RETINA OPHTHALMIC PEARLS

Diagnosis and Management of Autoimmune Retinopathy

utoimmune retinopathy (AIR) the population or manifesta- 1 comprises a spectrum of tions of other processes such retinal degenerative disorders as uveitis or even age-related A 3 that includes the paraneoplastic (PAIR) cataracts. Moreover, some and nonparaneoplastic (nPAIR) sub- AIR cases have been report- types. Both subtypes are triggered by ed in which no ARAs were molecular mimicry, a phenomenon in found.2 which there are similarities in sequence Diagnosis. Diagnosing between foreign antigens and self- AIR is challenging because antigens such that self-antigens can its signs and symptoms are cause an immune response. However, nonspecific, overlapping in PAIR, this molecular mimicry with many other retinal occurs between tumor antigens and conditions. The differential retinal proteins, whereas in nPAIR, the diagnosis includes hereditary CANCER-ASSOCIATED RETINOPATHY. Note mimicry is between retinal proteins and retinal disease, various ret- severe vascular attenuation without obvious pig- presumed infectious (bacterial or viral) inal degenerative disorders, mentary changes in the fundus of a patient with antigens. Both subtypes of AIR lead to toxic retinopathies, inflam- ovarian carcinoma. retinal degeneration and may result in matory diseases, infectious visual loss.1 causes, and diffuse unilateral subacute with the history, workup, and clinical The PAIR category is further sub­ neuroretinitis.2 picture.2 In addition, all patients who divided into cancer-associated retinop- The diagnosis of AIR is made based present with autoimmune retinopathy athy (CAR) and melanoma-associated on a careful history and clinical exam- without a history of cancer should be retinopathy (MAR); nPAIR, by defini- ination; visual field testing; multimodal thoroughly examined to rule out an tion, is not associated with underlying imaging, including optical coherence occult malignancy.2 malignancy and is more likely to occur tomography (OCT), fundus autofluo- Management. The different AIR in patients with a history of autoim- rescence, and fluorescein angiography; subtypes have similar treatments, with mune disease.2 full-field electroretinography (ffERG); immunosuppression as the mainstay retinal antibody testing; and malignan- of therapy. Follow-up testing, includ- AIR Overview cy evaluation.4 ing assessment of visual acuity, color Pathophysiology. Antiretinal antibod- Although techniques such as vision, visual field, OCT, and ffERG, is ies (ARAs) are believed to be intimately immunohistochemistry (IHC), en- generally done at 3-month intervals. linked to the pathogenesis of AIR. De- zyme-linked immunosorbent assay However, this interval may be adjusted pending on the specific disease subtype, (ELISA), and Western blot are effective depending on treatment type, patient

2016-2017, Section 12. Courtesy of John Heckenlively, MD. of John Heckenlively, Section 12. Courtesy 2016-2017, the antibodies target different retinal in determining the presence of auto- symptoms, and course of the condi- antigens.3 However, the isolated finding antibodies, this information alone is tion.5 of ARAs is not pathognomonic for AIR, not sufficient for the diagnosis of AIR4 as they may occur as normal variants in and must be considered in conjunction Cancer-Associated Retinopathy CAR (Fig. 1) has been observed in con- junction with many different types of BY SAIRA KHANNA, BA, ALEX RINGEISEN, MD, AND MIHAI MITITELU, MD, tumors, including small cell lung carci-

Basic Course, and Clinical Science MPH. EDITED BY SHARON FEKRAT, MD, AND INGRID U. SCOTT, MD, MPH. noma (the most frequent association),

