1040-5488/14/914S-0S66/0 VOL. 91, NO. 4S, PP. S66YS70 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry
CLINICAL CASE
Cystoid Macular Edema from Cancer-Associated Retinopathy Kristen Moyer*, Anthony DeWilde*, and Candice Law†
ABSTRACT Purpose. This article reviews the diagnosis and management of a patient with cancer-associated retinopathy (CAR) secondary to small cell lung cancer who developed a rare presentation of CAR, cystoid macular edema (CME). CAR is a rare cause of unexplained, often rapid, visual acuity and visual field loss. Case Report. A 67-year-old man with a recent history of photopsias and simultaneous dimming of vision presented to our clinic. Four months before, he had been diagnosed with small cell lung cancer. Retinal examination was normal, but the visual field was severely constricted. He was referred for an electroretinogram and an evaluation by a retina specialist because of a strong suspicion of CAR, which was confirmed. Despite a lack of strong clinical evidence for the treatment of CAR, and no clinical recommendations for CME found in CAR, our patient’s CME was initially treated with diclofenac QID and, subsequently, a sub-tenon injection of triamcinolone. Since his diagnosis of CME, he has been chronically managed with diclofenac QID to treat his edema, with relatively stable visual acuity. His visual fields remain highly constricted. Conclusions. CAR is a rare form of painless bilateral vision loss in patients with a history of cancer. Our patient developed CME from his CAR, and was treated with diclofenac and sub-tenon injections of triamcinolone. Despite potential options for treatment, none have demonstrated much efficacy, and the visual prognosis is typically poor. (Optom Vis Sci 2014;91:S66YS70) Key Words: cancer-associated retinopathy, cystoid macular edema, small cell lung cancer, recoverin, autoantibodies
C
ancer-associated retinopathy (CAR) is a rare visual syndrome mediated by an autoimmune response against tumor antigens that cross-react with retinal antigens, leading to toxicity and, ultimately, retinal cell death. Visual loss, whether by visual acuity (VA) or visual field (VF), is often rapid, and electroretinograms (ERGs) are highly abnormal. We report a case of a 67-year-old with small cell lung cancer, who was ultimately diagnosed with CAR and one of its rarer presentations, cystoid macular edema.
CASE REPORT A 67-year-old man presented to the Kansas City Veterans Affairs Medical Center optometry department complaining of simultaneous dimming of vision with occasional ‘‘flashing lights’’ OU for 4 months. He had been diagnosed a few months before with small cell lung cancer (SCLC) after being examined *OD, FAAO † OD, MS, FAAO Optometry Clinic, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri.
in the emergency room for similar symptoms of dimming vision. Retinal ischemia was suspected and therefore a computed tomography angiography (CTA) of the head and neck was performed, which showed a right paratracheal mass. A subsequent CTA of the chest revealed this paratracheal mass had extended from an upper lobe mass of the right lung, suggestive of a primary lung cancer. SCLC was confirmed upon further testing. Upon his visit to our clinic, his vision was 20/20 OD, 20/20 OS and his intraocular pressure (IOP) was 11 mm Hg OD and 11 mm Hg OS by Goldmann applanation tonometry. Slit-lamp biomicroscopy and dilated fundus examination were unremarkable. Optic nerves were pink and healthy with 0.20 cup-todisk ratios OU, with a normal macula, and normal arteriole and venous vasculature. Visual field testing revealed severe constriction OD and OS (Fig. 1). He was referred to a local medical center for an ERG and evaluation by a retinal specialist because of a strong suspicion of CAR. Communication of the results received from that referral confirmed CAR, as the ERGs collected were close to extinguished. Despite his serum analysis being negative for anti-recoverin autoantibodies, the retina specialist concluded that based on his symptoms and testing results, that
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
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FIGURE 1. Humphrey visual field perimetry results showing constricted visual fields. Reliable fields with central sparing OD and OS.
further work-up in the form of more extensive serum testing for CAR would be of little benefit. The retina specialist recommended a sub-tenon triamcinolone injection of one eye to evaluate treatment efficacy, to be given at our facility. The patient consented to a sub-tenon triamcinolone (0.5 mg of 40 mg/mL) injection to his OD. He was followed every 3 months to see if there was any objective or subjective improvement in his vision. During the following 9 months, there was no change in VA or visual field OU. Approximately 1 year after his initial visit, he was considered to be in remission from his cancer. He returned to the optometry clinic at that time. He reported no improvement in his vision OD despite the sub-tenon injection and now noted a decrease in his vision OS. His visual acuity was 20/25 OD and 20/80 OS. His
slit-lamp biomicroscopy examination was unremarkable. His intraocular pressures measured 28 mm Hg OD and 14 mm Hg OS. The increase in IOP OD was determined to be caused by a steroid response. Dilated fundus examination and subsequent optical coherence tomography (OCT) revealed cystoid macular edema (CME) OS only (Fig. 2), and he was scheduled for a fluorescein angiogram (FA). To manage the increased IOP in the right eye, we initiated treatment with travoprost OD only. His optic nerve OD had a 0.2 cup-to-disk ratio and had no signs of glaucomatous atrophy. Two weeks later, the FA was performed and minimal leakage was seen in both eyes. He was diagnosed with CME OU. His IOP measured 16 mm Hg on travoprost qhs OD only and 14 mm Hg OS. Based on the FA results and his history of steroid response,
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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S68 Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
FIGURE 2. Macular optical coherence tomography of our patient with cystoid macular edema from cancer-associated retinopathy in his left eye, pretreatment.
