Autoimmune retinopathy and antiretinal antibodies: a review.

Errors appear in the published version of this article. The corrected and republished article appears on page 1023 of this issue.

Review AUTOIMMUNE RETINOPATHY AND ANTIRETINAL ANTIBODIES: A REVIEW DILRAJ S. GREWAL, MD,* GERALD A. FISHMAN, MD,† LEE M. JAMPOL, MD* Purpose: To review the current state for diagnosis and management of autoimmune retinopathy. Methods: A review of the literature was performed, encompassing autoimmune retinopathy including paraneoplastic retinopathy (cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation) and non-paraneoplastic autoimmune retinopathy. Based on this review, current principles and techniques for diagnosis and the treatments reported for autoimmune retinopathy are discussed with the aim to clarify some of the confusion that exists regarding this complex entity. Results: Autoimmune retinopathy encompasses a spectrum of retinal degeneration phenotypes. The clinical features, fundus characteristics, and electroretinogram findings for paraneoplastic and non-paraneoplastic retinopathy are reviewed. The different antiretinal antibodies reported in these entities are described. The diagnostic approaches for detecting these antiretinal antibodies and their limitations are covered. The treatments reported for autoimmune retinopathy and their outcomes are reviewed. Conclusion: Among the myriad of antiretinal antibodies reported, challenges persist in determining which antibodies are pathogenic and which are benign and what factors cause antiretinal antibodies to become pathologic. There also remain difficulties in the detection and accurate measurement of antiretinal antibodies, and the response to therapeutic intervention in autoimmune retinopathy is variable. RETINA 34:827–845, 2014

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of AIRs that share similar clinical and immunologic features but are not associated with an underlying malignancy, classified as presumed non-paraneoplastic autoimmune retinopathy (npAIR). Diagnosis of AIR involves detection of antiretinal antibodies with concurrent clinical and electrophysiological evidence of retinal degeneration. Although the clinical findings of AIR are heterogeneous and quite diverse, it consists of overlapping clinical and immunologic phenotypes that include rapidly progressive, bilateral, and painless visual deterioration. The onset has been described as acute or subacute typically weeks to months, although slower onset has been documented.1 Electroretinographic abnormalities have been observed using both the full-field and multifocal electroretinogram (ERG) with reports of abnormal rod, cone, and in selective instances, bipolar cell responses.1 Multifocal electroretinogram (mfERG) and full-field ERG can be useful in that some presentations

utoimmune retinopathy (AIR) is an immunologic process that involves retinal antigens being aberrantly recognized as autoantigens, leading to retinal degeneration. It encompasses a spectrum of infrequently encountered autoimmune diseases, including cancerassociated retinopathy (CAR), melanoma-associated retinopathy (MAR), possibly bilateral diffuse uveal melanocytic proliferation (BDUMP), and a larger group

From the *Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and †Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, the Pangere Center for Hereditary Retinal Diseases, Chicago, Illinois. Supported in part by an unrestricted grant to the Northwestern Department of Ophthalmology from Research to Prevent Blindness (RPB, NY). None of the authors have any conflicting interests to disclose. Reprint requests: Lee M. Jampol, MD, Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611; e-mail: [email protected]

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of AIR, particularly those associated with anti-enolase and MAR, which have distinct changes on mfERG and full-field ERG, respectively. Patients with anti-enolase may have normal or near-normal full-field ERGs but very abnormal mfERGs. This presentation is usually associated with loss of contrast sensitivity and decreased visual acuity centrally. The mfERG and ERG are often valuable in AIR because they are often more abnormal than might be expected from the optical coherence tomography (OCT), which may be normal or demonstrate only mild findings at most in early disease. This is believed to be particularly the case where autoantibodies reduce retinal function but do not produce cell death at all early and thus allow for retention of structure for a prolonged time. On examination, the fundus may appear normal or there can be evidence of retinal degeneration such as attenuated retinal vessels, optic disk pallor, and retinal pigment epithelium (RPE) mottling or atrophic degenerative changes. A possible alternative presentation recently described for patients with metastatic melanoma is vitelliform or serous retinal detachments.2 There are no population-based epidemiological data on MAR, CAR, BDUMP, or npAIR, and these diseases are assumed to be rare, or at the least infrequently encountered, although other paraneoplastic syndromes are thought to occur in 10% to 15% of cancer patients.3 This literature review on AIR discusses CAR, MAR, BDUMP, and npAIR and reviews the current evidence and utility of antiretinal antibodies and the reported treatment protocols in AIR. Diagnostic Approaches for Antiretinal Antibodies Various laboratory techniques, including immunohistochemistry (IHC), Western blot, and enzyme-linked immunosorbent assay, have been described for the detection of circulating antiretinal antibodies in patient sera. Immunohistochemistry The essence of indirect IHC is to expose normal donor retina to the putative AIR patient serum, and then to wash, counterstain with fluorescent-tagged anti-IgG, followed by the examination of the donor retina under confocal laser microscopy. The intensity of staining observed on IHC sections may serve as a surrogate for relative titers of antiretinal antibodies when multiple serum samples are compared. It is important that IHC should be standardized before testing for antiretinal antibodies. The binding of antibodies to tissue sections is influenced by the type

of the fixative agent and whether the section is fresh, frozen, or fixed before incubation. It is also important to minimize the nonspecific binding of the secondary (anti-human immunoglobulin) antibody to the retinal proteins and normal human immunoglobulins in the tissue specimen. Because normal human serum can bind nonspecifically to normal retina sections, controls consisting of serum from healthy individuals are essential. Other limitations of IHC include its inability to distinguish reactions to specific proteins and variations in staining intensity due to the tissue processing and the fixation method used. Western Blot Although there are several variations in technique, most laboratories use normal donor retina, homogenize and dilute the sample, load it onto gels, after which they are separated into discrete bands based on their molecular weight using electrophoresis. These separated proteins are then transferred to a nitrocellulose membrane and incubated with varying dilutions of patient sera and counterstained for IgG. It is imperative that Western blots be performed using a control that consists of an antibody known to react with a specific protein in the protein sample. The intensity of the detected protein bands is then compared with the control. The secondary (anti-human immunoglobulin) antibody can occasionally bind to the antigen of interest or even to normal immunoglobulin present in retinal or purified protein samples thereby giving a false-positive result. This falsepositive binding can result in the detection of protein bands of molecular weight 25 kDa and 50 kDa, similar to recoverin (23 kDa) and a-enolase (46 kDa),4 which illustrates the importance of having a negative control consisting of only the secondary antibody while performing Western blots. Because more than one retinal protein may have the same molecular weight, identification of autoantibodies against certain molecular weights on Western blots of the whole retina extract need to be confirmed for recognizing a particular retinal protein. For example, if a patient’s sera tests positive for an autoantibody against a 23-kDa protein in whole retinal extract, the patient’s sera should be tested for pure recoverin in a confirmatory Western blot examination. One of the limitations in being able to assess the accuracy of reports of antiretinal antibodies detected using Western blots is the lack of use of positive loading controls, as well as negative controls in the available literature, which makes it difficult to interpret the presence of the observed bands. Interpretation of

