H. Nida Sen, Robert B. Nussenblatt, in Retina (Fifth Edition), 2013
Autoimmune retinopathies (AIR) represent a group of inflammatory mediated retinopathies with otherwise unexplained vision loss associated with visual field deficits, photoreceptor dysfunction as evidenced on electroretinography (ERG), and the presence of circulating autoantibodies targeted against retinal antigens. Clinically, the fundus often appears normal, but some patients may show retinal vascular attenuation, diffuse retinal atrophy with or without pigmentary changes or waxy disc pallor. There are usually few or no intraocular inflammatory cells.1,2
AIR presumably results from an immunologic attack on the retina by antibodies directed against retinal antigens. The first case of vision loss and photoreceptor degeneration associated with cancer was described by Sawyer et al. in 1976.3 Paraneoplastic retinopathy, as a term, was first used by Klingele and associates in 1984, and has become the more general term used for autoimmune retinopathies associated with systemic malignancy since then.4 Several forms of autoantibody-mediated retinopathy are described: cancer-associated retinopathy (CAR) syndrome, melanoma-associated retinopathy(MAR) syndrome, or autoimmune retinopathy of other types.3,5–11AIR can be categorized in two groups: (i) autoimmune retinopathyassociated with cancer or other malignancies (paraneoplastic retinopathy or paraneoplastic autoimmune retinopathy); (ii) autoimmune retinopathy without any evidence of malignancy (nonparaneoplastic autoimmune retinopathy). Cancer-associated retinopathy and other paraneoplastic retinopathies will be covered in Chapter 134 (Remote effects of cancer on the retina). Autoimmune retinopathy is the preferred term for an acquired, presumed immunologically mediated retinopathy caused by antiretinal autoantibodies in the absence of a malignancy. This chapter will emphasize the latter.
Landon Grange, Monica Dalal, MD, and H. Nida Sen, MD, MHsPUBLISHED 5 JUNE 2013
Autoimmune retinopathy (AIR) is an inflammatory mediated retinopathy characterized by vision loss, scotomas, visual field deficits, photoreceptor dysfunction and the presence of circulating antiretinal autoantibodies (ARAs). The sine qua non of AIR is the presence of circulating ARAs, which target retinal antigens and are believed to be responsible for the photoreceptor damage, though the precise mechanisms are not entirely understood.1-2 AIR can be studied in two groups: paraneoplastic and non-paraneoplastic (npAIR), with paraneoplastic further subdivided into cancer-associated retinopathy and melanoma-associated retinopathy. Paraneoplastic AIR was first described in 1976 and the term “paraneoplastic retinopathy” was coined in 1984.3-4
Evidence suggests that paraneoplastic AIR may be triggered by molecular mimicry between tumor antigens and retinal proteins. Similarly, npAIR may be triggered by molecular mimicry between retinal proteins and presumed viral or bacterial proteins. Multiple retinal proteins have been found to be antigenic; some of these are retina-specific (e.g., recoverin) and others can be found in nonretinal tissues as well (e.g., enolase). While recoverin and enolase are the most widely studied antigens in AIR, associations with autoantibodies against carbonic anhydrase, arrestin, transducin-β, TULP1, neurofilament protein, heat shock protein-70, photoreceptor-cell-specific nuclear receptor, Müller-cell-specific antigen, transient receptor potential cation channel, subfamily M, member 1 (TRPM1) and some yet-unidentified antigens have been reported.5-6Recoverin is most commonly associated with cancer-associated retinopathy but has also been found in npAIR as well.7 These ARAs can target any retinal cell type, including photoreceptor cells, ganglion cells or bipolar cells. However, the presence of ARAs alone is not sufficient for the diagnosis of this ocular disorder, as ARAs can also be found in the serum of healthy controls.8-10
Although it is believed to be rare, the prevalence of AIR is currently unknown. The overlap of clinical features with other degenerative retinal disorders and the lack of standardized diagnostic criteria, clinical and laboratory, may be contributing to the underestimation of its prevalence.
Signs and Symptoms
Patients with npAIR typically present with subacute vision loss, scotomas, photopsias, nyctalopia or photoaversion and dyschromatopsia. Visual acuity can be deceivingly good in the early stages. On examination, the fundus may appear unremarkable. Common clinical features in AIR patients include retinal vascular attenuation, diffuse retinal atrophy, retinal pigment epithelial changes and waxy disc pallor. AIR is usually bilateral but it can be asymmetric. Typically there are minimal or no intraocular inflammatory cells.11-14 Visual field testing shows constriction and central or paracentral scotomas, and ERG can show abnormalities in rods, cones or bipolar cell responses or a combination of these. Although rare, there may be retinal vascular leakage on angiography or cystoid macular edema on optical coherence tomography.11-12 Recent advances in imaging technology are promising. For instance, OCT and fundus autofluorescence are being investigated as tools to aid in the diagnosis of AIR, to understand its pathogenesis and to monitor disease progression.15-16
Figure 1. A non-paraneoplastic automimmune retinopathy patient with 20/20 vision. Top left: Fundus photo demonstrates a poor foveal reflex, with an otherwise normal-appearing fundus. Top right: Fundus autofluorescence reveals a ring of outer hyperautofluorescence. Bottom left: Spectral domain optical coherence tomography of the macula demonstrates loss of IS-OS junction and cystic intraretinal fluid. Bottom right: Humphrey visual field 30-2 with marked peripheral loss out of proportion to the clinical picture.