he was prescribed the formulary medication, diclofenac QID OU, to manage his bilateral edema. Because of the CME and increased risk of inflammation with prostaglandin treatment, the travoprost was discontinued and he was prescribed brominidine tartrate BID OD. Six weeks later, his visual acuity was 20/30 OD and 20/50 OS, and the intraocular pressures were 18 mm Hg OU. Dilation and OCT OU revealed no edema OD, but persistent CME OS. Based on his limited improvement OS, a sub-tenon injection of triamcinolone 20 mg (0.5 mL of 40 mg/mL) was given to the left eye, and brominidine tartrate BID OS was added as a prophylactic treatment against a steroid response. Oncology was consulted regarding the possibility of pursuing plasmapheresis or intravenous immunoglobulin (IVIg) treatment. These treatments were not pursued because of the lack of clinical evidence for improvement in visual outcomes. Six weeks later, his visual acuity was 20/60 OD secondary to a posterior subscapsular cataract that had likely developed from his sub-tenon injection. His vision remained stable at 20/30 OS because of his persistent CME. He underwent cataract extraction OD, and after a complicated postoperative course, his visual acuity stabilized at 20/30 OD. His macula was flat in this eye, and the macula in his OS had improved CME with vision of 20/30, approximately 3 months after his sub-tenon injection (Fig. 3). He eventually underwent cataract extraction in his left eye with an uncomplicated postoperative recovery. He continued to be evaluated every few months and his vision remained stable at 20/30 OD, 20/30 OS with persistent intermittent mild CME controlled with diclofenac QID OU, and intraocular pressures controlled with glaucoma medications. Three years after his initial visit, he continued to remain in remission with relatively stable VA and constricted visual fields.
of lights, or intermittent dimming of vision. Visual loss is progressive, bilateral, and typically painless.1Y6 It can occur rapidly or may slowly progress over a period of years.7 The fundus can appear normal or present with narrowing of the arterioles, and atrophy and mottling of the retinal pigment epithelium.1,4,6,8,9 Cystoid macular edema is rare in CAR.10Y12 The optic nerve usually appears normal but can develop a waxy pale appearance over a period of years.4 There have also been a few reports of associated uveitis, vitritis, and vascular sheathing.4,13 Circulating autoantibodies collected via a serum analysis may or may not be present.8 Abnormal visual fields are typically ring scotomas or severely restricted. Because CAR affects both rods and cones, patients will have abnormal electroretinograms.6,13 OCT findings include decreased macular thickness, loss of the photoreceptor layer or abnormal outer and inner segment junction (Fig. 3, arrow), loss of the outer nuclear layer, and mild to moderate focal retinal nerve fiber layer loss.5,14,15 Of those patients diagnosed with CAR, most cases are in small cell lung cancer (16Y66%) or breast cancer (16Y31%), but there have also been associated cases with cancer of the colon (6%),
DISCUSSION Clinical Presentation CAR may initially present with photopsias, glare, photosensitivity, blurred vision, night blindness, and abnormal color vision. The photopsias can be described as flickering or shimmering
FIGURE 3. Macular optical coherence tomography OS post treatment with nearly resolved cystoid macular edema. Also note loss of the photoreceptor inner and outer segment junction (arrow).