AUTOIMMUNE RETINOPATHY: A REVIEW GREWAL ET AL

Western blots is also influenced by multiple factors including the adequacy of protein transfer to the nitrocellulose membrane, exposure time to primary and secondary antibodies, the length of colorimetric development, and the exposure time of the photographic film. Enzyme-Linked Immunosorbent Assay This is a highly sensitive technique for the measurement of serum proteins. Small wells are coated with a specific retinal protein, various dilutions of patient sera are added and allowed to bind to the protein, after which the binding is detected using a secondary (anti-human immunoglobulin) antibody. A colorimetric reaction measured using a spectrophotometer is used to measure the amount of secondary antibody binding. There have been several reports for the use of enzyme-linked immunosorbent assay detection of anti-recoverin and anti-enolase antibodies. However, similar to reports with Western blots, most of these reports have not incorporated standard curves, positive controls, the use of replicates, or the use of serum from unaffected individuals.5–7 It is important to have positive controls to prove that the assay is measuring what is intended. Standard curves and positive controls use an antibody with known specificity against the retinal protein instead of the patient’s sera. The use of replicates allows for determination of the standard deviation associated with a particular antigen–antibody reaction, because well-to-well variation has been reported with enzyme-linked immunosorbent assay.4 Replicate wells are therefore essential to show whether the difference between two reactions is real and not due to inherent well-to-well variation. These limitations need to be kept in mind while interpreting current reports in the literature. A brief description of CAR, MAR, BDUMP, and npAIR along with their associated antiretinal antibodies follows. Paraneoplastic Retinopathy Cancer-Associated Retinopathy Introduction. Cancer-associated retinopathy was initially described in 1976 as photoreceptor degeneration, representing a remote effect of malignancy.8 Using Western blot analysis, the serum from CAR patients was shown to react with recoverin, a 23-kDa calcium-binding protein found in the photoreceptors.9 Cancer-associated retinopathy has been described in the setting of many tumors, including small-cell

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lung carcinoma,10 cervical cancer,11 mixed Müllerian tumor,12 endometrial carcinoma,13 and uterine sarcoma.14 Although anti-recoverin retinopathy has been reported in the absence of cancer,15 anti-recoverin antibodies with carcinoma is diagnostic for CAR.16 Cancer-associated retinopathy typically presents with bilateral, often asymmetric, progressive vision loss over days to years.1 It affects both cones and rods.17 Symptoms of cone dysfunction include photoaversion, prolonged glare after light exposure, reduced visual acuity, decreased color perception, and central scotomas. Rod dysfunction presents as nyctalopia, prolonged dark adaptation, midperipheral (ring) scotomas, and more extensive peripheral visual field deficits.18 There may be abnormalities of both the a- and b-waves on ERG and in some instances, selective involvement of the b-wave.19 The visual symptoms are typically worse than the clinical signs, and the fundus initially appears normal. There may be arteriolar attenuation, arteriolar sheathing, and periphlebitis later in some cases. Optic disk pallor is often not seen in early disease and is much more likely in established disease. The disks however rarely become as pale as those that result from optic nerve compression or primary atrophy. Cancer-associated retinopathy patients very seldom show cellular debris in the anterior vitreous on slit-lamp examination, although it is possible that there is an element of low-grade inflammation in some patients at certain stages. Adults with unexplained visual loss, with rod or cone dysfunction, or with a known or suspected malignancy in the absence of other neurologic symptoms merit a thorough investigation for CAR. On histopathological study, Sawyer et al8 demonstrated diffuse photoreceptor degeneration of both cones and rods, with scattered melanophages in the outer retina but sparing of ganglion cells in the inner retina, the optic nerve, and the geniculocalcarine pathway. Spectral domain optical coherence tomography has shown loss of outer-retinal structures such as the ellipsoid layer (previously referred to as the inner segment/outer segment junction), the external limiting membrane and the outer nuclear layer,20,21 and often also show cystic spaces or occasionally mild schisis-like changes and is relatively diagnostic for pathologic antiretinal antibodies in this setting. Fundus autoflourescence imaging has demonstrated areas of hyper-autofluorescence, which have been shown to correspond to the loss of outer retina. In a series of four patients, Lima et al22 demonstrated that fundus autofluorescence revealed a parafoveal ring of abnormally enhanced autofluorescence with normal autofluorescence inside the ring and a hypoautofluorescent retina outside the ring. Spectral domain OCT

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revealed disorganization and loss of ellipsoid layer, as well as thinning of the outer nuclear layer over the hyperautofluorescent transition zone, which led them to suggest that the loss of the ellipsoid layer represented the photoreceptor cilia affected by the initial triggers of apoptosis in AIR. In a series of 209 patients, Adamus17 reported that CAR generally developed after the age of 45 years with the average age being 65 and ranging from 24 (leukemia) to 85 (lung) years. Women were affected more than men at a ratio of approximately 2:1. The time from the cancer diagnosis to the onset of retinopathy varied from weeks to months (lung and lymphoma) to years (breast or prostate). The presence of antiretinal antibodies may precede the detection of tumor. Antiretinal antibodies associated with cancer-associated retinopathy. Anti-recoverin antibodies. Recoverin, a calcium-binding protein found in photoreceptors, has been shown to be aberrantly expressed in tumors of CAR patients10,23 leading to the hypothesis that CAR is secondary to antibodies generated against tumor-expressed recoverin that cross-react with photoreceptors. The diagnosis of anti-recoverin retinopathy has been described in small-cell lung carcinoma, cervical and ovarian carcinoma, mixed Müllerian tumors, endometrial carcinoma, breast cancer, invasive thymoma, and uterine sarcoma.24 A strong family history for autoimmune disorders have been correlated with the presence of AIR (60–70%), which implies that autoimmune genes are present in the family, thus increasing the prevalence of autoimmune diseases. The molecular mechanism of CAR has been suggested to be the apoptotic death of the photoreceptor cells mediated by caspase-dependent pathways along with intracellular calcium influx,25 attributed to autoantibodies to the photoreceptor protein recoverin.26 Caspase inhibitors and calcium channel blockers ameliorate anti-recoverin antibody toxicity in various experimental models.27 Anti-recoverin retinopathy in the absence of cancer has also been reported,5,15,28 however, the follow-up in these studies was limited. Anti-enolase antibodies. Enolase is a ubiquitously expressed 46-kDa glycolytic enzyme, which exists in 3 isoforms: a-enolase, found in many tissues; b-enolase, found predominantly in muscle; and g-enolase, found specifically in neurons and neuroendocrine tissues. In 1996, CAR, secondary to autoantibodies targeting a-enolase, was reported in patients with various tumors.29 Increased tumor expression of a-enolase, along with circulating anti-enolase antibodies, has been described in a number of patients with lung cancer. These observations suggest that, similar to antirecoverin autoantibodies, CAR secondary to anti-

enolase antibodies is mediated by autoantibodies that cross-react with the tumor and photoreceptor proteins, inducing apoptosis of retinal cells after cellular internalization, a process mediated by caspase pathways and an influx of intracellular calcium.30 Anti-enolase antibodies have been described in various systemic autoimmune diseases including systemic lupus erythematosus,31 in patients without identified cancer,32 and are also found in 10% of healthy subjects. Tubby-like protein 1. Tubby-like protein 1 (TULP1) is essential for normal photoreceptor function by participating in the transport of a subset of phototransduction proteins.33 It is exclusive to the rod and cone photoreceptor cells. Immunohistochemistry studies have demonstrated that TULP1 protein is localized primarily to the outer plexiform layer, and to a lesser extent to the inner segment of the photoreceptors. A disturbance in TULP1 would explain the ERG and histopathologic observations in CAR patients, which show alterations of rod and cone photoreceptors and the loss of photoreceptor cells. The amino acid sequence of TULP1 has no homology with the calcium-binding site determinants of recoverin that react with the sera of CAR patients. Tubby-like protein 1 is also one of the candidate genes for autosomal recessive retinitis pigmentosa (RP). Kikuchi et al34 reported a CAR patient with endometrial cancer whose sera contained anti-recoverin and anti-TULP1 antibodies. Heat shock cognate protein 70. Antibodies against 65-kDa heat shock cognate protein 70 (hsc 70) have also been identified in some patients with CAR.35 The hsc 70 family of proteins are synthesized in response to various cellular stresses and are present in normal unstressed cells. They play a role as chaperons, to help proteins translocate into organelles and to aggregate and degrade proteins. Elevated levels of heat shock proteins in peripheral monocytes and serum autoantibodies against heat shock proteins have been identified in patients with autoimmune diseases, such as lupus and rheumatoid arthritis. However, it is unclear how autoimmune reactions involving these various antibodies affect the onset and course of CAR, and the relationship between recoverin and hsc 70 in its pathogenesis remains to be elucidated. Glyceraldehyde 3-phosphate dehydrogenase. Glyceraldehyde 3-phosphate dehydrogenase (30 and 36 kDa) is a multifunctional glycolytic enzyme that converts glyceraldehyde 3-phosphate to D-glycerate 1,3bisphosphate and is expressed intracellularly and on the neuronal cell surface.36 It is involved in energy metabolism, cell signaling, and synaptic neurotransmission and has been shown to occur in the sera of


