Despite decades of research progress, the exact mechanisms underlying ocular immune privilege breakdown and the autoimmune attack on retinal cells in AIR remain unknown.

Conclusions: The diagnosis and management of AIR present ongoing challenges, with no international consensus on diagnostic criteria or treatment protocols. While several authors consider the identification of circulating ARAs crucial for diagnosis, there is disagreement on the pathogenicity of specific antibodies, including anti-recoverin. The lack of randomized controlled trials and a universally accepted treatment protocol for AIR further contribute to uncertainties in its management. Despite recent advances, AIR remains an enigmatic condition, necessitating further research to establish standardized diagnostic and therapeutic guidelines.

Keywords: Anti-retinal autoantibodies; Autoimmune diseases; Autoimmune retinopathy; Cancer-associated retinopathy; Malignancies; Masquerades; Melanoma-associated retinopathy.

Fig. 1

A 67-year-old female patient diagnosed with cancer-associated retinopathy showed Optos widefield color photos of the right (a) and left (b) eyes that could be deemed unremarkable. However, bilateral RPE changes, predominantly in the right eye, and a significant ring of hyperautofluorescence were evident in autofluorescence images (c right, d left). The hyperautofluorescent ring corresponds to a defect in the ellipsoid zone, as observed in the OCT scan (Heidelberg Spectralis EDI-OCT), revealing only a small central "island" of ellipsoid zone remaining in both eyes (e right, f left). The 24-2 Humphrey visual field test reveals bilateral nonspecific visual field defects (g). It is noteworthy to mention that electrodiagnostic tests revealed abnormalities in both eyes, with significantly attenuated mixed cone/rod and isolated rod ERG responses. These findings suggest retinal dysfunction, particularly affecting the rods. Moreover, occipital pattern VEPs exhibited severe degradation and broadening, pointing towards additional post-retinal dysfunction. EDI OCT, Enhanced depth imaging optical coherence tomography; ERG, Electroretinogram; RPE, Retinal pigment epithelium; VEPs, Visual evoked potentials

Fig. 1

A 67-year-old female patient diagnosed with cancer-associated retinopathy showed Optos widefield color photos of the right (a) and left (b) eyes that could be deemed unremarkable. However, bilateral RPE changes, predominantly in the right eye, and a significant ring of hyperautofluorescence were evident in autofluorescence images (c right, d left). The hyperautofluorescent ring corresponds to a defect in the ellipsoid zone, as observed in the OCT scan (Heidelberg Spectralis EDI-OCT), revealing only a small central "island" of ellipsoid zone remaining in both eyes (e right, f left). The 24-2 Humphrey visual field test reveals bilateral nonspecific visual field defects (g). It is noteworthy to mention that electrodiagnostic tests revealed abnormalities in both eyes, with significantly attenuated mixed cone/rod and isolated rod ERG responses. These findings suggest retinal dysfunction, particularly affecting the rods. Moreover, occipital pattern VEPs exhibited severe degradation and broadening, pointing towards additional post-retinal dysfunction. EDI OCT, Enhanced depth imaging optical coherence tomography; ERG, Electroretinogram; RPE, Retinal pigment epithelium; VEPs, Visual evoked potentials

Fig. 2

A diagnostic algorithm for autoimmune retinopathies. *The typical presentation is asymmetrically bilateral; however unilateral cases have been reported. **The clinical findings may vary depending on the severity and duration of the disease. In some cases, the examination may appear entirely normal. ***Vitreous biopsy can be crucial in ruling out intraocular lymphoma. ****Especially when malignancy is suspected [The major cancer associations observed included lung, breast, melanoma, hematological (lymphomas, leukemias, and myelomas), gynecological, prostate, and colon]. AIR, autoimmune retinopathy; ARAs, anti-retinal antibodies; CT, computed tomography; EDT, electrodiagnostic tests; MDT, multidisciplinary team; MRI, magnetic resonance imaging; PSA, prostatic specific antigen; PET, positron emission tomography; VF, visual fields

Fig. 3

75-year-old female with history of acute myeloid leukemia with myelodysplastic syndrome-related changes. Approximately 16 months post allogeneic peripheral blood stem cell transplant using Fludarabine, Treosulfan, and Alemtuzumab. Optos widefield fundus color images indicate macular pigmentary changes in the right eye (a) and left eye (b), corresponding to the hyper-autofluorescent ring observed in the fundus autofluorescence images (c right eye, d left eye). Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) demonstrates bilateral thinning of the outer nuclear layer and attenuation of the ellipsoid zone (e right eye, f left eye), along with an epiretinal membrane and intraretinal cystic spaces. g The results of the electrodiagnostic tests. Electrooculogram (EOGs) was normal. The mixed cone/rod flash electroretinogram (ERGs) and isolated cone ERGs were of borderline amplitudes. Rod ERGs were significantly reduced below the lower limits of normal amplitude. Pattern ERGs were of borderline amplitudes. Occipital pattern Visual Evoked Potential (VEPs) were degraded and broadened. These results were consistent with retinal dysfunction involving rods more than cones. Based on the above findings, a diagnosis of cancer-associated retinopathy was established, but the antiretinal autoantibodies were negative

Fig. 3

75-year-old female with history of acute myeloid leukemia with myelodysplastic syndrome-related changes. Approximately 16 months post allogeneic peripheral blood stem cell transplant using Fludarabine, Treosulfan, and Alemtuzumab. Optos widefield fundus color images indicate macular pigmentary changes in the right eye (a) and left eye (b), corresponding to the hyper-autofluorescent ring observed in the fundus autofluorescence images (c right eye, d left eye). Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) demonstrates bilateral thinning of the outer nuclear layer and attenuation of the ellipsoid zone (e right eye, f left eye), along with an epiretinal membrane and intraretinal cystic spaces. g The results of the electrodiagnostic tests. Electrooculogram (EOGs) was normal. The mixed cone/rod flash electroretinogram (ERGs) and isolated cone ERGs were of borderline amplitudes. Rod ERGs were significantly reduced below the lower limits of normal amplitude. Pattern ERGs were of borderline amplitudes. Occipital pattern Visual Evoked Potential (VEPs) were degraded and broadened. These results were consistent with retinal dysfunction involving rods more than cones. Based on the above findings, a diagnosis of cancer-associated retinopathy was established, but the antiretinal autoantibodies were negative