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
prostate (7%), gynecological (cervix, ovaries, endometrium) (9%), and hematological (lymphomas, leukemias) (15%). There is one case report each of CAR associated with a hepatocellular carcinoma, benign breast tumor, and thymoma.1,4,8,16 Average age at diagnosis is 65, with anywhere from an equal to 2:1 ratio women to men.2,8 Symptoms of CAR can sometimes precede diagnoses of the underlying cancer.6 In one study, approximately 4% of 209 patients were diagnosed with cancer after their diagnosis of CAR.8 However, there is usually a year or more latency between cancer diagnoses and the presence of CAR.8,17
Pathophysiology CAR is a subset of the autoimmune retinopathies (AIRs). Autoimmune retinopathies lead to rapid VA or visual field loss, have abnormal ERG testing, and are typically associated with autoantibodies against retinal antigens. They are divided into the paraneoplastic syndromes, which consist of CAR and melanomaassociated retinopathy, and the nonparaneoplastics autoimmune retinopathies (npAIR), which do not have any underlying cancer.10 All autoimmune retinopathies, including CAR, lead to retinal degeneration. In CAR, the loss of sight is associated with an autoimmune defense against the cancer. Autoimmunity triggered by the body’s response to tumor antigens cross-react with similar retinal antigens. The autoantibodies cross the blood retinal barrier and induce apoptosis of retinal cells.1,7,8,10,18,19 Small cell lung cancer is thought to derive from the tracheobronchial cells, which have neuroendocrine characteristics like those found in the central nervous system and retina. These tracheobronchial cells are thought to release peptides which have a toxic effect on retinal cells.1 One of the main peptides thought to be involved is the antigen targeting recoverin.1 Autoimmunity inactivates recoverin in the bipolar and photoreceptor cells, which leads to photoreceptor death.1,14,20 In an in vitro study of serum, greater concentration of anti-recoverin antibodies and greater time of exposure increased toxicity and retinal cell death.3 Autoantibodies can develop against other retinal antigens including alpha-enolase, heat-shock proteins, arrestin, transducin, carbonic anhydrase II (CAII), and TULP-1. These various autoantibodies can affect the inner segments, ganglion cells, and photoreceptors, leading to cell death.14,19,20 Normals may also have antiretinal antibodies, and their presence does not automatically indicate CAR.14 For example, studies show that anti-recoverin is present in 10% of normals, anti-alphaenolase is present in 10 to 30% of normals, and anti-CAII is present in 14 to 30% of normals.4,8,14 In contrast, up to a third of patients with CAR may be negative for autoantibodies. In one study of SCLC patients with CAR, 44% had anti-recoverin, 22% had other anti-retinal antibodies, and 33% were seronegative.8 In another study of 52 patients with CAR with varying cancers, 63.5% had autoantibodies. These autoantibodies can be detected in the blood serum from months to years after diagnosis of CAR.9
Diagnosis The diagnosis of CAR is made based on clinical symptoms, visual fields, and ERGs, and may be reinforced by a positive serum
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analysis. OCT may help aid in the diagnosis when the fundus appears normal. For example, loss of the photoreceptor inner and outer segment junction may be seen.14 ERG responses are variable, but there are usually decreased or absent scotopic and photopic responses.4,13 It is difficult to determine to what degree serum analysis aids in the diagnoses, given the lack of standardization in how and what antibodies to test for. Also unknown is the sensitivity, specificity, and positive and negative predictive values for autoantibody testing.4 Differential diagnosis of CAR is any of the other similar autoimmune retinopathies. Lesser differentials include hereditary retinal degenerative dystrophies, including retinitis pigmentosa (RP), or hereditary optic neuropathies. Electroretinograms, OCTs, and a systemic work-up for cancer can help aid in the final diagnosis. In those with a history of cancer, evaluation for infiltration of the primary malignancy needs to be conducted. One should consider referral for evaluation of CAR in a patient with a history of cancer and unexplained visual loss with the above symptoms and abnormal visual fields. This includes ERGs and possibly serum testing. Those without cancer should consider undergoing an evaluation for cancer.4,5,10,13,16
Treatment Treatment effectiveness has been variable, and no standard treatment exists. In theory, modulating the body’s immunity should improve visual outcomes.1 However, there is a poor visual prognosis in most cases. Treatment for any manifestation of CAR, including CME, may involve immunosuppressants such as steroids, IVIg, and plasmapheresis. Solid clinical evidence of treatment effectiveness is scarce.4 It is difficult to determine any effective treatment in part because of the rarity of the condition and the unlikeliness of gaining enough clinical evidence to conduct a controlled clinical trial, especially given the often fatal natures of the cancers associated with CAR.4 Samples sizes are small; most conclusions of treatment efficacy have to be deduced from a series of case reports or studies analyzing a series of case reports. Small case studies have reported transient improvement in visual symptoms while others have reported no improvement when treated with immunosuppressive agents such as steroids, IVIg, cyclosporine, azathioprine, and alemtuzumab.6,10,12,21 It has been demonstrated in some studies that the earlier immunosuppressive treatment is initiated, the more likely the patient is to experience improvement or stabilization before the majority of photoreceptor degeneration has occurred.5,6,10,13,21 Plasmapheresis has failed to improve visual outcomes.1 The presence or absence of the cancer itself has no direct effect on autoantibodies.9 In fact, autoantibodies and their effects can persist long after the cancer is in remission.22 Therefore, treatment of the primary cancer has been shown to be ineffective in stabilizing or improving CAR retinopathy.5,13 There is scarce literature available regarding the treatment of CME in CAR. Huynh et al reported an improvement in visual function of a man with CAR with bilateral CME treated with a series of intravitreal steroids who had not responded to systemic mycophenolate and IVIg therapy.11 VA improved from 20/ 125 OD to 20/40 OD, and from 20/60 OS to 20/32 OS. Intravitreal steroids may locally suppress the inflammatory response caused by the autoantibodies.11 Another case report demonstrating a