retinopathy patients.29 Glyceraldehyde 3-phosphate dehydrogenase is present in large quantities in rod outer segments, where it plays a role in the production of energy for these active cells. It has been suggested that the biological significance of anti–glyceraldehyde 3-phosphate dehydrogenase is related to the enzymatic role of glyceraldehyde 3-phosphate dehydrogenase in apoptosis, oxidative stress, activation of transcription, membrane fusion, and vesicle transport.37 Adamus37 analyzed 116 patients with antiretinal and antioptic nerve autoantibodies and found that 6/30 paraneoplastic patients with systemic cancers had the 30-kDa antiretinal antibody. It was associated with cervical cancer, non–small-cell lung cancer, melanoma, prostate cancer, renal cancer, and thyroid cancer. Anti-carbonic anhydrase II antibody. The role of antiCAII autoantibodies in paraneoplastic retinopathies has not been fully elucidated. Anti-CAII autoantibodies have the capacity to induce cellular damage by impairing CAII cellular function through a dosedependent inhibition of CAII catalytic activity.17 This leads to decreased intracellular pH and increased intracellular calcium, resulting in decreased retinal cell viability.17 Thus, anti-CAII autoantibodies can decrease retinal cell survival. Immunohistochemistry has shown the presence of autoantibodies against CAII in the outer segments of photoreceptors, the inner nuclear layer, and the ganglion cell layer.17 Treatment of cancer-associated retinopathy. There is no established treatment protocol for CAR, and the evidence base for therapeutic intervention is relatively limited. In a retrospective review of 30 patients with AIR, Ferreyra et al38 reported that with long-term immunosuppression, the most responsive subgroup was CAR. Treatment consisted of a triple therapy using cyclosporine (initial dose 100 mg/day), azathioprine (initial dose 100 mg/day), and oral prednisone (initial dose 20 to 40 mg/day) in patients with a classic severe presentation. In patients without a classic presentation of AIR or available positive Western blot information, treatment with 1-2 sub-Tenon methylprednisolone acetate (40 mg–60 mg) injections was given to 1 eye as a clinical trial to evaluate for a treatment effect. The response rates to treatment, judged by improvement in vision or expansion of the visual field area, were 100% (6/6) for CAR. Treatment efforts have had variable outcomes, at least in part, because once photoreceptors or other retinal structures are irreparably damaged, immunosuppressive therapy will unlikely be effective. Corticosteroids (prednisone and methylprednisolone). Based on the reported cases of CAR in the literature, treatment with steroids, especially with high-dose

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intravenous methylprednisolone more so than oral prednisone, have resulted in mild-to-moderate transient improvement in visual acuity and visual fields. In a review of 33 patients described in 19 reports, Guy and Aptsiauri11 noted that 16 patients (62%) who received corticosteroids recovered visual function. Prednisone treatments have usually been dosed between 60 mg to 80 mg daily. There have been a few reports of reduction in the levels of circulating autoantibodies in some patients with CAR who recovered visual function with corticosteroid treatment.39 Intravenous methylprednisolone has been used for the initiation of treatment. However, short-term treatment with intravitreal triamcinolone or sub-Tenon depomedrol does not treat the basis of the disease and long-term immunosuppression is required to stabilize and potentially regain the residual retinal function. Typically, patients on immunosuppression need at least 4 months to show improvements on visual field testing, and the treatment course may extend to over a year.16 Huynh et al40 reported that serial intravitreal injections of triamcinolone resulted in restoration of photoreceptor anatomy on OCT and visual improvement in a 67-year-old man with CAR secondary to poorly differentiated squamous cell lung carcinoma. Immunosuppressive agents. In addition to steroids, immunosuppressive drugs like cyclosporine (calcineurin inhibitor), azathioprine (purine antimetabolite), mycophenolate mofetil (purine synthesis inhibitor), rituximab (CD20-directed cytolytic antibody) and alemtuzumab (CD52-directed cytolytic antibody) have been described with limited success. Or et al41 recently reported treatment of a patient with CAR secondary to adrenal adenoma with rituximab, a monoclonal antibody that selectively targets CD20+ B lymphocytes. After 2 intravenous infusions, 1000 mg each, given 2 weeks apart, the patient’s symptoms resolved, vision improved, and the there was some restoration of the integrity of the inner segment/outer segment junction on OCT. Mahdi et al42 also reported treatment of CAR secondary to thyroid carcinoma with rituximab. Espandar et al43 reported treatment of CAR secondary to chronic lymphocytic leukemia with several rounds of alemtuzumab (Campath, Cambridge, MA), and after 8 years of follow-up, the best-corrected visual acuity was 20/25 and 20/70, compared with the baseline vision of 20/20 and 20/30 in the right and left eye, respectively. It is important to remember however that visual acuity is a poor evaluator to follow most AIR patients because it may fluctuate to a high degree and eventually become poor enough that it is not as useful for determining activity. Kinetic visual fields, as well as mfERG and full-field ERG, are helpful in following patients.

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Intravenous immunoglobulin. Intravenous immunoglobulin (IVIg) is used for several ocular autoimmune and neurologic disorders. In AIR, IVIg treatment is thought to be successful only if given before the onset of irreversible neuronal degeneration. There have been several mechanisms proposed for IVIg action, including an anti-idiotype reaction against membrane-bound B-cell receptor, neutralization of autoantibodies by anti-idiotypes, binding of complement components C1, inhibition of maturation of dendritic cells with consecutive inhibition of T-cell activation, and modulation of the expression of intercellular adhesion molecules. Intravenous immunoglobulin may contribute IgG4 that may help stabilize the disease.44 It has also been suggested that once IVIg-mediated modulation of the immune system occurs, a permanent cessation of autoantibody production may occur. The most serious adverse effects experienced with IVIg infusion are anaphylaxis, Stevens–Johnson syndrome, hypotension, acute respiratory distress syndrome, transfusionrelated lung injury, stroke, and seizures. Because so few cases have been treated with IVIg, no standard dosage has yet been established. Guy and Aptsiauri11 reported a patient with metastatic cancer and rapidly progressive vision loss from CAR treated with IVIg 400 mg/kg per day for 5 days who had a sustained improvement in visual acuity from hand movements to 20/40 and an expanded visual field. Antioxidants. It has been suggested that antioxidant vitamins such as b-carotene (in non-smokers), lutein, vitamin C, and vitamin E can be used also to help manage the retinal degeneration associated with AIR including CAR.16

Case History An elderly man has metastatic non–small-cell lung carcinoma. He is being treated with erlotinib and a new experimental chemotherapeutic agent. A month after starting the new agent, he complains of difficulty with night vision; central vision is good. There are significant ERG abnormalities in all modalities of testing, especially blue scotopic. Spectral domain OCT reveals extensive loss of the ellipsoid band and external limiting membrane, except centrally, where they are relatively preserved. Antiretinal antibody testing is positive for anti–a-enolase. Discussion. Is the vision problem the result of the new chemotherapeutic agent? Is this CAR? What is the significance of the antibody, and how does one determine whether this is CAR? Follow-up. In the case presented at the beginning, the new chemotherapeutic agent was discontinued.

