Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic retinopathy usually associated with small cell lung carcinoma. To our knowledge, there is no previous report in the English literature of CAR syndrome occurring in lymphoma patients. We describe a rare case of CAR syndrome in a 62-year-old male with non-Hodgkin’s lymphoma (NHL) treated with four doses of intravenous immunoglobulin

Chisti, Mohammad Muhsin

Daw, Hamed

Jaiyesimi, Ishmael

Klamerus, Justin F.

Muslimani, Alaa

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18 Global Journal of Hematology and Blood Transfusion, 2014, 1, 18-20   Cancer Associated Retinopathy in Non-Hodgkin’s Lymphoma  Mohammad Muhsin Chisti2,3,*,  Alaa Muslimani1,  Hamed Daw4,  Ishmael Jaiyesimi3  and Justin F. Klamerus2  1Donayre Cancer Center 711 N Franklin St Ste B Whiteville, NC 28472 (910) 641-8220 2Karmanos Cancer Institute, Detroit, MI Department of Hematology and Oncology 4100 John R Road, Detroit, MI, USA 3Oakland University William Beaumont School of Medicine Department of Hematology and Oncology William Beaumont Hospital 3577 W 13 Mile Rd, Suite 202A Royal Oak, MI 48073 USA 4Cleveland Clinic Cancer Center 18200 Lorain Ave Cleveland, OH 44111 USA Abstract: Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic retinopathy usually associated with small cell lung carcinoma. To our knowledge, there is no previous report in the English literature of CAR syndrome occurring in lymphoma patients. We describe a rare case of CAR syndrome in a 62-year-old male with non-Hodgkin’s lymphoma (NHL) treated with four doses of intravenous immunoglobulin.  Keywords: CAR, Retinopathy, Lymphoma.  INTRODUCTION  Paraneoplastic neurologic syndromes are a group of neurologic disorders caused by mechanisms other than metastases. Metabolic deficit, infections and the side effects of chemotherapy are all possible causes of these disorders. One such syndrome in this group is the paraneoplastic visual syndrome comprising cancer- associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and paraneoplastic optic neuropathy [1]. The CAR syndrome is uncommon and usually associated with small cell lung carcinoma [2, 3]. We report, to our knowledge, the first case in the English literature of CAR syndrome occurring in a patient with non-Hodgkin’s lymphoma and treated with intravenous  immunoglobulin.  CASE REPORT  A 62-year-old male was diagnosed with stage IV, B- cell follicular non-Hodgkin’s lymphoma, and he was treated with six cycles of rituximab and conventional chemotherapy (R-CHOP).  Five weeks after the last cycle, he presented with progressive decrease of vision in both eyes, flickering lights and night blindness, over a two weeks period. Laboratory tests showed a low hemoglobin level (10.2 g/dL), elevated total serum protein (11.8 g/dL), lactate dehydrogenase (305 IU/L) and creatinine level (2.3 mg/dL). Serum IgG level was increased   to   8760   mg/dL   (nl.   564-1765).   On   *Address correspondence to this author at the Michigan State University Faculty, Karmanos Cancer Institute, MI 43097 Woodward Ave, Suite 100 Bloomfield Hills, MI 48302 248 334 0050 Fax 248 334 1368 E-mail: mohsinchisti@yahoo.com examination, corrected visual acuity was 20/80 and 20/100 in the right and left eye, respectively. The pupils were equal in size and reactive to light and near accommodation, extra-ocular movements were full without nystagmus, and color vision by the Ishihara method was diminished bilaterally. Intraocular pressure was within the normal limits in both eyes. Fundus examination revealed pallor of the optic disks while visual field examination showed profound field constriction. Magnetic resonance imaging of the head and orbits showed no signs of metastases or other abnormalities.  We initially performed visual evoked potentials, which were diffusely abnormal, but not diagnostic. A multi-focal electroretinogram (ERG) revealed dysfunction of both rods and cones characteristic of diffuse photoreceptor degeneration, which is supporting the diagnosis of CAR syndrome. Western blot analysis of the patient’s serum showed a positive antibody reaction with 23-kDa component coinciding with the molecular mass of human recoverin.  