Among npAIR patients, there is a female predominance (63 to 66 percent), and a history of autoimmune disease is common.11,12,14,17 The typical patient would be an adult female in her fifth to sixth decade with no history of visual problems prior to the onset of photopsias, presence of scotomas, and no family history of retinitis pigmentosa. If these features and the circulating ARAs are present, and if there is no malignancy at presentation or following a thorough investigation, a tentative diagnosis of npAIR can usually be made.
As might be expected for an entity with no consensus in diagnosis, retrospective studies in patients with npAIR showed that clinical features vary considerably. In one study, diffuse retinal atrophy was seen in the majority of patients (83 percent) and pigment deposits in only a small proportion (13 percent), and macular edema was present in approximately half of the cases. In another study pigmentary changes were seen in approximately half of the patients and macular edema was present in only 24 percent.9,11,12,14
Due to the lack of definitive or standardized diagnostic criteria, the diagnosis of npAIR is difficult. Currently, the diagnosis is made based on the presence of clinical manifestations and the demonstration of serum ARAs. ARAs can be detected using Western blot, immunohistochemistry or enzyme-linked immunosorbent assay, and the majority of AIR patients may have more than one antibody.
Diagnosis is made more difficult due to the fact that the mere presence of ARAs is not diagnostic. ARAs can be found in other systemic autoimmune diseases as well as retinal degenerations, uveitis and in normal controls.18-21
Differential diagnosis of npAIR includes paraneoplastic AIR (e.g., cancer- or melanoma-associated retinopathy), white-dot syndrome spectrum disorders (particularly acute zonal occult outer retinopathy), retinal degenerative disorders (such as RP and cone-rod dystrophy), and non-infectious and infectious uveitis syndromes. RP patients can have very similar clinical features to AIR, and approximately 10 to 37 percent of patients with RP may have circulating ARAs, which makes differentiating these two entities with overlapping features very difficult.22-23 It is unclear if the antibodies in RP patients precede the onset of retinopathy or are a consequence of retinal damage. Some uveitis syndromes such as Vogt-Koyanagi Harada syndrome and sympathetic ophthalmia13,24 can also demonstrate ARAs but most of these syndromes have typical fundus findings that help differentiate them from AIR.
Because of significant implications, it is important to differentiate paraneoplastic AIR from npAIR, and an extensive investigation to rule out any malignancy should be undertaken in any patient who presents with signs and symptoms suggestive of AIR. This should include a thorough physical exam and basic laboratory investigations accompanied by an age- and gender-appropriate workup, best performed by the primary-care physician with clear communication between the ophthalmologist and primary medical team so appropriate investigations can be undertaken. Imaging with CT, MRI or PET scan should be guided by the review of systems and the patient’s individual risk factors.
Paraneoplastic retinopathies, similar to npAIR, are characterized by vision loss, photopsias, nyctalopia and scotomas with a more rapid decline. Cancer-associated retinopathy is typically associated with antirecoverin antibody, and most commonly associated with small-cell carcinoma of the lung and ERG shows involvement of cone responses.7,25-26 Melanoma-associated retinopathy occurs most commonly in patients with cutaneous melanoma and is characterized by a negative waveform on standardized full-field ERG due to reduction in b-wave amplitudes. CAR can precede the diagnosis of cancer, whereas MAR typically presents after the diagnosis of melanoma.13
Figure 2. Full-field electroretinogram responses from the same patient as shown earlier (top row) and a control subject (bottom row). Rod responses are absent from the patient. Photopic and 30 Hz tests reveal cone responses that are extremely reduced and delayed.
Acute zonal occult outer retinopathy (AZOOR) can present with symptoms, visual fields and ERG findings similar to AIR. It is typically bilateral but asymmetric and the majority of patients either stabilize or show partial recovery without treatment. Multiple evanescent white dot syndrome (MEWDS), despite having similar symptoms, is a unilateral retinopathy that is characterized by an afferent pupillary defect, optic nerve swelling and spontaneous recovery, and hence is more readily differentiated from AIR. Both AZOOR and MEWDS may show an enlarged blind spot on visual fields. In addition, the majority of eyes affected by AZOOR may show characteristic and striking fundus autofluorescence abnormalities, which has not been observed in AIR.17,27-28 FA and ICG in AIR are often unrevealing, while in MEWDS FA frequently demonstrates early hyperfluorescence with late staining and ICG may show hypofluorescent lesions throughout the posterior pole more numerous than apparent on clinic examination. OCT in AZOOR and MEWDS may demonstrate loss of the retinal photoreceptor inner and outer segments similar to AIR, although in MEWDS it may return to a more normal appearance after the acute episode. Given the overlap and often nonspecific imaging findings, correlation with the clinical history and exam is needed to differentiate AIR.