The patient was followed, his night vision improved promptly over the next year, the OCT changed, and the ERG also improved. Retesting for anti–a-enolase was still positive with approximately the same titer. It was concluded that the chemotherapeutic agent was the main problem, although a possible interaction with the a-enolase antibody cannot be ruled out. Melanoma-Associated Retinopathy Introduction. Though less heterogeneous in presentation than CAR, atypical presentations have been reported.45 Unlike CAR, which usually manifests at the onset of a malignancy, MAR commonly presents after the melanoma has been diagnosed, often at the stage of metastases. It is typically seen in patients with metastatic cutaneous or uveal melanoma and is more common in men than in women. Patients may develop vision problems years later, which are often associated with non-ocular metastasis, such as newly diagnosed metastasis to the liver. Visual symptoms include sudden onset of shimmering, flickering, or pulsating photopsias, difficulty seeing in the dark, and progressive visual loss over several months. There is peripheral visual field depression or midperipheral visual field loss. Adamus17 and Keltner et al46 reported that the average latency from melanoma diagnosis to the recognition of MAR was 3.6 years and ranged from 2 months to 11 to 19 years. In a series of 62 patients, Keltner et al46 reported a fundus appearance ranging from normal to optic nerve pallor, vessel attenuation, RPE changes, and the presence of vitreous cells. Central and paracentral scotomas were common and visual acuity at the time of diagnosis was $20/60 in 82% of patients. The ERG in MAR may have a characteristic pattern of a markedly reduced dark adapted b-wave, indicating compromised bipolar cell function, and a normal dark-adapted a-wave (negative appearance) indicating normal photoreceptor cell function, which is seen in approximately half of the patients.46 The characteristic alteration of the light adapted a-wave morphology and the b-wave amplitude result from a selective dysfunction of the “ON” bipolar cells.47 These symptoms of night blindness and selective b-wave reduction also resemble the complete form of congenital stationary night blindness. Some MAR patients may have a reduced a-wave amplitude in the photopic or scotopic ERG, reduced oscillatory potential amplitudes, and abnormalities in the 30-Hz flickerresponse implicit time or amplitude. All patients have an abnormal ERG. There has been histopathologic evidence of ganglion cell trans-synaptic atrophy, and a decrease of bipolar neurons in the inner nuclear layer with normal photoreceptor cells in the outer nuclear


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layer.47 Indirect immunohistologic examination for positive staining of antiretinal antibodies is diagnostic, particularly of the bipolar layer. More recently, there have been several reports of MAR associated with serous or vitelliform detachments of the neurosensory retina and subretinal accumulation of hyperautofluorescent material in the posterior pole.2,48–50 Paraneoplastic vitelliform retinopathy, associated with cutaneous or uveal melanoma, may be part of the spectrum of MAR. Unlike the typical normal-appearing fundus in MAR, paraneoplastic vitelliform retinopathy is characterized by vitelliform retinal lesions with associated serous retinal detachment. Although many patients with MAR do not have exudative vitelliform lesions, acute exudative polymorphous vitelliform maculopathy characterized by serous retinal detachment and subretinal accumulation of hyperautofluorescent yellowish material in the posterior pole has been reported with detection of antibodies to peroxiredoxin 3, an RPE protein, as well as antibodies to aldolase C, aldolase A, CAII, recoverin, and heat shock protein 1.51 Borkowski et al52 reported atypical retinal findings in two MAR patients, one with round and oval white macular lesions involving the outer retina and RPE (possibly vitelliform retinopathy) and the other with diffuse RPE loss of pigment and numerous small atrophic lesions that involved the retina, RPE, and choroid, sparing the macula and associated with vitiligo. Antiretinal antibodies. Autoantibodies against retinal bipolar cells53,54 transducin,55 rhodopsin,56 arrestin,57 CAII, interphotoreceptor retinoid-binding protein,49 bestrophin,58 a-enolase, myelin basic protein, and rod outer segment proteins have been found in MAR.

Transient receptor potential cation channel, subfamily M, member 1. Transient receptor potential M1 (also known as melastatin 1 or MLSN1) (200 kDa) was recently identified as the cation channel mediating the light response in all types of ON bipolar cells.60 Transient receptor potential M1 is a component of the ON bipolar cell transduction channel and is expressed in normal melanocytes. It is the only bipolar cell protein so far to be implicated in MAR. It has been suggested that the antibodies bind the TRPM1 channel on the ON bipolar cells and either directly block the channel or indirectly interfere with the signal transduction, causing loss of night vision (mediated by the rod bipolar cells, which comprise the majority of ON bipolar cells) and a reduced ERG b-wave and a nearly undetectable rod response. Kondo et al61 identified TRPM1 autoantibodies in the serum of one CAR patient (lung cancer) and two MAR patients (skin melanoma) with ERG findings indicating selective ON-bipolar cell dysfunction and a defect in the signal transmission from photoreceptors to ON bipolar cells in both rod and cone pathways. The photopic longflash ERG showed a severely reduced ON response and normal OFF response. Spectral domain optical coherence tomography was normal in these eyes. Dhingra et al62 reported the presence of autoantibodies against TRPM1 in two MAR patients. Mutations of human TRPM1 have also reported to be associated with the complete-type of congenital stationary night blindness.63 Wang et al64 reported TRPM1 antibody against human retinal bipolar dendritic tips in a melanoma patient with paraneoplastic vitelliform retinopathy (MAR).

Bestrophin. Bestrophin-1 is a 68-kDa transmembrane protein localized to the basal lateral membrane of the RPE.59 It is a modulator for voltage-dependent calciumactivated chloride channels in the RPE cells. Paraneoplastic vitelliform lesions in the setting of a melanoma (MAR) may manifest with the clinical appearance of Best macular dystrophy, and have an abnormal electrooculogram, and have been shown to be associated with circulating autoantibodies directed against bestrophin-1.58 It is still unclear how bestrophin-1 dysfunction results in a Best macular dystrophy phenotype with a vitelliform macular appearance and a light peak reduction in an electrooculogram. Best macular dystrophy is known to have a large variability in expressivity, and recent studies showed that the disorder might have an autosomal recessive pattern of inheritance, in addition to the well-known autosomal dominant pattern. VMD2 encoding bestrophin-1 is important in ocular development and autoantibodies to bestrophin-1 would cause a loss of protein function.

Anti-aldolase A and C autoantibodies. Aldolase is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. There are 3 isozymes of aldolase: aldolase A in muscle, aldolase B in liver, and aldolase C, together with aldolase A in brain.65 Aldolase C is specifically expressed in the hippocampus and Purkinje cells of the brain and retina.66 Light exposure has been shown to induce oxidative modification on aldolase C and a-enolase in a mice model, which is associated with initiation of the retinal degeneration.67 In a series of 11 MAR patients, Lu et al68 reported anti–aldolase A antibody (39 kDa) (2 patients) and anti–aldolase C antibody (39 kDa) (4 patients) using Western blots. Anti–aldolase C antibody has also been identified in patients with diabetic retinopathy69 and in neovascular age-related macular degeneration patients with choroidal neovascularization,70 whereas anti–aldolase A antibody has been reported in rheumatoid arthritis,71 and Alzheimer’s

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disease.72 It has been suggested that the presence of circulating anti–aldolase A and anti–aldolase C antibody should serve as an indicator of blood–retinal barrier damage in patients with MAR. Aldolase C is expressed in the ganglion cell and inner nuclear layers of the retina.66 Autoantibodies to interphotoreceptor retinoid-binding protein. Interphotoreceptor retinoid-binding protein is a 145-kDa glycoprotein expressed by retinal photoreceptors73 and thought to mediate the transport of retinoids between the retinal photoreceptor cells and the RPE. Interphotoreceptor retinoid-binding protein has also been isolated from cancers such as cerebellar medulloblastoma, retinoblastoma, and pineocytoma. Interphotoreceptor retinoid-binding protein has been described in a patient with MAR secondary to metastatic skin melanoma.49 A mutation in interphotoreceptor retinoid-binding protein has been associated with a form of autosomal recessive RP.74

