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Unilateral manifestation of autoimmune retinopathy

      Autoimmune retinopathy (AIR) encompasses a spectrum of rare autoimmune diseases, including cancer-associated retinopathy and nonparaneoplastic-associated retinopathy, which primarily affect retinal photoreceptor function, and melanoma-associated retinopathy (MAR), which primarily affects bipolar cell function. Clinical features include panretinal degeneration with no or little pigment deposition, progressive visual field deficits, and photopsias with or without a history of carcinoma or melanoma at the time of ocular presentation.
      • Heckenlively J.R.
      • Ferreyra H.A.
      Autoimmune retinopathy: a review and summary.
      The condition is initially unilateral with symptoms generally spreading to the contralateral eye within an interval of 4 days to 2 months.
      • Kellner U.
      • Bornfeld N.
      • Foerster M.H.
      Severe course of cutaneous melanoma associated paraneoplastic retinopathy.
      We report a case of AIR that has remained unilateral during an observation period of over 3 years.
      A squamous cell carcinoma was resected from the month and tongue of a 50-year-old male with an extensive history of cigarette smoking and alcohol consumption. At the time of resection, there was no evidence of systemic disease and the patient did not undergo any radiation or systemic chemotherapy. The patient presented 11 years later with a visual acuity of 20/20 OU and a chief complaint of a small central scotoma in only his right eye. Fundus examination revealed macular granularity and attenuation of the arteries and veins (Fig. 1). Loss of the I1e isopter, scattered central scotomas to the I4e isopter, and irregular constriction of the I2e and I4e isopters was seen on Goldmann visual fields (GVFs; Fig. 1). Optical coherence tomography (OCT; Heidelberg Spectralis, Heidelberg, Germany) displayed diffuse disruption of the photoreceptor inner segment–outer segment junction and diffuse thinning of all retinal layers throughout the macula; OCT of the left eye was normal (Fig. 2). The intraocular pressure was 18 and 17 mm Hg in the right and left eyes, respectively. Fundus autofluorescence and intravenous fluorescein angiography did not reveal any significant abnormal findings in either eye.
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      Fig. 1Fundus photograph of the macula and optic nerve and Goldmann visual fields (GVFs) at initial presentation for the right and left eyes (top panel). The right eye demonstrated granularity in the macular area with attenuation of the arteries with temporal pallor of the optic nerve. GVF testing of the right eye revealed loss of the I1e isopter, marked constriction of the I2e isopter, scattered central scotomas to the I4e isopter, irregular peripheral constriction of the I4e isopter, and enlargement of the blind spot. The left eye is normal. GVFs of the right eye over time (middle panel). There was increased constriction of the I2e isopter and increase of the I4e scotomas. Fundus photography of the macula and optic nerve and GVFs at final presentation for the right and left eyes (bottom panel). The right eye showed further vascular attenuation with continued temporal pallor of the optic nerve. GVF testing of the right eye revealed minimal remaining I2e isopter and further constriction of the I4e isopter. The left eye remained normal at a follow-up of over 3 years.
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      Fig. 2Spectral-domain optical coherence tomography (OCT) image of the right and left eyes. A, The central macular thickness was 229 μm OD and 288 μm OS. The right eye demonstrated disruption of the photoreceptor inner segment–outer segment junction with focal areas of photoreceptor loss. There is thinning of all retinal layers in the right eye. B, The left eye is normal.
      Full-field electroretinogram (ERG) displayed flat cone and rod responses with a severely attenuated maximal combined response in the right eye with normal responses in the left eye. Multifocal ERG (mfERG) demonstrated a severely attenuated response in the right eye with normal waveforms in the left eye. Anti-retinal antibodies (Ocular Immunology Lab, Oregon Health & Science University, Portland, Oregon) were positive for enolase (46-kDa), aldolase (40-kDa), arrestin (48-kDa), and carbonic anhydrase II (30-kDa), but negative for recoverin (23-kDa). Subsequent work-up revealed a negative computed tomography scan of the head, neck, and chest for systemic metastasis, negative dental evaluation for local recurrence, and negative internal medicine work-up for occult metastasis. Over the course of 3 years, his left eye remained unaffected with normal visual acuity, GVF, OCT, full-field ERG, mfERG, and fundus autofluorescence.