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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S70 Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
patient diagnosed with mild CME from CAR in neuroendocrine carcinoma was not treated. The patient maintained relatively stable acuity.12 Combination treatment of local and systemic agents for CAR, and CME in npAIR, has been investigated. One study involved 30 patients with either CAR or npAIR, of which 11 of the npAIR patients had CME. No CAR patients had CME. Subjects were treated with systemic cyclosporine, azathioprine, and prednisone or sub-tenon injections, or both, of methylprednisolone acetate. There was no standardized treatment, and many patients discontinued the systemic therapy because of side effects. All CAR patients either improved by VA, VF, or ERG. Of those npAIR patients with CME, three patients did not improve, six improved by visual field only, and only two improved by VA. The CME improved in six of these eight ‘‘responders,’’ but no specifics were given for any of the measures.10 There was only one pretreatment measurement of VF and VA, and only a summary of the final measures of VF. Therapeutic efficacy was therefore difficult to determine.23
CONCLUSIONS CAR is a rare cause of painless binocular vision loss triggered by an autoimmune response against cancer antigens that leads to retinal cell toxicity and death. Diagnosis is made on clinical presentation, ophthalmic testing, and blood serum testing. Treatment effectiveness is largely undetermined because of the absence of solid clinic evidence and clinical trials as well as the rarity of the condition. This includes the management of CME in cases of CAR. Much appears to still be unknown about CAR. Given that autoantibodies are found in only two thirds of those with CAR, and that immunosuppression therapy is generally ineffective, there may be alternate or contributing factors that are still unknown.
ACKNOWLEDGMENTS The authors have no conflicts of interest in the materials or techniques used in this paper. Received October 7, 2013; accepted December 11, 2013.
REFERENCES 1. Tanaka A, Takase H, Adamus G, Mochizuki M. Cancer-associated retinopathy caused by benign thymoma. Br J Ophthalmol 2010;94: 526Y8. 2. Carboni G, Forma G, Bond AD, Adamus G, Iannaccone A. Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss. Doc Ophthalmol 2012;125: 63Y70. 3. Adamus G, Machnicki M, Seigel GM. Apoptotic retinal cell death induced by antirecoverin autoantibodies of cancer-associated retinopathy. Invest Ophthalmol Vis Sci 1997;38:283Y91. 4. Braithwaite T, Vugler A, Tufail A. Autoimmune retinopathy. Ophthalmologica 2012;228:131Y42. 5. Ling CP, Pavesio C. Paraneoplastic syndromes associated with visual loss. Curr Opin Ophthalmol 2003;14:426Y32.
6. Sakamori Y, Kim YH, Okuda C, Togashi Y, Kinose D, Masago K, Mio T, Uji A, Mishima M. Two cases of cancer-associated retinopathy combined with small-cell lung cancer. Jpn J Clin Oncol 2011;41:669Y73. 7. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105:372Y5. 8. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev 2009;8:410Y4. 9. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004;4:5. Available at: http://www.biomedcentral.com/ 1471-2415/4/5. Accessed: August 2, 2013. 10. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol 2009;127:390Y7. 11. Huynh N, Shildkrot Y, Lobo AM, Sobrin L. Intravitreal triamcinolone for cancer-associated retinopathy refractory to systemic therapy. J Ophthalmic Inflamm Infect 2012;2:169Y71. 12. Raghunath A, Adamus G, Bodurka DC, Liu J, Schiffman JS. Cancerassociated retinopathy in neuroendocrine carcinoma of the fallopian tube. J Neuroophthalmol 2010;30:252Y4. 13. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003;48:12Y38. 14. Abazari A, Allam SS, Adamus G, Ghazi NG. Optical coherence tomography findings in autoimmune retinopathy. Am J Ophthalmol 2012;153:750Y6. 15. Pepple KL, Cusick M, Jaffe GJ, Mruthyunjaya P. SD-OCT and autofluorescence characteristics of autoimmune retinopathy. Br J Ophthalmol 2013;97:139Y44. 16. Chang PY, Yang CH, Yang CM. Cancer-associated retinopathy in a patient with hepatocellular carcinoma: case report and literature review. Retina 2005;25:1093Y6. 17. Saito W, Kase S, Ohguro H, Furudate N, Ohno S. Slowly progressive cancer-associated retinopathy. Arch Ophthalmol 2007;125:1431Y3. 18. Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL. The cancerassociated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992;33:2768Y72. 19. Adamus G, Karren L. Autoimmunity against carbonic anhydrase II affects retinal cell functions in autoimmune retinopathy. J Autoimmun 2009;32:133Y9. 20. Ren G, Adamus G. Cellular targets of anti-alpha-enolase autoantibodies of patients with autoimmune retinopathy. J Autoimmun 2004;23:161Y7. 21. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 1999;117:471Y7. 22. Espandar L, O’Brien S, Thirkill C, Lubecki LA, Esmaeli B. Successful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol 2007;83:295Y302. 23. Heckenlively JR, Ferreyra HA, Jayasundera T. Controversies of diagnosing autoimmune retinopathy. Arch Ophthalmol 2010;128: 147Y8; author reply 8Y9.