Treatment. Although several treatment modalities for MAR including oral, sub-Tenon’s, or intravenous corticosteroids, plasmapheresis, IVIg, azathioprine, gabapentin, and x-irradiation of metastases or cytoreductive surgery have been described, overall the treatment of the visual loss associated with MAR has been disappointing. Keltner et al46 in a review of 62 patients with MAR noted 7 patients experienced visual improvement after receiving various treatment regimens. Four of the seven patients were treated with metastasectomy and two of them with IVIg therapy. Vision in one patient each improved with IVIg treatment alone, plasmapheresis and methylprednisolone treatment, and with radiation treatment to sites of melanoma recurrence. Unpublished cases suggest that immunosuppression in MAR may help release the immunologic suppression on the melanoma and lead to premature death. Plasmapheresis. Plasmapheresis is a form of therapeutic apheresis in which plasma is removed from the patient and replaced with donor plasma or normal saline and albumin. The process requires special access such as a temporary dual-lumen venous catheter. Plasmapheresis is hypothesized to remove the antiretinal antibodies produced in MAR, circulating immune complexes, and cytokines contributing to the immunologic response. Three MAR patients have been reported treated with plasmapheresis with a favorable response achieved in 2/3 patients.46 However, because plasmapheresis was performed in combination with prednisone, azathioprine, and gabapentin, it is not possible to attribute the response solely to it. Powell and Dudek75 suggested that plasmapheresis could be

considered for nonresponders or those who do not qualify for other therapies. Intravenous immunoglobulin. In the series studied by Keltner et al,46 one patient reported improvement with IVIg alone and two in combination with cytoreductive surgery. Subhadra et al76 reported improvement in visual fields after resection of metastasis and IVIg (100 g IVIg for 2 consecutive days and then every 4–8 weeks) in a 56-year-old man with MAR secondary to metastatic cutaneous melanoma. Different pools of immunoglobulin from human donors are used by the various manufacturers, and they contain a wide range of anti-idiotypic antibody specificities; however, there are no documented differences in the efficacy for a specific disease. The empirical therapeutic dose of IVIg is 2 g/kg, and the current recommendation is to divide the total dose into 2 daily doses of 1 g/kg each. Intravenous immunoglobulin rapidly diffuses into the extravascular space, thus achieving a high concentration of IVIg within 2 days.77 However, the rate of infusion should not exceed 200 mL/hour or 0.08 mL/kg per minute. Cytoreduction. Cytoreduction is believed to decrease the amount of antiretinal antibody production by decreasing the tumor burden. This can be achieved by radiation therapy or surgery. Radiation therapy. Radiation therapy is used as palliative or curative therapy in a number of different malignancies. It is thought that radiation therapy can be used as a cytoreductive technique to reduce tumor burden, and thus antiretinal antibody production. Radiation therapy in MAR has been reported to be effective in one patient in the series reported by Keltner et al.46 There are no clinical studies or other large case series evaluating the procedure. Advantages of the technique include its ease of use, and the fact that it is relatively well tolerated and may be particularly useful in patients who are not candidates for surgery or chemotherapy. Cytoreductive metastatic surgery (metastasectomy). Metastasectomy is a cytoreductive surgery that involves the surgical removal of metastatic disease thereby decreasing the overall tumor burden. This may decrease the levels of antiretinal antibody production. In a series of 62 patients with MAR, Keltner et al46 reported that metastasectomy was associated with the best results. Currently, cytoreductive surgery (complete metastasectomy) and adjuvant immunotherapy are the preferred initial treatment for most patients with metastatic melanoma.78 It may be used as an adjunct with plasmapheresis and IVIg.


Steroids. The use of immunosuppressive agents, including corticosteroids, has been largely ineffective in MAR with oral prednisone alone not shown to be beneficial in six of seven patients treated in the series studied by Keltner et al.46 Jacobzone et al79 described treatment of MAR secondary to malignant melanoma of the skin with one intravenous bolus of corticosteroids, 750 mg/day for 3 consecutive days, followed by oral taper and reported an improvement in the symptoms and a 30% increase of b-wave amplitude.

Bilateral Diffuse Uveal Melanocytic Proliferation Introduction. Bilateral diffuse uveal melanocytic proliferation is a rare paraneoplastic syndrome resulting in bilateral vision loss. The syndrome has been described to have five characteristic signs: bilateral multiple, subtle round or oval subretinal round red patches in the RPE, early fluorescence of these lesions on fluorescein angiography, multiple elevated pigmented and nonpigmented uveal melanocytic tumors with diffuse uveal tract thickening, exudative retinal detachments, and rapid cataract development.80 This is generally associated with a systemic cancer, which may not be recognized at the time of the ocular signs and symptoms. Ocular symptoms and signs often precede the onset of systemic symptoms. As a consequence, recognition of BDUMP by an ophthalmologist may have an impact on patient morbidity and mortality. Males and females seem to be equally affected, and visual loss often precedes the cancer from months to years. Other tumors associated with BDUMP syndrome include ovarian cancer, lung cancer, uterine cancer, melanoma, pancreatic carcinoma, colon and rectal cancer, and metastatic cancer from unknown causes.81–83 Histopathologically, diffuse uveal tract thickening has been described to be the most characteristic feature of BDUMP.81 Miles et al84 demonstrated that patients with BDUMP have a factor in the IgG fraction that selectively causes melanocyte proliferation. Paraneoplastic phenomena like extraocular pigmentation85 and palmar fasciitis86 have been reported in association with BDUMP. Antiretinal antibodies associated with bilateral diffuse uveal melanocytic proliferation. Saito has reported a case of BDUMP associated with CAR in which antibodies to recoverin and heat shock cognate protein 70 (hsc 70) were detected. Vision improved after a course of oral corticosteroids.87 Antiretinal antibodies against 33 kDa and 34 kDa have been reported in a case of BDUMP associated with metastatic bronchogenic carcinoma that demonstrated visual recovery after plasmapheresis.88

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Treatment. Approximately 30 cases of BDUMP have been reported in the literature. The average survival from initial presentation has been approximately 17 months. Retention of visual acuity is poor, but intervention with corticosteroids, ocular surgery, chemotherapy, and radiotherapy can be helpful. Mets et al88 reported visual recovery and resolution of serous detachments after plasmapheresis in a 72-year-old man with BDUMP secondary to metastatic bronchogenic carcinoma. Jaben et al89 reported maintenance of visual acuity in two women with gynecologic malignancies who were treated with plasmapheresis for BDUMP. Sen et al86 reported regression of BDUMP in a 62year-old man after resection of a poorly differentiated lung adenocarcinoma. Ritland et al90 described the use of external beam irradiation with drainage of subretinal fluid and noted improvement of vision in a 70-year-old woman with BDUMP secondary to uterine cancer. Non-Paraneoplastic Autoimmune Retinopathy Introduction. Non-paraneoplastic autoimmune retinopathy is the most common form of AIR and can be similar in phenotype and electrophysiological findings to CAR. Patients need to be fully investigated for an occult malignancy before a diagnosis of npAIR can be considered. Some npAIR patients have cystic macular changes that may not leak on fluorescein angiography.38 Heckenlively et al have shown that cystic changes in RP maculae are significantly associated with the presence of circulating antiretinal antibodies and systemic immunosuppressive drugs have been used for cystoid macular edema (CME) in patients with RP.32,91 The clinical phenotype of npAIR is very similar to CAR, but the onset has been reported at a younger age than in CAR,6,92 and there is often a strong family or medical history of autoimmune disease.38 The pathophysiology of npAIR is still relatively poorly understood, but it has been suggested that a component of npAIR could be attributed to aberrant tumor retinal antigen expression, where the tumor is controlled by immune surveillance and does not manifest clinically. At present, there is no definite evidence of tumor activity in npAIR, though it has been suggested to be theoretically possible.93 Thinning of the outer nuclear layer and an irregular ellipsoid layer have been demonstrated on spectral domain optical coherence tomography along with a reduction in full-field ERG.94 Some of these patients are diagnosed as having RP based on clinical findings, but they have no family history of RP. There have been reports of a few cases of hereditary RP developing secondary AIR with rapid visual field loss and severe CME.32 Based on these reports, it has

