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.5-6 Recoverin 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
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
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.
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: firstname.lastname@example.org.
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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