Kristen Moyer Kansas City VA Medical Center Optometry Clinic 4801 East Linwood Blvd Kansas City, MO 64128 e-mail: [email protected]
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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CLINICAL CASE
Cystoid Macular Edema from Cancer-Associated Retinopathy Kristen Moyer*, Anthony DeWilde*, and Candice Law†
ABSTRACT Purpose. This article reviews the diagnosis and management of a patient with cancer-associated retinopathy (CAR) secondary to small cell lung cancer who developed a rare presentation of CAR, cystoid macular edema (CME). CAR is a rare cause of unexplained, often rapid, visual acuity and visual field loss. Case Report. A 67-year-old man with a recent history of photopsias and simultaneous dimming of vision presented to our clinic. Four months before, he had been diagnosed with small cell lung cancer. Retinal examination was normal, but the visual field was severely constricted. He was referred for an electroretinogram and an evaluation by a retina specialist because of a strong suspicion of CAR, which was confirmed. Despite a lack of strong clinical evidence for the treatment of CAR, and no clinical recommendations for CME found in CAR, our patient’s CME was initially treated with diclofenac QID and, subsequently, a sub-tenon injection of triamcinolone. Since his diagnosis of CME, he has been chronically managed with diclofenac QID to treat his edema, with relatively stable visual acuity. His visual fields remain highly constricted. Conclusions. CAR is a rare form of painless bilateral vision loss in patients with a history of cancer. Our patient developed CME from his CAR, and was treated with diclofenac and sub-tenon injections of triamcinolone. Despite potential options for treatment, none have demonstrated much efficacy, and the visual prognosis is typically poor. (Optom Vis Sci 2014;91:S66YS70) Key Words: cancer-associated retinopathy, cystoid macular edema, small cell lung cancer, recoverin, autoantibodies
C
ancer-associated retinopathy (CAR) is a rare visual syndrome mediated by an autoimmune response against tumor antigens that cross-react with retinal antigens, leading to toxicity and, ultimately, retinal cell death. Visual loss, whether by visual acuity (VA) or visual field (VF), is often rapid, and electroretinograms (ERGs) are highly abnormal. We report a case of a 67-year-old with small cell lung cancer, who was ultimately diagnosed with CAR and one of its rarer presentations, cystoid macular edema.
CASE REPORT A 67-year-old man presented to the Kansas City Veterans Affairs Medical Center optometry department complaining of simultaneous dimming of vision with occasional ‘‘flashing lights’’ OU for 4 months. He had been diagnosed a few months before with small cell lung cancer (SCLC) after being examined *OD, FAAO † OD, MS, FAAO Optometry Clinic, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri.
in the emergency room for similar symptoms of dimming vision. Retinal ischemia was suspected and therefore a computed tomography angiography (CTA) of the head and neck was performed, which showed a right paratracheal mass. A subsequent CTA of the chest revealed this paratracheal mass had extended from an upper lobe mass of the right lung, suggestive of a primary lung cancer. SCLC was confirmed upon further testing. Upon his visit to our clinic, his vision was 20/20 OD, 20/20 OS and his intraocular pressure (IOP) was 11 mm Hg OD and 11 mm Hg OS by Goldmann applanation tonometry. Slit-lamp biomicroscopy and dilated fundus examination were unremarkable. Optic nerves were pink and healthy with 0.20 cup-todisk ratios OU, with a normal macula, and normal arteriole and venous vasculature. Visual field testing revealed severe constriction OD and OS (Fig. 1). He was referred to a local medical center for an ERG and evaluation by a retinal specialist because of a strong suspicion of CAR. Communication of the results received from that referral confirmed CAR, as the ERGs collected were close to extinguished. Despite his serum analysis being negative for anti-recoverin autoantibodies, the retina specialist concluded that based on his symptoms and testing results, that
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
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FIGURE 1. Humphrey visual field perimetry results showing constricted visual fields. Reliable fields with central sparing OD and OS.