ARAs have also been found in patients with retinal vasculitis, uveitis patients with VKH, Behçet’s disease and sympathetic ophthalmia. In patients with VKH, antibody reactivity to photoreceptors correlated with disease activity. All these syndromes are characterized by significant intraocular inflammation in addition to their unique fundus findings, making the differentiation rather unproblematic. Other rare cases of retinopathies associated with ARAs include onchocerciasis and ocular toxoplasmosis. Antibodies to retinal pigment epithelium, neural retina or photoreceptor layer have been described in these infectious retinopathies.24,29,30 Typical fundus findings in these
entities are helpful in differentiating them from AIR. In all of the aforementioned diseases, it is unclear if the antibodies preceded the retinal disease or if the immune reactivity is simply a consequence of the retinal degenerative process.
Because of the presumed autoimmune nature of AIR, various forms of immunomodulatory approaches have been tried. However, the ambiguity in diagnosis creates an enormous challenge in the management of AIR. Immunomodulatory therapy can be considered empiric. For paraneoplastic retinopathies, decreasing tumor burden using surgery, chemotherapy or radiation, as applicable, is the best approach. Common approaches to both para- and non-paraneoplastic AIR include systemic or local corticosteroids, intravenous immunoglobulin or plasmapheresis. Table 1. Diagnostic Criteria for Non-paraneoplastic Autoimmune Retinopathy
No evidence of malignancy
No evidence of RP
(+) serum anti-retinal antibodies
ERG abnormality or visual field abnormality
Nyctalopia or Photoaversion
Table 2. Proteins Targeted by Antiretinal Antibodies
Recoverin (23 kD), Alpha-Enolase (46 kD), Tubby-like protein 1 (TULP-1) (65 kD), Heat shock protein 70 (HSC 70) (70 kD), Unknown Proteins (34, 40, 46, 60, 70 kD)
Transducin (35 kD), Arrestin (S-Antigen) (48 kD)
Recoverin, Alpha-Enolase, Arrestin (S-Antigen), Interphotoreceptor binding protein (IRBP) (141 kD), Unknown Proteins (22, 34, 35, 37, 40, 68 kD)
Antibodies against the listed proteins were identified in the serum of patients with AIR or AIR-like clinical findings. CAR, cancer-associated retinopathy; MAR, melanoma-associated retinopathy; npAIR, non-paraneoplastic autoimmune retinopathy. (Modified from Retina, 5th Ed, Ryan et al., Vol. 2, Section 2, Ch. 77)
Additionally for npAIR, antimetabolites such as mycophenolate mofetil, azathioprine and T-cell inhibitors such as cyclosporine have been used.11-12 Less frequently, targeted B-cell therapy, such as anti-CD20 monoclonal antibody (Rituximab), has also been used in the treatment of npAIR.31-32 Therapy is not helpful once widespread retinal degeneration occurs.11,12,22,33
In a cohort of 24 nonparaneoplastic AIR patients who received therapy with various combinations of prednisone, cyclosporine, azathioprine, mycophenolate mofetil, periocular or intravitreal steroid injections, 15 of the 24 showed varying degrees of improvement in visual acuity or visual field, and CME improved in almost half of the patients. Decrease in ARAs following treatment may be seen in some cases,11,24,33 however clinical significance of this finding is unclear.
In summary, there are currently no clear parameters to guide treatment and no clear indicators for prognosis. Whether changes in autoantibody levels correlate with clinical improvement is still unclear. The response to treatment is very variable, with more favorable results achieved in paraneoplastic retinopathy, particularly CAR, with a combination of chemotherapy and immunosuppression. Whether an earlier attempt to treat with immunosuppression in npAIR would be more beneficial is not known. Early treatment attempts are limited by lack of sensitive and specific assays and more definitive clinical criteria. Additional studies are needed to identify the specificity and pathogenicity of ARAs and the appropriate treatment. REVIEW
Mr. Grange is a medical student at the University of California, San Diego, who, as a participant in the National Institutes of Health Medical Research Scholars Program, is conducting clinical research with the Ocular Immunology Laboratory of the National Eye Institute. Dr. Dalal is a uveitis and ocular immunology fellow at the NEI. Dr. Sen is the director of the Uveitis and Ocular Immunology Fellowship Program at the NEI with a joint appointment as associate clinical professor with the Department of Ophthalmology at the George Washington University. Correspondence should be addressed to Dr. Sen at: email@example.com.
This work was supported by the NEI Intramural Research Program and the NIH MRSP, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, the Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at fnih.org.
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