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Paraneoplastic visual syndromes

Josep Dalmau, MD, PhD
Myrna R Rosenfeld, MD, PhD
Section Editor
Lisa M DeAngelis, MD, FAAN, FANA
Deputy Editor
April F Eichler, MD, MPH


Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. In most cases, their pathogenesis is believed to be immune-mediated.

Paraneoplastic visual syndromes are rare; they include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), paraneoplastic optic neuropathy (optic neuritis), and bilateral diffuse uveal melanocytic proliferation.

This topic discusses paraneoplastic visual syndromes. An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting peripheral nerve and muscle" and "Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia" and "Paraneoplastic and autoimmune encephalitis" and "Paraneoplastic cerebellar degeneration".)


Cancer-associated retinopathy (CAR), while rare, is probably the most common of the paraneoplastic visual syndromes. The pathogenesis of CAR is believed to be a B-cell mediated autoimmune response directed against an antigen expressed by both tumor and retina [1]. T-cell responses may also play a role.

Although at least 20 antigens have been described in the CAR syndrome, the first described was recoverin, a calcium-binding protein involved in transduction of light by photoreceptors (picture 1) [2-4]. Recoverin is expressed in the tumors of patients with lung cancer with or without CAR; antibodies to CAR may occur in patients without visual symptoms, although the titres are relatively low compared with patients with visual loss [4,5]. Anti-recoverin antibodies have been shown to induce apoptotic death of photoreceptor cells in vitro [6]. Anti-enolase antibodies are associated with a less severe retinopathy that affects mainly the cones; not all patients with anti-enolase associated retinopathy have cancer [7-10]. Other antigens have been identified in patients with CAR; about 35 percent of patients with CAR are seronegative suggesting that other antigens remain to be characterized [11,12].