further work-up in the form of more extensive serum testing for CAR would be of little benefit. The retina specialist recommended a sub-tenon triamcinolone injection of one eye to evaluate treatment efficacy, to be given at our facility. The patient consented to a sub-tenon triamcinolone (0.5 mg of 40 mg/mL) injection to his OD. He was followed every 3 months to see if there was any objective or subjective improvement in his vision. During the following 9 months, there was no change in VA or visual field OU. Approximately 1 year after his initial visit, he was considered to be in remission from his cancer. He returned to the optometry clinic at that time. He reported no improvement in his vision OD despite the sub-tenon injection and now noted a decrease in his vision OS. His visual acuity was 20/25 OD and 20/80 OS. His
slit-lamp biomicroscopy examination was unremarkable. His intraocular pressures measured 28 mm Hg OD and 14 mm Hg OS. The increase in IOP OD was determined to be caused by a steroid response. Dilated fundus examination and subsequent optical coherence tomography (OCT) revealed cystoid macular edema (CME) OS only (Fig. 2), and he was scheduled for a fluorescein angiogram (FA). To manage the increased IOP in the right eye, we initiated treatment with travoprost OD only. His optic nerve OD had a 0.2 cup-to-disk ratio and had no signs of glaucomatous atrophy. Two weeks later, the FA was performed and minimal leakage was seen in both eyes. He was diagnosed with CME OU. His IOP measured 16 mm Hg on travoprost qhs OD only and 14 mm Hg OS. Based on the FA results and his history of steroid response,
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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S68 Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
FIGURE 2. Macular optical coherence tomography of our patient with cystoid macular edema from cancer-associated retinopathy in his left eye, pretreatment.
he was prescribed the formulary medication, diclofenac QID OU, to manage his bilateral edema. Because of the CME and increased risk of inflammation with prostaglandin treatment, the travoprost was discontinued and he was prescribed brominidine tartrate BID OD. Six weeks later, his visual acuity was 20/30 OD and 20/50 OS, and the intraocular pressures were 18 mm Hg OU. Dilation and OCT OU revealed no edema OD, but persistent CME OS. Based on his limited improvement OS, a sub-tenon injection of triamcinolone 20 mg (0.5 mL of 40 mg/mL) was given to the left eye, and brominidine tartrate BID OS was added as a prophylactic treatment against a steroid response. Oncology was consulted regarding the possibility of pursuing plasmapheresis or intravenous immunoglobulin (IVIg) treatment. These treatments were not pursued because of the lack of clinical evidence for improvement in visual outcomes. Six weeks later, his visual acuity was 20/60 OD secondary to a posterior subscapsular cataract that had likely developed from his sub-tenon injection. His vision remained stable at 20/30 OS because of his persistent CME. He underwent cataract extraction OD, and after a complicated postoperative course, his visual acuity stabilized at 20/30 OD. His macula was flat in this eye, and the macula in his OS had improved CME with vision of 20/30, approximately 3 months after his sub-tenon injection (Fig. 3). He eventually underwent cataract extraction in his left eye with an uncomplicated postoperative recovery. He continued to be evaluated every few months and his vision remained stable at 20/30 OD, 20/30 OS with persistent intermittent mild CME controlled with diclofenac QID OU, and intraocular pressures controlled with glaucoma medications. Three years after his initial visit, he continued to remain in remission with relatively stable VA and constricted visual fields.
of lights, or intermittent dimming of vision. Visual loss is progressive, bilateral, and typically painless.1Y6 It can occur rapidly or may slowly progress over a period of years.7 The fundus can appear normal or present with narrowing of the arterioles, and atrophy and mottling of the retinal pigment epithelium.1,4,6,8,9 Cystoid macular edema is rare in CAR.10Y12 The optic nerve usually appears normal but can develop a waxy pale appearance over a period of years.4 There have also been a few reports of associated uveitis, vitritis, and vascular sheathing.4,13 Circulating autoantibodies collected via a serum analysis may or may not be present.8 Abnormal visual fields are typically ring scotomas or severely restricted. Because CAR affects both rods and cones, patients will have abnormal electroretinograms.6,13 OCT findings include decreased macular thickness, loss of the photoreceptor layer or abnormal outer and inner segment junction (Fig. 3, arrow), loss of the outer nuclear layer, and mild to moderate focal retinal nerve fiber layer loss.5,14,15 Of those patients diagnosed with CAR, most cases are in small cell lung cancer (16Y66%) or breast cancer (16Y31%), but there have also been associated cases with cancer of the colon (6%),
DISCUSSION Clinical Presentation CAR may initially present with photopsias, glare, photosensitivity, blurred vision, night blindness, and abnormal color vision. The photopsias can be described as flickering or shimmering
FIGURE 3. Macular optical coherence tomography OS post treatment with nearly resolved cystoid macular edema. Also note loss of the photoreceptor inner and outer segment junction (arrow).
