Non-Paraneoplastic Autoimmune Retinopathy
Autoimmune retinopathies are a rare set of diseases that often lead to retinal degeneration. The two main types of autoimmune retinopathy are paraneoplastic retinopathy, which is associated with an underlying malignancy, and non-paraneoplastic autoimmune retinopathy (npAIR) which arises independently of cancer.
npAIR is characterized by bilateral, rapidly progressive vision loss, visual field defects and photoreceptor dysfunction . It is caused by cross-reactivity of serum autoantibodies to the retina and retinal photoreceptor antigens. 
Diagnosis of npAIR is one of exclusion, and is often difficult and delayed given a wide variety of clinical findings and symptoms associated with the disease. Variable disease expression is thought to be due to the different permutations of autoantibodies in patients. Given this delay in diagnosis and treatment initiation, the visual prognosis in npAIR is often poor.
The first case report of paraneoplastic AIR (specifically, cancer-associated retinopathy) was published in 1976 by Sawyer et al. but the term “paraneoplastic retinopathy” was used to describe malignancy-associated AIRs by Klingele et al. later in 1984. In 1997, the first case of npAIR was described and its clinical similarity to cancer associate retinopathy (CAR) was noted. 
The prevalence of npAIR is unknown. The disease is more prevalent in females (63–66%) and typically occurs between the fifth and sixth decade of life.  npAIR is associated with autoimmune disease, most commonly hypothyroidism.
Although the mechanism of the disease is not yet fully understood, it is thought to be caused by circulating autoantibodies against the retina causing destruction of photoreceptors and widespread degenerative changes in the retina and retinal pigment epithelium (RPE) . Given that the RPE is a major component of the blood-retinal barrier and contributes to immune regulation, it is often the target of the degenerative progress . There have been a number of anti-retinal antibodies found to be associated with npAIR with the most significant being anti-recoverin, anti-carbonic anhydrase II, anti-α-enolase, and anti-rod transducin-α antibodies .
A bacterial or viral infection may trigger the cross reaction of retinal protein and bacterial/viral protein . Retinal damage of photoreceptors, ganglion cells, and bipolar cells occurs through caspases and intracellular calcium influx apoptotic mechanisms .
The diagnosis of npAIR is challenging given its rarity, various clinical manifestations, and non-specific findings. Typically patients present with vague and subtle symptoms that are often bilateral and asymmetric including photopsias, dyschromatopsia and nyctalopia. Spontaneous improvement of these symptoms are possible Fundus exam may appear benign, however, some non-specific findings may be present, such as pigmentary changes, retinal vascular attenuation, optic disc pallor, macular edema, retinal atrophy, or retinal pigmentary depositionTypically there is minimal to no intraocular inflammation.
Associated Systemic Diseases
It is common for patients who have npAIR to have associated systemic pathologies, particularly related to autoimmune dysfunction. In a series, the most commonly associated finding was hypothyroidism, however, there are other associations described, such as rheumatoid arthritis, multiple sclerosis, autoimmune hepatitis, Hashimoto´s Thyroiditis, myasthenia gravis and graves disease. Given the circumstances, it is important for the clinician to bear in mind this fact in its diagnostic work-up, given the rarity of npAIR, and to exclude neoplasm.
Fundus autofluorescence (FAF) can may indicate hyperautofluorescence around the macula and hypoautofluorescence around the optic nerve, hyperautofluorescent ring around the macula and hypoautofluorescent patches in the posterior pole 
In a series, scotoma was described in 61% of cases.. Peripheral constriction, enlarged blind spot and other types of visual field defects (superior, paracentral) were described.
There are no pathognomonic features of AIR. Dysfunction may occur in either cones and/or rods but typically patients develop rod dysfunction as the disease progresses over time. The ERG may completely extinguish. The rate of ERG dysfunction tends to be more rapid in AIR than in retinal degenerative diseases.
Numerous ARAs have been identified including antibodies against recoverin, α-enolase, rod transducin-α, Carbonic Anhydrase II, the inner retinal layer, arrestin, interphotoreceptor-binding protein) Not all patients with npAIR have detectable antibodies, and retinal autoantibodies can be elevated in other diseases, such as cancer . Immunohistochemistry, Western blot, ELISA, and multiplex assays can all be used in the detection of these antibodies. In addition, anti-retinal antibodies have been detected in other retinopathies (Age-related Macular Degeneration, RP, making this a less specific test.
Optical Coherence Tomography
Multimodal imaging, including spectral domain optical coherence tomography (SD-OCT) can often times reveal non-specific changes, including attenuation of both the Outer Nuclear Layer and the Ellipsoid Zone, Decreased Macular Thickness and Cystoid Macular Edema.
Differential diagnosis of npAIR includes acute zonal occult outer retinopathy (AZOOR), idiopathic big blind spot syndrome, retinal degenerative disorders such as retinitis pigmentosa (RP) and hereditary cone dystrophies, non-infectious and infectious uveitis, and vitamin A deficiency. 
Treatment of npAIR is primarily aimed at thwarting the immune response caused by the anti-retinal antibodies and furthering disease progression.
Short-term treatment with corticosteroids include intravitreal Triamcinolone, subtenon injection of depomedrol, or intravenous immunoglobulin (IVIG) infusions. If corticosteroid treatment alone is not enough to stop progression, or if the side effects of long term steroid use become unmanageable, immunosuppressive agents such as Mycophenolate, Azathioprine, Cyclosporine and Infliximab should be considered .
In addition, supplementation with antioxidant vitamins such as β-carotene, vitamin C and vitamin E may have some effect against progressive retinal degeneration.
