Non-Paraneoplastic Autoimmune Retinopathy

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Introduction:

Autoimmune retinopathy (AIR) is a rare entity, caused by serum autoantibodies that are cross-reactive with retinal and retinal-like antigens, also known as anti-retinal antibodies (ARAs). AIR consists of a spectrum of diseases that share in common clinical findings, associations, and symptoms that in the end culminate in retinal degeneration. Two forms of AIR are described: Paraneoplastic AIR and Non-Paraneoplastic AIR (npAIR). There are also two subtypes of Paraneoplastic AIR: cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). NpAIR does not have any associated underlying neoplasm (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 ).

Autoimmune retinopathy (AIR) exists on a spectrum with autoimmune-related retinopathy and optic neuropathy (AARON) where AARON has the retinal features of AIR with optic neuropathy. Both of AIR and AARON can mimic retinal degenerations such as retinitis pigmentosa (RP); however, asymmetry can be an important sign in differentiating AARON from retinal degenerations. When AIR presents as a symmetric bilateral retinopathy, the differentiation from RP can be difficult. In most reports of AIR, a bilateral hyperautofluorescent ring is seen. This hyperautofluorescent ring is common in retinal degenerative diseases and is referred to as the Robson-Holder ring in RP. NpAIR is classically thought of as a bilateral condition, however, it may also present unilaterally (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 ).

There are still no diagnostic criteria standardized for npAIR, however, no evidence of malignancy, positive serum (anti-retinal antibodies) ARAs, absence of fundus lesions or degenerative retinal disease that can explain the ERG or Visual Field loss, and absence of Intraocular Inflammation were proposed (Sen HN, Grange L, Akanda M, et al. Autoimmune retinopathy: current concepts and practices (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2018;115:T8.). Supportive criteria were also included, such as photopsias, scotomas, dyschromatopsia, nyctalopia, systemic autoimmune disease, and acute or subacute vision loss. NpAIR is a diagnosis of exclusion that requires testing to rule out other causes of vision loss. It can mimic some other conditions such as paraneoplastic AIR and RP (Minaker outra vez).

Fundus examination can demonstrate nonspecific signs of retinal degeneration such as waxy disc pallor, attenuated vasculature and pigmentary changes. For this reason, many patients are initially diagnosed with nonspecific retinal degenerations. Although both RP and npAIR are more likely to have cystoid macular edema than acute zonal occult outer retinopathy (AZOOR), intraretinal bone spicule migration is rare in both npAIR and AZOOR, which can help differentiate between these conditions. Finally, AZOOR is defined by unique features on multimodal imaging such as zonal degeneration of the outer retina and retinal pigment epithelium (RPE) on both fundus autofluoresence (FAF) and optical coherence tomography (OCT) (Minaker outra vez)


Historical Background

The first case report of paraneoplastic AIR (specifically, cancer-associated retinopathy) was published in 1976 by Sawyer et al. (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.)., but the term “paraneoplastic retinopathy” was coined to describe malignancy-associated AIRs by Klingele et al. later in 1984 (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.). In 1997, the first case of npAIR was described and its clinical similarity to CAR was noted (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)


Epidemiology

The prevalence of npAIR is unknown, and in a series of patients, the mean age of presentation was 55,9 years (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). npAIR is more prevalent in females (63–66%) and is associated with a family history of autoimmune disease (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.)


Clinical findings:

The diagnosis of npAIR is a challenging one, given it´s rarity, various clinical manifestations, and non-specifity of it´s findings. It is a diagnosis of exclusion, and there are various symptoms which patients may present, none of them specific. Typically, they refer progressive Best Corrected Visual Acuity (BCVA) deterioration. Other symptoms include Photopsia, Dyschromatopsia and Nyctalopia. Spontaneous improvement of this symptoms, even without treatment, is not rare(Khanna outra vez)

Fundus observation can be completely innocent, however, some non-specific signs may be present, such as pigmentary changes, retinal vascular attenuation and optic disc pallor. For this reason, many times npAIR may be misdiagnosed, for example, as RP, or other retinal degenerations (1- 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.; 2- 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.):)


Associated Systemic Diseases:

It is common for patients who have npAIR to have systemic pathologies associated, particularly autoimmune. In a series, the most commonly associated finding was Hypothyroidism (Khana outra vez). However, there are other associations described, such as Rheumatoid arthritis, Multiple Sclerosis, Autoimmune Hepatitis, Hashimoto´sThyroiditis, Myastenia Gravis and Graves Disease. Given the circumstances, it is important for the clinician to bear in mind this fact in it´s diagnostic work-up, given the rarity of npAIR, and to exclud neoplasm.


Fundus autofluorescence:

- Fundus Autofluorescent (FAF) can document various alterations, including hyperautofluorescence around the macula and hypoautofluorescence around the optic nerve, hyperautofluorescent ring around the macula and hypoautofluorescent patches in the posterior pole (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

Visual Fields:

In a series, a scotoma was described in the majority (61% of cases). Peripheral constriction, enlarged blind spot and other types (superior, paracentral) were described.


Electrophysiologic Testing:

There are no pathognomonic features of AIR. Generally, most patients present with greater rod than cone dysfunction, and as the disease progresses over time, the ERG recording becomes extin- guished in most patients. The deterioration of visual outcomes and ERG results tend to be more rapid in AIR than in retinal degenerative diseases. (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.


Serology:

- 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) (1- 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. 2- 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, and there are various techniques available to investigate their presence, such as Western Blotting, ELISA, and Imunohistochemistry. Npair is an exclusion diagnosis, therefore, serum antibodies should not be used in isolation in its diagnosis. Also, Anti-retinal antibodies have been detected in other pathologies (Age-related Macular Degeneration, Retinitis Pigmentosa) (1- 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. 2- 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)

Optical Coherence Tomography (1- 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. 2- 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.):

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


Management:

For a long time, observation has maintained itself as the mainstay of management of npAIR, and there still isn't available a definitive protocol on how to treat npAIR. However, given it´s systemic associations, particularly it´s autoimmune nature, immunomodulatory strategies have been employed in the management of npAIR, but this still isn't linear (1- Fox AR, Gordon LK, Heckenlively JR et al (2016) Consensus on the diagnosis and management of nonparaneoplastic autoimmune retinopathy using a modified Delphi approach. Am J Ophthalmol 168:183–190. https://doi.org/ 10.1016/j.ajo.2016.05.013; 2- Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: A clinically and immunologi- cally distinctive disease. Am J Ophthalmol. 1998;126(2):230–37. doi:10.1016/S0002-9394(98)00149-4. Cited in PubMed; PMID: 9727517.). There are various immunomodulatory options, including mycophenolate mofetil, azathioprine, intravenous immunoglobulin, cyclosporine, and infliximab. However, it does not appear they have a significant impact on visual acuity. (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.)


Conclusion:

NpAIR is a complex pathology, as it has a lot of clinical ambiguity (non-specific symptoms, non-specific finding, some systemic associations, etc). Therefore, it is important for clinicians to stay alert for it, given it´s rarity and possible systemic associations, some of which may be treatable. It is a diagnosis of exclusion, so exhaustive testing may be needed to rule it out, and it is easily misdiagnosed as other entities, as it has some clinical features which are similar to other pathologies, such as RP and other retinal degenerations. Even though immunossupressive therapy does not have a major impact on visual outcomes, they are the best alternative at the moment, and of course further studies are needed to clarify their role in this hard to diagnose and hard to get pathology.

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