EYENET MAGAZINE • 41 cervical cancer, mixed Müllerian tumor, affected more than men at a 2:1 ratio.1 body) or other ARAs by means of IHC, endo­metrial carcinoma, and uterine It presents with bilateral, slowly pro- ELISA, or Western blot in the setting of sarcoma.1 CAR is most commonly asso- gressive vision loss. Patients will have carcinoma can point toward a diagno- ciated with the anti-recoverin antibody. signs and symptoms related to both rod sis of CAR. The presence of ARAs and Recoverin is a retina-specific calcium- and cone dysfunction, such as glare, the visual symptoms can precede the binding protein in photoreceptors.3 decreased color perception, scotomas, diagnosis—and may prompt an investi- Anti-recoverin antibodies induce an light aversion, nyctalopia, and periph- gation—of the systemic cancer. Because increase in intracellular calcium, leading eral visual field deficits. Optic disc certain tumors typically express specific to retinal apoptosis and, ultimately, pallor may develop later in the disease.1 antibodies, information on the type retinopathy through caspase-dependent Diagnosis. CAR is a clinical diag- of antibody present may be useful in pathways.4 Other autoantibodies that nosis based upon the symptoms and diagnosing the underlying cancer.1 have been associated with CAR include findings described above, most often Treatment. Of the AIR subtypes, antibodies against alpha-enolase, tubby- in the context of a clinically identified CAR typically is the most responsive to like protein 1, heat shock cognate protein carcinoma. ffERG may show abnormal- treatment. Therapy for CAR includes 70, glyceraldehyde 3-phosphate dehy- ities in both a- and b-waves. On OCT, corticosteroids, other immunosup- drogenase, and carbonic anhydrase II.3 cystic spaces may be seen, as well as loss pressive agents, intravenous immu- Patient presentation. CAR may of the ellipsoid layer, external limiting noglobulin (IVIG), and antioxidants.2 present either after or before the diag- membrane, and outer nuclear layer.1 Treatment outcomes are variable and nosis of cancer. CAR generally develops Identification of anti-recoverin anti- depend on the severity of damage to after the age of 45, and women are bodies (the most prevalent autoanti- the photoreceptors. Triple therapy with

Table 1: Characteristic Features of AIR Subtypes CAR MAR nPAIR Presentation • Associated with malignancy • Associated with melanoma • History of autoimmune (may present before or after • May present years after disease cancer diagnosis) diagnosis • Younger patients • 2:1 ratio female:male • More prevalent in men • More prevalent in women • > 45 years old • Vitelliform retinopathy (rare) • Bilateral, subacute vision loss • Bilateral, slowly progressive • Diffuse retinal atrophy vision loss • Rod and cone dysfunction Associated • Recoverin • Transducin • Recoverin antibodies • Alpha-enolase • Arrestin • Alpha-enolase • Tubby-like protein 1 • Bestrophin • Carbonic anhydrase II • Heat shock cognate protein 70 • Anti-aldolase A and C • Transducin-alpha • Glyceraldehyde 3-phosphate • Rhodopsin • Müller cell–associated antigen dehydrogenase • Carbonic anhydrase II • Carbonic anhydrase II • Myelin basic protein • Interphotoreceptor retinoid-binding protein Diagnostic • ffERG: a- and b-wave abnor- • ffERG: reduced b-wave, • ffERG: diffuse depression studies malities normal dark-adapted a-wave • OCT: thinning of outer layer, • OCT: loss of the ellipsoid layer, • IHC: staining of ARAs in irregular ellipsoid layer external limiting membrane, bipolar layer and outer nuclear layer; cystic spaces Treatment • Steroids • Plasmapheresis • Local/systemic steroids • IVIG • IVIG • Antimetabolites • Immunosuppressive agents • Radiation therapy/surgery • Antioxidants to reduce tumor burden SOURCE: Adapted from Grewal DS et al. Retina. 2014;34(5):827-845. Abbreviations: ARAs, antiretinal antibodies; ffERG, full- field electroretinogram; IHC, immunohistochemistry; IVIG, intravenous immunoglobulin; OCT, optical coherence tomography.