It is crucial to differentiate the paraneoplastic AIR from the non-paraneoplastic. A thorough investigation to rule out malignancy should be undertaken in patients who present with signs and symptoms suggestive of autoimmune retinopathy with all age and gender appropriate testing including mammography, abdominal, pelvic, and chest CT, brain MRI, and colonoscopy .
Monitoring of Disease
Consider monitoring of disease every three to six months with a full ophthalmological evaluation and ERG.
- Canamary AM, Takahashi WY, Sallum JMF. Autoimmune retino- pathy: A Review. Int J Retin Vitr. 2018;4(1):1. doi:10.1186/s40942- 017-0104-9. Cited in PubMed; PMID: 29340169.
- Chan, J.W., Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol, 2003. 48(1): p. 12-38.
- Heckenlively JR, Ferreyra HA. Autoimmune retinopathy: A review and summary. Semin Immunopathol. 2008;30 (2):127–34. doi:10.1007/s00281-008-0114-7. Cited in PubMed; PMID: 18408929
- Khanna, Saira; Martins, Aline; Oakey, Zackery; Mititelu, Mihai (2019). Non-paraneoplastic autoimmune retinopathy: multimodal testing characteristics of 13 cases. Journal of Ophthalmic Inflammation and Infection, 9(1), 6–.doi:10.1186/s12348-019-0171-1
- Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol. 1976;81(5):606–13. doi:10.1016/0002- 9394(76)90125-2. Cited in PubMed; PMID: 179323.
- Chan CC, Palestine AG, Nussenblatt RB, Roberge FGBD. Anti- retinal auto-antibodies in vogt-koyanagi-harada syndrome, beh- cet’s disease and sympathetic ophthalmia. Ophthalmology. 1985;92(8):1025–28. doi:10.1016/S0161-6420(85)33911-8. Cited in PubMed; PMID: 3900848.
- Mizener JB, Kimura AE, Adamus G, Thirkill CE, Goeken JA, Kardon RH. Autoimmune retinopathy in the absence of cancer. Am J Ophthalmol. 1997;123(5):607–18. doi:10.1016/S0002- 9394(14)71073-6. Cited in PubMed; PMID: 9152066
- Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009;127(4):390–97. doi:10.1001/archophthal- mol.2009.24. Cited in PubMed; PMID: 19365013
- Choi, E.Y., et al., Non-Paraneoplastic Autoimmune Retinopathy: The First Case Report in Korea. Yonsei Med J, 2016. 57(2): p. 527-31.
- Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol. 2004;4:1–9. doi:10.1186/1471-2415-4-5.
- Gass, J.D., A. Agarwal, and I.U. Scott, Acute zonal occult outer retinopathy: a long-term follow-up study. Am J Ophthalmol, 2002. 134(3): p. 329-39.
- Detrick, B. and J.J. Hooks, Immune regulation in the retina. Immunol Res, 2010. 47(1-3): p. 153-61.
- Minaker, Samuel A.; Kohly, Radha P. (2020). Asymmetric presentation and fundus autofluorescence findings in non-paraneoplastic autoimmune retinopathy. Canadian Journal of Ophthalmology, (), S0008418220306736–.doi:10.1016/j.jcjo.2020.06.015
- Boudreault K, Justus S, Sengillo JD, Schuerch K, Lee W, Cabral T, Tsang SH. Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy. Orphanet J Rare Dis. 2017;12(1):1–15. doi:10.1186/ s13023-017-0680-7. Cited in PubMed; PMID: 28709429
- Comlekoglu DU, Thompson IA, Sen HN. Autoimmune retinopathy. Curr Opin Ophthalmol. 2013;24(6):598–605. doi:10.1097/ICU.0b013e3283654e1e. Cited in PubMed; PMID: 24100366
- Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal antibodies: a review. Retina. 2014;34(5):827–45. doi:10.1097/IAE.0000000000000119. Cited in PubMed; PMID: 24646664
- Takiuti, J.T., et al., Non-paraneoplastic related retinopathy: clinical challenges and review. Ophthalmic Genet, 2019. 40(4): p. 293-297.
- Patel N, Ohbayashi M, Nugent AK, Ramchand K, Toda M, Chau KY, Bunce C, Webster A, Bird AC, Ono SJ, et al. Circulating anti-retinal antibodies as immune markers in age-related macular degeneration. Immunology. 2005;115(3):422–30. doi:10.1111/ j.1365-2567.2005.02173.x. Cited in PubMed; PMID:15946260
- Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N. Autoimmune retinopathy: patients with antirecoverin immunor- eactivity and panretinal degeneration. Arch Ophthalmol. 2000;118 (11):1525–33. doi:10.1001/archopht.118.11.1525. Cited in PubMed; PMID: 11074809)
- Grange L, Dalal M, Nussemblat RBSN. Autoimmune retinopathy. Am J Ophthalmol. 2014;157(2):266–72. doi:10.1016/j. ajo.2013.09.019. Cited in PubMed; PMID: 24315290.
- Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic reti- nopathy and optic neuropathy: evaluation and management. Surv Ophthalmol. 2013;58(5):430–58. doi:10.1016/j.sur- vophthal.2012.09.001. Cited in PubMed; PMID: 23969019.
- Dot, C., J. Guigay, and G. Adamus, Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung. Am J Ophthalmol, 2005. 139(4): p. 746-7.
- Dutta Majumder, P., et al., An update on autoimmune retinopathy. Indian J Ophthalmol, 2020. 68(9): p. 1829-1837.