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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 5 Table 1. Heckenlively et al Diagnostic Criteria for AIR97

Strong Evidence

Supportive Evidence

Anti-recoverin antibody Negative waveform ERG findings History of autoimmune disease in 50% of immediate family Cystoid macular edema in panretinal degeneration Response to trial of sub-Tenon methylprednisolone History of cancer (for CAR)

Helpful Evidence

Other antiretinal antibody bands on Western blot testing Abnormal ERG findings in conjunction with typical symptoms and no pigment deposits Family history of autoimmune disease

Anti–a-enolase antibody, anti-arrestin antibody

Sudden onset with photopsias, vision normal before onset Rapid progression by history or visual fields Negative family history of RP

Diffuse retinal atrophy

been suggested that RP with antibodies may have a worse prognosis, but this has not been proven. Non-paraneoplastic autoimmune retinopathy has been reported with apparently inflammatory diseases like acute zonal occult outer retinopathy, multiple evanescent white dot syndrome, and birdshot retinopathy. However, these are as yet just isolated reports, and the antibodies were not thought to play a primary role in these entities but rather believed to be an epiphenomenon. They have not been proven to relate to the underlying disease process. Because circulating antiretinal antibodies are present in patients with many retinal diseases, the challenge remains to determine which ones are pathogenic and/or benign, and what other factors are present that cause antiretinal antibodies to become pathologic. The cellular immunity

response in AIR is unknown and needs to be investigated. It is important to note that antibodies although sometimes pathogenic could also be coincidental or an epiphenomenon. Antiretinal antibodies associated with nonparaneoplastic autoimmune retinopathy. Antibodies against recoverin,5 the inner plexiform layer,28 the inner retinal layer (35-kDa antibody against retinal Müller cell–associated antigen),95 a-enolase,6 CAII,96 and rod transducin-a17 have been described in npAIR. Antibodies to rod transducin-a. Transducin, also referred to as G-protein, is a 3-subunit guanine nucleotide-binding protein that stimulates the coupling of cGMP-phosphodiesterase to cGMP in the phototransduction cascade leading to hyperpolarization of

Table 2. Antiretinal Antibodies and the Assay Methods Used to Detect Them Antiretinal Antibody Anti-recoverin (23 kDa)11,13,24 Anti–a-enolase (46 kDa)30 Heat shock cognate protein 70 (hsc70)36,99 (65 kDa) Anti–tubby-like protein 1 (TULP1)35 78 kDa Photoreceptor cell–specific nuclear receptor100 (41 kDa) Antibodies against neurofilament protein101 Antibodies against retinal bipolar cells46,54 22-kDa neuronal antigen102 Antitransducin antibody55 (35 kDa) Carbonic anhydrase II (CAII) (30 kDa) Interphotoreceptor retinoid-binding protein50 Bestrophin58 (68 kDa) Autoantibody against transient receptor potential M1 cation channels of retinal ON bipolar cells62,105 Peroxiredoxin 3 (26 kDa)60 Arrestin (48 kDa) Mitofilin and Titin119 Aldolase C (39 kDa) and Aldolase A (39 kDa)69

Assay Method(s) Described Western blot, IHC, enzyme-linked immunosorbent assay Western blot, IHC, enzyme-linked immunosorbent assay Western blot Western blot Western blot Western blot Western blot Western blot Western blot Western blot Western blot Western Western Western Western

blot blot blot blot

Develops after diagnosis of May precede diagnosis of Usually develops after cancer cancer, months to years cancer by months diagnosis, months to years, but also may precede Precedes diagnosis of cancer by months to years

.30% 40% 90%

Association with cancer Time of cancer diagnosis to retinopathy onset

Normal to severely depressed Severely abnormal mfERG

Subnormal response of rods Full-field ERG

Mildly to severely abnormal

Rapid rod and cone loss, often Gradual, variable rate of loss, rate rapid progression to LP or NLP worse than 20/300 vision Equally severe rod and cone loss Variable, normal to severe cone loss, normal to moderate rod loss Course

Defects primarily in rod (scotopic) photoreceptor function Decreased amplitudes, delayed timing ,25%

Sudden progressive Subacute, chronic Very symmetric Often symmetric Mild, patchy to global acuity Mild vitritis, mild to severe and field loss constriction of fields, color vision loss Slowly progressive Mildly progressive Subacute, chronic Often symmetric Variable, central, or global vision loss Acute, sudden Usually very symmetric Severe central and peripheral vision loss Onset Ocular symmetry Presentation

Anti-transducin Anti-enolase Anti-recoverin Features

Table 3. Retinal Phenotypes of Anti-recoverin, Anti-enolase, Anti-transducin, and Anti-CAII Antiretinal Antibodies1,18,98

Anti-CAII


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the photoreceptor. The transducin a-subunits in rods and cones are encoded by separate genes; GNAT1 in rods and GNAT2 in cones. The antigen is aberrantly expressed in cancer cells, and inactivation by autoantibodies is hypothesized to reduce signaling and lead to changes in intracellular calcium with resulting apoptosis. Treatment. Ferreyra et al38 reported treatment results in a series of 24 patients with npAIR with treatment ranging from 4 to 89 months. They used a triple therapy regimen consisting of cyclosporine (100 mg/day), azathioprine (100 mg/day), and prednisone (20–40 mg/day) for patients with a severe presentation. In addition, IVIg was administered to three patients, infliximab (Remicade, Janssen Biotech, Inc, Philadelphia, PA) to two patients and intravitreal triamcinolone acetate to four patients. Overall, treatment response defined as improvement in visual acuity, expansion of visual field or improvement in ERG or CME, was seen in 54% of npAIR cases and 73% of npAIR patients with CME. However, a reanalysis of their data showed that there was an improvement in vision in only 19% of npAIR without CME patients and in 25% of npAIR with CME patients.97 They also found that the prevalence of an autoimmune family history was higher in the treatment nonresponders (83%) compared with those responding to the treatment (57%). Heckenlively et al98 proposed a set of diagnostic criteria for AIR (Table 1) that segregates evidence into “strong,” “supportive,” or “helpful.” Table 2 illustrates a summary of the antiretinal antibodies currently identified along with the assay techniques used for their detection and measurement. Table 3, adapted from Weleber et al1 and Adamus et al17,106 summarizes the retinal phenotypes with anti-recoverin, anti-enolase, anti-transducin, and anti-CAII antiretinal antibodies. Although, there is sufficient evidence for the utility of anti-recoverin and anti-enloase in the detection of AIR, the role of anti-transducin and anti-CAII is not that well established. Discussion There are no well-established diagnostic criteria for CAR. Currently, it is a clinical diagnosis made by combining signs and symptoms and the diagnosis of systemic cancer until we accurately identify diagnostic biomarkers and positive antibodies against retinal proteins. There are multiple antibodies that have been associated with CAR, most commonly against the following proteins: recoverin, a-enolase, arrestin, CA, TULP1, HSP70, and photoreceptor cell–specific nuclear receptor. Antiretinal antibodies have also been

Study

Diagnosis CAR

Ferreyra 200938

CAR, npAIR, npAIR with CME

Subhadra 200876

MAR

Keltner 200146

MAR

Jacobzone 200479

MAR

Yamamoto 2012120

MAR

Espandar 200743

CAR

Mahdi 2010121

CAR

a-enolase

None

Autoantibodies against retinal bipolar cells None

Recoverin

Type of Cancer Poorly differentiated squamous cell carcinoma of the lung For CAR patients (breast, ovarian, colon, prostate)