42 • SEPTEMBER 2017 the bipolar layer can be di- ARAs is also critical; many patients may 2A agnostic. ERG abnormalities present with multiple antibodies, which are present, with the charac- aid in the diagnosis of nPAIR. Diffuse teristic ffERG pattern being depression on ffERG and thinning of a reduced b-wave and a the outer nuclear layer with irregularity normal dark-adapted a-wave of the ellipsoid layer may be seen on due to the dysfunction of the OCT. 2 Finally, an absence of retinal de- “on” bipolar cells.3 generation, fundus lesions, or intraocu- 2B Treatment. Most of the lar inflammation further points toward treatment modalities for the diagnosis of nPAIR.2 MAR are not supported Treatment. Local or systemic ster­ by evidence of definitive oids and antimetabolites are first-line improvement.5 Plasmaphe­ treatments in the management of resis is intended to remove nPAIR. Monoclonal antibodies (such as SD-OCT IN AZOOR. (2A) Parafoveal outer retinal the antibodies and cytokines rit­uxim­ab) or IVIG can be considered loss with central sparing (“flying saucer sign”). involved in the pathogenesis as second-line therapies. However, ther- (2B; different patient) Diffuse loss of the retinal from the blood, but patients apy has not been shown to be helpful photoreceptor inner and outer segments. in a trial that investigated if retinal degeneration has already plasmapheresis also received occurred.2 an initial dosage of 100 mg/day cyclo- other treatments; thus, it is difficult to sporine, 100 mg/day azathioprine, and determine its effect in isolation.5 IVIG Conclusion 20 to 40 mg/day prednisone has been may be used at a dose of 1 g/kg twice The diagnosis of AIR can be difficult reported to be associated with improve- daily to shorten the half-life of the anti- and requires a thorough workup. ment in visual acuity or an increased bodies.5 Radiation therapy and surgery Although the presence of ARAs can visual field.1 may also be useful to reduce tumor size be helpful in supporting or prompting and, thus, the load of antibodies. the workup of malignancy, a positive Melanoma-Associated test for ARAs is not independently Retinopathy nPAIR diagnostic. Once the clinician has made Typically, MAR is observed in patients Nonparaneoplastic autoimmune reti- the diagnosis, treatment primarily in whom melanoma has already been nopathy is the most common subtype involves immunosuppression. Mea- diagnosed and has metastasized. MAR of AIR. There are various diseases on surement of ARA titers has not been is most commonly associated with mel- the spectrum of nPAIR, such as acute demonstrated to be useful in clinical anomas of cutaneous origin or uveal zonal occult outer retinopathy (AZOOR), practice; improvement is judged based melanoma.4 MAR is more common an inflammatory disorder (Fig. 2). Re- on serial visual field and ERG assess- in men than in women.1 It has been coverin, Müller cell–associated antigen, ments. Further research is warranted associated with autoantibodies against alpha-enolase, CAII, inner retinal layer, to guide treatment and to gain a better bipolar cells, bestrophin, enolase, my- and rod transducin are all ARAs that understanding of prognosis associated elin basic protein, aldolase, rhodopsin, have been associated with nPAIR.3 with each of the AIR subtypes. and arrestin, among others.4 Patient presentation. The clinical Patient presentation. Patients with picture of nPAIR is similar to that of 1 Grewal DS et al. Retina. 2014;34(5):827-845. MAR may present with visual symp- CAR, although nPAIR patients tend to 2 Grange L et al. Am J Ophthalmol. 2014;157(2): toms many years after the diagnosis of be younger and have a family history 266-272. melanoma. They commonly experience of autoimmune disease.5 Typically, 3 ten Berge JC et al. PLoS One. 2016;11(12): photopsia and peripheral field loss; nPAIR presents bilaterally. Symptoms e0167909. doi:10.1371/journal.pone.0167909. they may also complain of nyctalopia.4 include subacute vision loss, photop- 4 Braithwaite T et al. Ophthalmologica. 2012; Visual symptoms progress over time. sias, scotomas, and/or decreased color 228(3):131-142. Fundus examination may be un- vision. Fundus examination may be 5 Fox AR et al. Am J Ophthalmol. 2016;168:183-190. remarkable or may reveal optic nerve unremarkable or may demonstrate pallor, retinal pigment epithelium optic disc pallor. Visual acuity is usually Ms. Khanna is a medical student at the University abnormalities, and vessel changes. preserved early in the course of the dis- of Wisconsin School of Medicine and Public Some patients with melanoma have a ease process. Most patients have diffuse Health, in Madison. Dr. Ringeisen is a retina rare type of retinopathy that presents retinal atrophy.2 fellow at VitreoRetinal Surgery PA, in Minne- with vitelliform lesions and serous Diagnosis. To make the diagnosis apolis. Dr. Mititelu is an assistant professor, in retinal detachment.1 of nPAIR, the clinician must rule out the Department of Ophthalmology and Visual Diagnosis. As with CAR, diagnosis malignancy and retinitis pigmentosa Sciences, University of Wisconsin School of depends largely on the clinical picture. (RP), as their clinical presentations Medicine and Public Health. Relevant financial 1

Mihai Mititelu, MD Mihai Mititelu, The indirect IHC staining of ARAs in are similar to nPAIR. The presence of disclosures: None.

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