The patient was started on oral prednisone 60 mg daily. However, three weeks later he still complained of decreased vision in both eyes. Intravenous immunoglobulin (400 mg/kg/day) was given for four doses. Following the second dose, the patient showed signs of improvement. Four weeks after finishing the full treatment, visual acuity improved to 20/40 in both eyes, with no relapse during 8 months follow up period.  E-ISSN: 2408-9877/14 © 2014 Cosmos Scholars Publishing House Cancer Associated Retinopathy in Non-Hodgkin’s Lymphoma Global Journal of Hematology and Blood Transfusion, 2014, Vol. 1, No. 2   19   DISCUSSION  Ocular involvement in NHL lymphoma is rare and can be classified clinically into two major groups: 1- primary ocular NHL and 2- systemic NHL with secondary metastatic ocular involvement [4]. Primary ocular NHL usually presents as chronic vitritis that dose not respond to topical steroid treatment [4, 5]; Such primary ocular NHL is generally associated with central nervous system involvement by NHL later in the course of the disease [6].  The second group, which occurs more frequently, consists of ocular involvement in systemic NHL, as a result of metastatic spread of the lymphoma to the choroid or the anterior chamber [7, 8]. In addition, there are occasional reports of optic nerve neuropathy or infiltration by lymphoma [9-11]. Finally, and very rarely, there may be a lymphoma stimulated uveitis in the absence of metastases [12].  To our knowledge, there has been only one previous report (in the French literature) of CAR syndrome in lymphoma patients. Matus et al. described two NHL patients with symptoms of CAR, which was confirmed by the presence of anti-reoverin antibodies. Both cases were treated by corticosteroids with only minimal response [13].  Patients with CAR develop symptoms related to dysfunction of both cones (photosensitivity, abnormal visual acuity, color vision abnormalities, central scotomata) and/or rods (nyctalopia or night blindness, prolonged dark adaptation, peripheral or ring-like scotomata), and the ERG is extremely helpful in the diagnosis of CAR syndrome [14, 15]. Fifteen different antigens have been described in association with CAR. However, the only characteristic paraneoplastic marker is the presence of antibodies against recoverin [16, 17] and the a-enolase [18]. Recoverin is a retina-specific calcium binding protein that is expressed in photoreceptors and retinal bipolar cells [19]. The discovery of anti-recoverin antibodies in CAR patients’ serum led to the hypothesis that the retinal degeneration that occurs in this syndrome is caused by the recoverin-specific antibodies reacting with the retinal tissue [20, 21]. Interestingly, a group of patients with anti-recoverin antibodies has been identified without any malignancy; these patients presented similar progressive visual loss, retinal degeneration and ERG changes as did CAR patients [22]. Since CAR syndrome is a rare condition, no specific treatment has been shown to be effective, and the visual prognosis is usually poor [23]. Treating the underlining malignancy has not been shown to result in better visual outcomes [24] and immuno-suppression with oral or intravenous corticosteroid exhibits only a transient or undetectable response [13, 25]. Furthermore, plasmapheresis has not been effective [22]. Finally, intravenous immunoglobulin (IVIG) therapy has also been employed with various results; improvement of visual acuity and fields was noted in one patient, improvement of visual fields only in a second patient, and no effect in the third [26, 27]. However, our patient showed significant improvement after four cycles of treatment with IVIG.  Conclusion: CAR may occur in NHL as well as the more common small cell cancer and other malignancies. Intravenous immunoglobulin may be an effective option for treating these patients, especially if started early enough before permanent retinal damage occurs. The results of present case represent the potential use of IVIG in this condition.  