      Our case is most consistent with a diagnosis of AIR given the history of carcinoma, visual field loss, photoreceptor abnormalities, significant cone and rod reduction on ERG, and positive anti-retinal antibodies. This is unique given the unilateral pathology despite 3 years of monitoring. To the best of our knowledge, there are only 2 other reported cases of unilateral AIR in the ophthalmic literature: a case of MAR
      • Janaky M.
      • Paffy A.
      • Kolozsvari L.
      • Benedek G.
      Unilateral manifestation of melanoma-associated retinopathy.
      and a case of AIR not associated with cancer.
      • Mizener J.B.
      • Kimura A.E.
      • Adamus G.
      • Thirkill C.E.
      • Goeken J.A.
      • Kardon R.H.
      Autoimmune retinopathy in the absence of cancer.
      Patients with AIR have an anti-retinal antibody seropositve rate of approximately 65%, with most active cases of AIR having a minimum of 3 different anti-retinal antibodies present.
      • Heckenlively J.R.
      • Ferreyra H.A.
      Autoimmune retinopathy: a review and summary.
      To date, more than 15 different target retinal antigens have been identified, and this reflects a degree of heterogeneity in the autoimmune response.
      • Adamus G.
      • Ren G.
      • Weleber R.G.
      Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy.
      Our case is congruent with a predominantly enolase-mediated AIR that can be asymmetric with subacute or chronic progression and relatively good visual acuity.
      • Weleber R.G.
      • Watzke R.C.
      • Shults W.T.
      • et al.
      Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies.
      It is postulated that antibody-epitope binding in photoreceptors triggers apoptotic cell death via the mitochondrial caspase pathway.
      • Weleber R.G.
      • Watzke R.C.
      • Shults W.T.
      • et al.
      Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies.
      Enolase-associated AIR most commonly demonstrates normal rod responses with central (evident on mfERG) and global (evident on full-field ERG) cone abnormalities
      • Weleber R.G.
      • Watzke R.C.
      • Shults W.T.
      • et al.
      Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies.
      ; however, our case demonstrates flat cone and rod responses in the affected eye. The rod ERG findings in our case may be related to relative contributions from additional anti-retinal antibodies like arrestin (48-kDa), which is highly abundant in rod photoreceptors.
      • Craft C.M.
      • Deming J.D.
      Cone arrestin: deciphering the structure and functions of arrestin 4 in vision.
      In addition, it known that arrestin serves as both a single-photon response quencher and an instrument of rod cell survival in bright light, and loss of arrestin may lead to rod photoreceptor cell death.
      • Sommer M.E.
      • Hofmann K.P.
      • Heck M.
      Not just signal shutoff: the protective role of arrestin-1 in rod cells.
      These factors are postulated to contribute to the abnormal ERG rod response seen in our case.
      The diagnosis of AIR remains a clinical challenge because of its rare incidence, frequent dissociation between symptoms and signs, limited access to necessary investigations for diagnosis, and absence of an evidence-based treatment strategy. It is possible, although highly unlikely, that our case contained some damage to the contralateral eye despite the asymptomatic nature and negative diagnostic testing of this eye.
      Our work fully adhered to the Declaration of Helsinki and all federal and state laws.

      Supported by

      This work was supported by the Retina Foundation of Canada (D.A.), Department of Veterans Affairs, Rehabilitation Research and Development Division, Department of Defense (Telemedicine & Advanced Technology Research Center) (R.K.), and National Eye Institute (R.K.).

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        Severe course of cutaneous melanoma associated paraneoplastic retinopathy.
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        Autoimmune retinopathy in the absence of cancer.
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        Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy.
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