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Literature review current through: Oct 2017. | This topic last updated: Sep 11, 2017.
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  1. Ohguro H, Nakazawa M. Pathological roles of recoverin in cancer-associated retinopathy. Adv Exp Med Biol 2002; 514:109.
  2. Thirkill CE, FitzGerald P, Sergott RC, et al. Cancer-associated retinopathy (CAR syndrome) with antibodies reacting with retinal, optic-nerve, and cancer cells. N Engl J Med 1989; 321:1589.
  3. Polans AS, Burton MD, Haley TL, et al. Recoverin, but not visinin, is an autoantigen in the human retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:81.
  4. Polans AS, Witkowska D, Haley TL, et al. Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad Sci U S A 1995; 92:9176.
  5. Bazhin AV, Shifrina ON, Savchenko MS, et al. Low titre autoantibodies against recoverin in sera of patients with small cell lung cancer but without a loss of vision. Lung Cancer 2001; 34:99.
  6. Shiraga S, Adamus G. Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway. J Neuroimmunol 2002; 132:72.
  7. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol 2005; 139:780.
  8. Adamus G, Aptsiauri N, Guy J, et al. The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol 1996; 78:120.
  9. Dot C, Guigay J, Adamus G. Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung. Am J Ophthalmol 2005; 139:746.
  10. Magrys A, Anekonda T, Ren G, Adamus G. The role of anti-alpha-enolase autoantibodies in pathogenicity of autoimmune-mediated retinopathy. J Clin Immunol 2007; 27:181.
  11. Eichen JG, Dalmau J, Demopoulos A, et al. The photoreceptor cell-specific nuclear receptor is an autoantigen of paraneoplastic retinopathy. J Neuroophthalmol 2001; 21:168.
  12. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev 2009; 8:410.
  13. Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of paraneoplastic syndromes. J Neuroophthalmol 2008; 28:58.
  14. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 1990; 28:162.
  15. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003; 48:12.
  16. Jacobson DM, Adamus G. Retinal anti-bipolar cell antibodies in a patient with paraneoplastic retinopathy and colon carcinoma. Am J Ophthalmol 2001; 131:806.
  17. Katsuta H, Okada M, Nakauchi T, et al. Cancer-associated retinopathy associated with invasive thymoma. Am J Ophthalmol 2002; 134:383.
  18. Yamada G, Ohguro H, Aketa K, et al. Invasive thymoma with paraneoplastic retinopathy. Hum Pathol 2003; 34:717.
  19. Espandar L, O'Brien S, Thirkill C, et al. Successful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol 2007; 83:295.
  20. Chang PY, Yang CH, Yang CM. Cancer-associated retinopathy in a patient with hepatocellular carcinoma: case report and literature review. Retina 2005; 25:1093.
  21. Ohguro H, Yokoi Y, Ohguro I, et al. Clinical and immunologic aspects of cancer-associated retinopathy. Am J Ophthalmol 2004; 137:1117.
  22. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004; 4:5.
  23. Heckenlively JR, Fawzi AA, Oversier J, et al. Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol 2000; 118:1525.
  24. Keltner JL, Thirkill CE, Tyler NK, Roth AM. Management and monitoring of cancer-associated retinopathy. Arch Ophthalmol 1992; 110:48.
  25. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 1999; 117:471.
  26. Murphy MA, Thirkill CE, Hart WM Jr. Paraneoplastic retinopathy: a novel autoantibody reaction associated with small-cell lung carcinoma. J Neuroophthalmol 1997; 17:77.
  27. Mahdi N, Faia LJ, Goodwin J, et al. A case of autoimmune retinopathy associated with thyroid carcinoma. Ocul Immunol Inflamm 2010; 18:322.
  28. Damek DM. Paraneoplastic Retinopathy/Optic Neuropathy. Curr Treat Options Neurol 2005; 7:57.
  29. Boeck K, Hofmann S, Klopfer M, et al. Melanoma-associated paraneoplastic retinopathy: case report and review of the literature. Br J Dermatol 1997; 137:457.
  30. Milam AH, Saari JC, Jacobson SG, et al. Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34:91.
  31. Potter MJ, Adamus G, Szabo SM, et al. Autoantibodies to transducin in a patient with melanoma-associated retinopathy. Am J Ophthalmol 2002; 134:128.
  32. Bazhin AV, Dalke C, Willner N, et al. Cancer-retina antigens as potential paraneoplastic antigens in melanoma-associated retinopathy. Int J Cancer 2009; 124:140.
  33. Hartmann TB, Bazhin AV, Schadendorf D, Eichmüller SB. SEREX identification of new tumor antigens linked to melanoma-associated retinopathy. Int J Cancer 2005; 114:88.
  34. Pföhler C, Preuss KD, Tilgen W, et al. Mitofilin and titin as target antigens in melanoma-associated retinopathy. Int J Cancer 2007; 120:788.
  35. Ladewig G, Reinhold U, Thirkill CE, et al. Incidence of antiretinal antibodies in melanoma: screening of 77 serum samples from 51 patients with American Joint Committee on Cancer stage I-IV. Br J Dermatol 2005; 152:931.
  36. Lu Y, Jia L, He S, et al. Melanoma-associated retinopathy: a paraneoplastic autoimmune complication. Arch Ophthalmol 2009; 127:1572.
  37. Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Ophthalmol 1988; 106:307.
  38. Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 2001; 21:173.
  39. Subhadra C, Dudek AZ, Rath PP, Lee MS. Improvement in visual fields in a patient with melanoma-associated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol 2008; 28:23.
  40. Jacobzone C, Cochard-Marianowski C, Kupfer I, et al. Corticosteroid treatment for melanoma-associated retinopathy: effect on visual acuity and electrophysiologic findings. Arch Dermatol 2004; 140:1258.
  41. Chan C, O'Day J. Melanoma-associated retinopathy: does autoimmunity prolong survival? Clin Exp Ophthalmol 2001; 29:235.
  42. Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and "optic neuritis": paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34:788.
  43. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49:146.
  44. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003; 54:38.
  45. Ducray F, Roos-Weil R, Garcia PY, et al. Devic's syndrome-like phenotype associated with thymoma and anti-CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 2007; 78:325.
  46. Moss HE, Liu GT, Dalmau J. Glazed (vision) and confused. Surv Ophthalmol 2010; 55:169.
  47. de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 1998; 55:405.
  48. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuroophthalmol 2006; 26:168.
  49. Thambisetty MR, Scherzer CR, Yu Z, et al. Paraneoplastic optic neuropathy and cerebellar ataxia with small cell carcinoma of the lung. J Neuroophthalmol 2001; 21:164.
  50. Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin Neuroophthalmol 1992; 12:137.
  51. Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in small-cell carcinoma of the lung. J Neuroophthalmol 1998; 18:178.
  52. Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis. Report of a case. Arch Neurol 1988; 45:353.
  53. Pulido J, Cross SA, Lennon VA, et al. Bilateral autoimmune optic neuritis and vitreitis related to CRMP-5-IgG: intravitreal triamcinolone acetonide therapy of four eyes. Eye (Lond) 2008; 22:1191.
  54. Arés-Luque A, García-Tuñón LA, Saiz A, et al. Isolated paraneoplastic optic neuropathy associated with small-cell lung cancer and anti-CV2 antibodies. J Neurol 2007; 254:1131.
  55. Murakami Y, Yoshida S, Yoshikawa H, et al. CRMP-5-IgG in patient with paraneoplastic optic neuritis with lung adenocarcinoma. Eye (Lond) 2007; 21:860.
  56. Asproudis IC, Nikas AN, Psilas KG. Paraneoplastic optic neuropathy in a patient with a non-small cell lung carcinoma: a case report. Eur J Ophthalmol 2005; 15:420.
  57. O'Neal KD, Butnor KJ, Perkinson KR, Proia AD. Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol 2003; 48:613.
  58. Duong HV, McLean IW, Beahm DE. Bilateral diffuse melanocytic proliferation associated with ovarian carcinoma and metastatic malignant amelanotic melanoma. Am J Ophthalmol 2006; 142:693.
  59. Saito W, Kase S, Yoshida K, et al. Bilateral diffuse uveal melanocytic proliferation in a patient with cancer-associated retinopathy. Am J Ophthalmol 2005; 140:942.
  60. Ritland JS, Eide N, Tausjø J. Bilateral diffuse uveal melanocytic proliferation and uterine cancer. A case report. Acta Ophthalmol Scand 2000; 78:366.
  61. Kiratli H, Erkan K. Loss of Retinal Pigment Epithelium Associated with Bilateral Diffuse Uveal Melanocytic Proliferation. Ophthalmic Surg Lasers Imaging 2010; :1.
  62. Besirli CG, Comer GM. High-resolution OCT imaging of RPE degeneration in bilateral diffuse uveal melanocytic proliferation. Ophthalmic Surg Lasers Imaging 2010; 41 Suppl:S96.
  63. Wu S, Slakter JS, Shields JA, Spaide RF. Cancer-associated nummular loss of the pigment epithelium. Am J Ophthalmol 2005; 139:933.
  64. Sen J, Clewes AR, Quah SA, et al. Presymptomatic diagnosis of bronchogenic carcinoma associated with bilateral diffuse uveal melanocytic proliferation. Clin Exp Ophthalmol 2006; 34:156.
  65. Miles SL, Niles RM, Pittock S, et al. A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes. Retina 2012; 32:1959.
  66. Jansen JC, Van Calster J, Pulido JS, et al. Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation. Br J Ophthalmol 2015; 99:943.