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
prostate (7%), gynecological (cervix, ovaries, endometrium) (9%), and hematological (lymphomas, leukemias) (15%). There is one case report each of CAR associated with a hepatocellular carcinoma, benign breast tumor, and thymoma.1,4,8,16 Average age at diagnosis is 65, with anywhere from an equal to 2:1 ratio women to men.2,8 Symptoms of CAR can sometimes precede diagnoses of the underlying cancer.6 In one study, approximately 4% of 209 patients were diagnosed with cancer after their diagnosis of CAR.8 However, there is usually a year or more latency between cancer diagnoses and the presence of CAR.8,17
Pathophysiology CAR is a subset of the autoimmune retinopathies (AIRs). Autoimmune retinopathies lead to rapid VA or visual field loss, have abnormal ERG testing, and are typically associated with autoantibodies against retinal antigens. They are divided into the paraneoplastic syndromes, which consist of CAR and melanomaassociated retinopathy, and the nonparaneoplastics autoimmune retinopathies (npAIR), which do not have any underlying cancer.10 All autoimmune retinopathies, including CAR, lead to retinal degeneration. In CAR, the loss of sight is associated with an autoimmune defense against the cancer. Autoimmunity triggered by the body’s response to tumor antigens cross-react with similar retinal antigens. The autoantibodies cross the blood retinal barrier and induce apoptosis of retinal cells.1,7,8,10,18,19 Small cell lung cancer is thought to derive from the tracheobronchial cells, which have neuroendocrine characteristics like those found in the central nervous system and retina. These tracheobronchial cells are thought to release peptides which have a toxic effect on retinal cells.1 One of the main peptides thought to be involved is the antigen targeting recoverin.1 Autoimmunity inactivates recoverin in the bipolar and photoreceptor cells, which leads to photoreceptor death.1,14,20 In an in vitro study of serum, greater concentration of anti-recoverin antibodies and greater time of exposure increased toxicity and retinal cell death.3 Autoantibodies can develop against other retinal antigens including alpha-enolase, heat-shock proteins, arrestin, transducin, carbonic anhydrase II (CAII), and TULP-1. These various autoantibodies can affect the inner segments, ganglion cells, and photoreceptors, leading to cell death.14,19,20 Normals may also have antiretinal antibodies, and their presence does not automatically indicate CAR.14 For example, studies show that anti-recoverin is present in 10% of normals, anti-alphaenolase is present in 10 to 30% of normals, and anti-CAII is present in 14 to 30% of normals.4,8,14 In contrast, up to a third of patients with CAR may be negative for autoantibodies. In one study of SCLC patients with CAR, 44% had anti-recoverin, 22% had other anti-retinal antibodies, and 33% were seronegative.8 In another study of 52 patients with CAR with varying cancers, 63.5% had autoantibodies. These autoantibodies can be detected in the blood serum from months to years after diagnosis of CAR.9
Diagnosis The diagnosis of CAR is made based on clinical symptoms, visual fields, and ERGs, and may be reinforced by a positive serum
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analysis. OCT may help aid in the diagnosis when the fundus appears normal. For example, loss of the photoreceptor inner and outer segment junction may be seen.14 ERG responses are variable, but there are usually decreased or absent scotopic and photopic responses.4,13 It is difficult to determine to what degree serum analysis aids in the diagnoses, given the lack of standardization in how and what antibodies to test for. Also unknown is the sensitivity, specificity, and positive and negative predictive values for autoantibody testing.4 Differential diagnosis of CAR is any of the other similar autoimmune retinopathies. Lesser differentials include hereditary retinal degenerative dystrophies, including retinitis pigmentosa (RP), or hereditary optic neuropathies. Electroretinograms, OCTs, and a systemic work-up for cancer can help aid in the final diagnosis. In those with a history of cancer, evaluation for infiltration of the primary malignancy needs to be conducted. One should consider referral for evaluation of CAR in a patient with a history of cancer and unexplained visual loss with the above symptoms and abnormal visual fields. This includes ERGs and possibly serum testing. Those without cancer should consider undergoing an evaluation for cancer.4,5,10,13,16
Treatment Treatment effectiveness has been variable, and no standard treatment exists. In theory, modulating the body’s immunity should improve visual outcomes.1 However, there is a poor visual prognosis in most cases. Treatment for any manifestation of CAR, including CME, may involve immunosuppressants such as steroids, IVIg, and plasmapheresis. Solid clinical evidence of treatment effectiveness is scarce.4 It is difficult to determine any effective treatment in part because of the rarity of the condition and the unlikeliness of gaining enough clinical evidence to conduct a controlled clinical trial, especially given the often fatal natures of the cancers associated with CAR.4 Samples sizes are small; most conclusions of treatment efficacy have to be deduced from a series of case reports or studies analyzing a series of case reports. Small case studies have reported transient improvement in visual symptoms while others have reported no improvement when treated with immunosuppressive agents such as steroids, IVIg, cyclosporine, azathioprine, and alemtuzumab.6,10,12,21 It has been demonstrated in some studies that the earlier immunosuppressive treatment is initiated, the more likely the patient is to experience improvement or stabilization before the majority of photoreceptor degeneration has occurred.5,6,10,13,21 Plasmapheresis has failed to improve visual outcomes.1 The presence or absence of the cancer itself has no direct effect on autoantibodies.9 In fact, autoantibodies and their effects can persist long after the cancer is in remission.22 Therefore, treatment of the primary cancer has been shown to be ineffective in stabilizing or improving CAR retinopathy.5,13 There is scarce literature available regarding the treatment of CME in CAR. Huynh et al reported an improvement in visual function of a man with CAR with bilateral CME treated with a series of intravitreal steroids who had not responded to systemic mycophenolate and IVIg therapy.11 VA improved from 20/ 125 OD to 20/40 OD, and from 20/60 OS to 20/32 OS. Intravitreal steroids may locally suppress the inflammatory response caused by the autoantibodies.11 Another case report demonstrating a
Optometry and Vision Science, Vol. 91, No. 4S, April 2014
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S70 Cystoid Macular Edema from Cancer-Associated RetinopathyVMoyer et al.