REFERENCES  [1] Keltner JL, Thirkill CE. Cancer-associated retinopathy vs recoverin-associated retinopathy. Am J Ophthalmol  1998; 126 (2): 296-302. [2] Grunwald GB, Klein R, Simmonds MA, et al. Autoimmune basis for visual  paraneoplastic syndrome in patients with small cell lung carcinoma. Lancet 1985; 1: 658-661. [3] Kornguth SE, Klein R, Appen R, et al. Occurrence of anti- retinal ganglion cell antibodies in patients with small carcinoma of the lung. Cancer 1982; 50: 1289-1293. [4] Peterson K, Gordon K, Heinemann M, et  al.  the  clinical spectrum of ocular lymphoma. Cancer 1993; 72: 843-849. [5] Verbraeken HE, Hanssens M, Priem H, et al. Ocular non- Hodgkin's lymphoma: a clinical study of nine cases. Br J Opht 1997; 81(1): 31-36. [6] Coutinho AB, Muccioli C, Martins MC, et al. Extranodal B-cell lymphoma of the uvea: a case report. Can J Opht 2005; 40 (5): 623-626. [7] Whitcup SM, Desmet MD, Rubin BI, et al. intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 1993; 100: 1399-1406. [8] Fredrick DR, Char DH, Ljung BM, et al. Solitary intraocular lymphoma as an initial presentation of widespread disease. Arch Opht 1989; 107(3): 395-397. [9] Strominger MB, Schatz NJ, Glaser JS. Lymphomatous optic neuropathy. Am J Opht 1993; 15; 116(6): 774-776. [10] El Kettani A, Lamari H, Lahbil D, et al. Bilateral optic neuropathy and non-Hodkin's lymphoma. Bull Soc Belge Opht 2006; (300): 35-39. [11] Lee LC, Howes EL, Bhisitkul RB. Systemic non-Hodgkin's lymphoma with optic nerve infiltration in a patient with AIDS. Retina 2002; 22(1): 75-79. [12]     Neetens A, Clemens A, van den Ende P, et al. Optic neuritis in non-Hodgkin's lymphoma. Klin Monatsbl Augenheilkd 1992; 200(5): 525-528. 20   Global Journal of Hematology and Blood Transfusion, 2014, Vol. 1, No. 2 Chisti et al.    [13] Saga T, Ohno S, Mastsuda H, et al. Ocular involvement by a peripheral T-cell lymphoma. Arch Opht 1984; 102 (3); 399- 402. [14] Matus G, Dicato M, Focan C. Cancer associated retinopathy (CAR). Two clinical cases and review of the literature. Rev Med Liege 2007; 62(3): 166-169. [15] Sawyer RA, Selhorst JB, Zimmerman LE, et al. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Opht 1976; 181: 606-613. [16] 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: 7; 321(23): 1589-1594. [17] 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 USA 1995; 92(20): 9176-9180. [18] Adamus G, Aptsiauri N, Guy J, et al. the occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopath 1996; 78: 120-129. [19]    Kawamura S, Rhodopsin Phosphorylation as a mechanism of cyclic GMP phosphodiesterase regulation by S-modulin. Nature 1993; 362: 855-857. [20] Adamus G, Machnicki M, Seigel GM, et al. Apoptotic retinal cell death induced by anti-recoverin autoantibodies of cancer-associated retinopathy. Invest Opht Vis Sci 1997; 38: 283-291. [21] Ohguro H, Ogawa K, Maeda T, et al. cancer-associated retinopathy induced by both anti-recoverin and anti-hsc70 antibodies in vivo. Invest Opht Vis Sci 1999; 40(3): 160-167. [22] Whitcup SM, Vistica BP, Milam AH, et al. Recoverin- associated retinopathy: a clinically and immunologically distinctive disease. Am J Opht 1998; 126(2): 230-237. [23] Khan N, Huang JJ, Foster CS.  Cancer  associated retinopathy: An autoimmune-mediated paraneoplastic syndrome. Semin Opht 2006; 21(3): 135-141. [24] Maeda T, Maeda A, Maruyama I, et al. Mechanisms of photoreceptor cell death in cancer-associated retinopathy. Invest Opht Vis Sci 2001; 42(3): 705-712. [25] Hooks JJ, Tso MO, Detrick B. Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol 2001; 8(5): 853-858. [26] Keltner JL, Thirkill CE, Tyler NK, et al. Management and monitoring of cancer-associated retinopathy. Arch Opht 1992; 110(1): 48-53. [27] Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Opht 1999; 117(4): 471-477.   Received on 19-9-2014 Accepted on 14-10-2014 Published on 20-11-2014  http://dx.doi.org/10.15379/2408-9877.2014.01.02.04  © 2014 Chisti et al.; Licensee Cosmos Scholars Publishing House. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. 

Cancer Associated Retinopathy in Non-Hodgkin’s Lymphoma

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Cancer Associated Retinopathy in Non-Hodgkin’s Lymphoma

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