Malignant melanoma of forehead

Malignant melanoma

Cutaneous malignant melanoma, metastatic Breast cancer

Thyroid carcinoma

Treatment Serial intravitreal injections of triamcinolone

Patients

67-year-old man Vision preserved at 20/40

30 patients Triple therapy using cyclosporine (100 mg/day), azathioprine (100 mg/day), and prednisone (20–40 mg/ day). Sub-Tenon methylprednisolone acetate (40–60 mg) injections as trial in atypical patients. Periocular or intravitreal corticosteroid injection if intolerant to systemic immunosuppression 100 g IVIg for 2 consecutive days and then monthly and tapered thereafter over 12 months 62 patients Oral, sub-Tenon’s, or intravenous corticosteroids, plasmapheresis, IVIg, azathioprine, gabapentin, and x-irradiation of metastases or cytoreductive surgery

70-year-old One intravenous bolus of woman corticosteroids, 750 mg/d for 3 consecutive days, followed by oral corticosteroids, 60 mg/d for 1 month 33-year-old Metastasectomy, weekly woman followed by monthly local infusions of 3 million units interferon-b at the edges of the tumor resection for 1 year Alemtuzumab (Campath), 30 mg intravenously 3 times a week for 4 weeks Rituximab

Outcome

21/30 patients improved: 6/6 with CAR, 7/13 with npAIR, 8/11 with npAIR/CME, respectively. Vision improvement in 5/21 patients and .25% expansion of the visual field area in 15/21 patients

Improvement in vision and visual fields. No improvement in ERG IVIg (400 mg/kg per day for 5 days): visual acuity improved 1 patient, combination of intravenous methylprednisolone/ plasmapheresis improved visual acuity in 1 patient. Cytoreductive surgery improved vision in 4 patients Improvement in vision, ERG with 30% increase in b-wave amplitude, improved visual field Improvement in vision. Electroretinogram and visual fields returned to normal Improvement in vision and visual fields, had two recurrences both treated with alemtuzumab Slowing of visual loss


Huynh 201240

Antibodies

838

Table 4. Summary of Treatment Reports for CAR, MAR, and npAIR

Vision acuity improved in 1/3, visual field defects in 2/3 Adrenal adenoma 51-year-old Resolution of symptoms, woman improved vision in the right eye, partial improvement in integrity of inner segment/ outer segment junction on spectral domain optical coherence tomography Improvement of night vision, Removal of a metastasis in the 33-year-old Cutaneous malignant white woman glare sensitivity, and lymph nodes of the right axilla melanoma (nodular normalization of previously (radical lymph node malignant melanoma) abnormal rod-isolated dissection) followed by scotopic b-wave response chemotherapy with vindesine Metastatic Plasmapheresis, sorafenab 72-year-old man Improvement in vision, bronchogenic resolution of serous carcinoma detachments, decreased retinal pigmentation IVIg (400 mg/kg per day) for 5 days Two intravenous infusions of rituximab, 1000 mg each, given 2 weeks apart CAR

MAR

BDUMP

Or 201342

Palmowski 2002122

Mets 201189

Guy 1999

33- and 34-kDa retinal proteins

Enolase, recoverin CAR

Treatment Type of Cancer Antibodies Diagnosis

12

Study

Table 4.

(Continued )

Patients

Outcome


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described in the serum of healthy individuals although the appropriateness of the control sera in the study has been questioned.107 In CAR or MAR patients, Western immunoblots typically show these antibodies as having IgG bands of activity. Most active cases have a minimum of three different antiretinal antibodies positive on Western blot.16 Therefore, the presence of isolated antiretinal antibodies, especially in the absence of other typical clinical findings, does not automatically confirm the diagnosis of CAR. They have to be considered in the context of the patients’ clinical findings. Patients with other autoimmune disorders such as diabetes, lupus, and rheumatoid arthritis have antiretinal antibodies that are toxic to the retina. For this same reason, the positive predictive value of antiretinal antibodies in tested serum of patients with cancer remains unknown. Major cancers associated with CAR include breast (31%), lung (16%), melanoma (16%), hematologic malignancies (15%), gynecologic neoplasms (95), prostate (7%), and colon (6%). Cancer-associated retinopathy typically develops after the age of 45 years, with the average age of onset being 65 years, although reports have ranged from 24 years (leukemia) to 85 years (lung).17 The major autoantigens detected in patients with paraneoplastic syndromes are summarized in Table 5. Autoimmune retinopathy has been associated with other ocular and systemic conditions that are not neoplastic. Antiretinal antibodies have been detected in 10% to 90% of patients with RP, including those with concomitant macular edema,15,108 as well as in patients with macular edema of various etiologies109 including Vogt–Koyanagi–Harada disease, Behcet’s, and sympathetic ophthalmia.110 A plethora of antiretinal antibodies (including one with molecular weight between 28 kDa and 32 kDa) have also been isolated in dry and exudative forms of age-related macular degeneration.111–113 Compared with controls, more cases with onchocerciasis114 and toxoplasmosis115 have antiretinal antibodies. In addition, antiretinal antibodies, including anti-aldolase, a-enolase, and CAII have been isolated from the serum of patients with diabetic retinopathy.69 Morohoshi et al70 reported retinol-binding protein 3 and aldolase C in neovascular age-related macular degeneration patients. The same antibody can also be associated with different phenotypes. Antiretinal antibodies have been associated with non-neoplastic systemic conditions. Yanagi et al116 reported a case of AIR that developed after chronic renal allograft rejection and hypothesized that autoantibodies induced by chronic renal rejection from glomerulonephritis caused a profound retinopathy with a nondetectable ERG. This retinopathy was associated

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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2014 VOLUME 34 NUMBER 5 Table 5. Major Autoantigens Detected in Patients With Paraneoplastic Syndrome122 Seropositive Patients

Antigens (Molecular Weight, kDa)

Breast Gynecological

40/65 14/18

23, 30, 40, 46 23, 35, 46, 75, 84

Lung Colon Prostate Hematologic Cutaneous melanoma Ulcerative colitis Autoimmune retinopathy in CMV-positive anterior uveitis Concomitant Best’s disease and choroidal malignant melanoma58

15/32 13/13 9/15 15/15 19/34

Cancer

1/1

Major Antigens

Enolase, transducin Recoverin (endometrial), enolase (cervical) 23, 30, 35, 40, 46, 68, 100 Recoverin (SCCL) CAII, PDE 30, 40, 46 Transducin CAII 30, 46, 23, 40 Enolase, CAII 46, 67, 62, 23 Enolase 40, 46 Transducin, enolase 40 45 and 69 68

Bestrophin-1 (type of RPE antigen), anti–a-enolase

RPE, retinal pigment epithelium; PDE, phosphodiesterase inhibitor; SCCL, small cell cancer of the lung.

with anti- 50, 60, and 70-kDa antibodies, which were undetectable after the patient subsequently underwent hemodialysis. Little is known about the dynamic nature of antiretinal antibodies. In a patient with CAR associated with small cell carcinoma of the lung, serum tests showed a 35-kDa antiretinal antibody a week after surgery while a 46-kDa (similar to anti–a-enolase) antiretinal antibody was detected a month after surgery.117 This change from 35- to 46-kDa antibodies against a-enolase after tumor resection is consistent with “epitope spreading,” a process associated with development of an immune response toward epitopes distinct from the disease causing epitopes, and the one which ultimately enhances the pathogenicity and heterogeneity of the antibodies in CAR.