patient diagnosed with mild CME from CAR in neuroendocrine carcinoma was not treated. The patient maintained relatively stable acuity.12 Combination treatment of local and systemic agents for CAR, and CME in npAIR, has been investigated. One study involved 30 patients with either CAR or npAIR, of which 11 of the npAIR patients had CME. No CAR patients had CME. Subjects were treated with systemic cyclosporine, azathioprine, and prednisone or sub-tenon injections, or both, of methylprednisolone acetate. There was no standardized treatment, and many patients discontinued the systemic therapy because of side effects. All CAR patients either improved by VA, VF, or ERG. Of those npAIR patients with CME, three patients did not improve, six improved by visual field only, and only two improved by VA. The CME improved in six of these eight ‘‘responders,’’ but no specifics were given for any of the measures.10 There was only one pretreatment measurement of VF and VA, and only a summary of the final measures of VF. Therapeutic efficacy was therefore difficult to determine.23
CONCLUSIONS CAR is a rare cause of painless binocular vision loss triggered by an autoimmune response against cancer antigens that leads to retinal cell toxicity and death. Diagnosis is made on clinical presentation, ophthalmic testing, and blood serum testing. Treatment effectiveness is largely undetermined because of the absence of solid clinic evidence and clinical trials as well as the rarity of the condition. This includes the management of CME in cases of CAR. Much appears to still be unknown about CAR. Given that autoantibodies are found in only two thirds of those with CAR, and that immunosuppression therapy is generally ineffective, there may be alternate or contributing factors that are still unknown.
ACKNOWLEDGMENTS The authors have no conflicts of interest in the materials or techniques used in this paper. Received October 7, 2013; accepted December 11, 2013.
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6. Sakamori Y, Kim YH, Okuda C, Togashi Y, Kinose D, Masago K, Mio T, Uji A, Mishima M. Two cases of cancer-associated retinopathy combined with small-cell lung cancer. Jpn J Clin Oncol 2011;41:669Y73. 7. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105:372Y5. 8. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev 2009;8:410Y4. 9. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004;4:5. Available at: http://www.biomedcentral.com/ 1471-2415/4/5. Accessed: August 2, 2013. 10. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol 2009;127:390Y7. 11. Huynh N, Shildkrot Y, Lobo AM, Sobrin L. Intravitreal triamcinolone for cancer-associated retinopathy refractory to systemic therapy. J Ophthalmic Inflamm Infect 2012;2:169Y71. 12. Raghunath A, Adamus G, Bodurka DC, Liu J, Schiffman JS. Cancerassociated retinopathy in neuroendocrine carcinoma of the fallopian tube. J Neuroophthalmol 2010;30:252Y4. 13. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003;48:12Y38. 14. Abazari A, Allam SS, Adamus G, Ghazi NG. Optical coherence tomography findings in autoimmune retinopathy. Am J Ophthalmol 2012;153:750Y6. 15. Pepple KL, Cusick M, Jaffe GJ, Mruthyunjaya P. SD-OCT and autofluorescence characteristics of autoimmune retinopathy. Br J Ophthalmol 2013;97:139Y44. 16. Chang PY, Yang CH, Yang CM. Cancer-associated retinopathy in a patient with hepatocellular carcinoma: case report and literature review. Retina 2005;25:1093Y6. 17. Saito W, Kase S, Ohguro H, Furudate N, Ohno S. Slowly progressive cancer-associated retinopathy. Arch Ophthalmol 2007;125:1431Y3. 18. Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL. The cancerassociated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 1992;33:2768Y72. 19. Adamus G, Karren L. Autoimmunity against carbonic anhydrase II affects retinal cell functions in autoimmune retinopathy. J Autoimmun 2009;32:133Y9. 20. Ren G, Adamus G. Cellular targets of anti-alpha-enolase autoantibodies of patients with autoimmune retinopathy. J Autoimmun 2004;23:161Y7. 21. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 1999;117:471Y7. 22. Espandar L, O’Brien S, Thirkill C, Lubecki LA, Esmaeli B. Successful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol 2007;83:295Y302. 23. Heckenlively JR, Ferreyra HA, Jayasundera T. Controversies of diagnosing autoimmune retinopathy. Arch Ophthalmol 2010;128: 147Y8; author reply 8Y9.
Kristen Moyer Kansas City VA Medical Center Optometry Clinic 4801 East Linwood Blvd Kansas City, MO 64128 e-mail: [email protected]
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