Diagnostic and Prognostic Utility of Antiretinal Antibodies Patient’s visual symptoms may precede the diagnosis of systematic cancer by months to years, making the diagnosis of CAR difficult initially. Other causes of retinal dysfunction or retinal degeneration such as hereditary or toxic retinal degenerations, including congenital stationary night blindness must be ruled out. Knowing the association with paraneoplastic disease (Table 5) might help the ophthalmologist and the primary care physician narrow down the workup of a suspected disease. Numerous retinal antigens have been described as targets of retinal autoantibodies in patients with suspected AIR. Tumors may aberrantly express proteins normally exclusive to retinal tissue, leading to the production of antibodies directed against these retinal antigens. There have been suggestions that it may be possible to discriminate CAR and

MAR subtypes by their autoantibodies rather than by ERG and vision tests alone.62 Knowledge of the presence and type of antiretinal antibodies play an important role in treatment options. First, recoverin is a calcium-binding protein, and autoantibodies to it penetrate the retina and induce apoptosis through the mitochondrial pathway. Molecular research has shown that calcium channel blockers such as nifedipine limit the increase in intracellular calcium, which is believed to lead to retinal dysfunction and degeneration in CAR,117 although this remains of limited clinical value because of a lack of conclusive data from human subjects. Although the identification of the antigenic proteins is helpful, the exact role of cellmediated immunity in AIR remains to be determined. The importance of lymphocytes and other leukocytes and cytokines in the pathogenesis of the condition remains to be investigated. Such studies may provide other pathways for the treatment of the condition. Second, the presence of positive antiretinal antibodies in the setting of advanced visual loss and known diagnosis of cancer suggests that there could be visual improvement after treatment with systemic and/ or local steroids such as systemic methylprednisolone and/or sub-Tenon’s triamcinolone. It has been suggested that not all cases of CAR are associated with malignant neoplasms, because benign tumors have been hypothesized to cause CAR. A case of colon polyp consistent with tubular adenoma with mild atypia, positive for anti-23 kDa antibodies, showed improvement in the visual acuity after tumor resection and treatment with oral prednisolone and sub-Tenon’s injection of triamcinolone.118 So, surgical excision of the underlying etiology can help induce remission of the autoimmune response. An initial seropositive test, specially with recoverin, could be helpful in


diagnosing cancer, and follow-up tests of autoantibody levels can be used as a biomarker of disease activity associated with worsening of vision. Although current evidence for CAR and MAR points to antigens expressed in various organs, including the eyes, as being the source of the immune attack leading to retinal diseases, the trigger factors in AIR remain unclear99 and should be explored by further research studies. Conversely, seronegative CAR and MAR have been described, with more than one third of patients suffering from retinopathy not having any positive antiretinal antibodies detected.17 This suggests a high rate of false-negatives when testing for antiretinal antibodies in the context of AIR. Even when antiretinal antibody testing is positive, the concordance rates between Western blot testing by different laboratories is very low. Most recent literature100 quotes this figure at 36% for detecting same-size (within 1 kDa) antiretinal antibodies. One possible factor for the difference between the two laboratories could be the use of human retinal extract with positive and negative controls versus a pig retinal extract with normal controls. With Western blot testing, it is also important to confirm that the band that is being called positive is tested in the setup gel with the specific antibody. On retesting the serum with this method, 50% to 60% of the time, the anti-recoverin or a-enolase antibodies are not identified. Immunohistochemistry is one of the preferred methods for testing for CAR and MAR and staining with the 23-kDa photoreceptor cell-specific protein antibody (anti-recoverin) has been shown to be quite specific for CAR. The foremost implication is that management can be different based on antibody testing results. We emphasize the importance of sending blood samples to at least two laboratories if the clinical suspicion is high. Ideally, the testing methodology should be similar between the two laboratories. The role of Multiplex systems such as dual laser flow cytometry and the line immunoassay as tools for the detection and measurement of antiretinal antibodies has been suggested but needs to be validated.57 Standardized assays and multicenter collaborations will be essential to further our understanding and definition of these syndromes. It is preferable to obtain results from Clinical Laboratory Improvement Amendments–certified laboratories for clinical diagnosis and management. The Ocular Immunology Laboratory, located at Oregon Health & Science University, obtained Clinical Laboratory Improvement Amendments certification in 2005 for testing antiretinal antibody and anti–optic nerve autoantibody by Western blotting and IHC.101 Other laboratories include the University of Michigan, the University of

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California at Davis, and ophthalmology research laboratories, as well a commercially available antirecoverin assay through Athena Diagnostics.102,105 The current level of evidence suggests that the presence of these antibodies should only be used to confirm or support the diagnosis of CAR or MAR and should not be used in isolation as the diagnostic test. Autoimmune retinopathy thus poses a diagnostic challenge. The diagnosis is ultimately clinical, supported by a characteristic disease onset, diffuse photoreceptor cell degeneration, without or with limited retinal pigmentary changes, and the presence of antiretinal antibodies. However, the challenge with antiretinal antibodies is to identify which antibodies are pathogenic and which are not clinically significant because there is often the frequent finding of multiple serum autoantibodies in a single patient. Autoantibodies against recoverin and a-enolase have been the most widely studied antibodies regarding their pathogenicity, detection, and measurement. Recoverin is the most specific and should be the most alerting to the presence of CAR. Others are not that well proven yet and are still speculative. As discussed above, there is no established treatment protocol for CAR, MAR, or presumed npAIR, and the evidence base for therapeutic intervention includes only few retrospective case series and case reports. The myriad of antiretinal antibodies and the wide spectrum of disease expression add to the challenges of treatment. Treatment efforts have had variable outcomes, at least in part, because once photoreceptors or other retinal structures are irreparably damaged, immunosuppressive therapy will likely not be effective. Recent reports on treatment of AIR are summarized in Table 4. Although visual outcomes are the most important endpoint to monitor during the treatment of AIR, a surrogate serum marker of disease activity such as the antiretinal antibody titer could also be valuable in monitoring these patients. Titers of antiretinal antibodies have previously been shown to decline in response to therapeutic intervention.11 The challenge of obtaining detailed immunologic investigations in clinical practice might limit the potential clinical usefulness of this approach. Additionally, because of assay limitations as described earlier, these results are difficult to interpret, and for accurate measurement of the response to therapeutic intervention, a validated and reproducible assay is essential.

Differential Diagnosis and Summary As discussed, AIR is a complex disorder, and often does not present in a fixed pattern, presumably

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because there are several different combinations of antiretinal antibodies, which result in variations in disease expression. The differential diagnosis of patients with AIR includes 1) hereditary diseases; 2) toxic retinopathies (e.g., plaquenil toxicity); 3) inflammatory white spot diseases like acute zonal occult outer retinopathy, multifocal choroiditis, multiple evanescent white dot syndrome, etc.; 4) DUSN (diffuse unilateral subacute neuroretinitis); and 4) infections such as syphilis, toxoplasmosis, herpes viruses, and others. The detection of antiretinal antibodies in a patient can represent 1) the primary pathogenic explanation of retinal changes; 2) a normal unrelated finding; 3) an epiphenomenon resulting from the release of retinal antigens by a pathologic process; or 4) a secondary process that worsens a pathologic progress. At present, it is difficult in many cases to determine which of the above are operational. However, irrespective of the initiating event, the presence of antiretinal antibodies may contribute to the pathologic processes involved in these retinopathies. Patients without cancer, and some with hereditary, toxic, and inflammatory diseases, may share common clinical features (photopsias, visual loss, night blindness, and visual field loss), there are no antiretinal antibodies that have been reproducibly demonstrated in these patients.16 The role of antiretinal antibodies in the pathogenesis of these conditions is still unclear, and it is probable that they are often an epiphenomenon and not pathogenic in these entities. The challenge is to determine which antibodies are pathogenic and which are benign, and what are the factors present that cause antiretinal antibodies to become pathologic, a sentiment that has also been echoed in recent reviews on the subject.102–104 Our understanding of antiretinal antibodies from an immunologic and genetic standpoint is still in its infancy. Further studies are required to refine the identification of antiretinal autoantibodies, to test their pathogenic potentials through in vivo and in vitro methods, to define clinical and electrophysiological indicators for seropositive patients, and to evaluate treatments.

Method of Literature Search The authors conducted a literature search using the National Library of Medicine’s PubMed database for all English language articles published through June 2013 with the following search terms: Autoimmune retinopathy, anti-retinal antibodies, anti-recoverin, anti-enolase, anti-CA II, bilateral diffuse uveal melanocytic proliferation, cancer associated retinopathy, melanoma associated

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