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Show ORIGINAL CONTRIBUTION Improvement in Visual Fields in a Patient With Melanoma- Associated Retinopathy Treated With Intravenous Immunoglobulin Chereddy Subhadra, MD, Arkadiusz Z. Dudek, MD, PhD, Pamela P. Rath, MD, and Michael S. Lee, MD Abstract: Melanoma- associated retinopathy ( MAR) is a rare disorder characterized by photopsias, shimmering vision, nyctalopia, and dysfunction of rod photoreceptor cells. We describe a 56- year- old man with metastatic cutaneous melanoma to the lymph nodes and MAR. He underwent resection of the metastasis followed by radiation therapy. Over the ensuing 2 months, visual function worsened so he was treated with intravenous immunoglobulin ( IVIg). Visual fields, but not electroretinography, improved steadily over the next year. No evidence of recurrence or metastatic disease has been found. Our patient indicates that even after a reduction or elimination of melanoma tumor burden and presumably the attenuation of the antigenic stimulus driving MAR, this disorder can continue to progress. In this setting, IVIg therapy should be considered a viable treatment option. ( J Neuro- Ophthalmol 2008; 28: 23- 26) elanoma- associated retinopathy ( MAR) is a rare paraneoplastic syndrome occurring in the presence of cutaneous malignant melanoma ( 1). Patients with MAR commonly develop subacute visual loss within months to years after diagnosis of malignant melanoma of the skin. Symptoms usually include positive visual Division of Hematology, Oncology, and Transplantation ( CS, AZD), University of Minnesota, Minneapolis, Minnesota; Retina Vitreous Consultants ( PPR), Pittsburgh, Pennsylvania; and Departments of Ophthalmology, Neurology, and Neurosurgery ( MSL), University of Minnesota, Minneapolis, Minnesota. This work was supported by an unrestricted grant from Research to Prevent Blindness, New York, NY, and Lions Club of Minnesota ( MSL). Address correspondence to Arkadiusz Z. Dudek, MD, PhD, University of Minnesota Medical School, Department of Medicine, Division of Hematology, Oncology, and Transplantation, MMC 480,420 Delaware St. S. E., Minneapolis, MN 55455; E- mail: dudek002@ umn. edu phenomena, peripheral visual field loss, and night blindness. Electroretinography ( ERG) reveals significant scoto-pic abnormalities with a severely decreased rod- specific response and a negative maximal response. The photopic responses, although much less affected, have a characteristic broadened a- wave trough and sharply rising b- wave peak, suggesting an impairment of the rod ON bipolar cell pathway ( 2). MAR presumably results from antibodies produced against unknown melanoma- associated antigens that cross- react with retinal bipolar cells leading to defective signal transduction and visual loss ( 1,3). Treatment of the visual loss associated with MAR has been disappointing. Use of corticosteroids and chemotherapy has been ineffective ( 4) with the exception of one patient who had MAR associated with uveitis ( 5). In a review of 62 patients with MAR, only 7 patients experienced visual improvement after receiving various treatment regimens ( 2). Four of the 7 patients were treated with meta-stasectomy and 2 of them with intravenous immunoglobulin ( IVIg) therapy. Vision in 1 patient improved with IVIg treatment alone, vision in 1 improved with plasmapheresis and methylprednisolone treatment, vision in 1 improved with radiation treatment to sites of melanoma recurrence ( 2). We provide the second report of a patient with MAR whose visual function appeared to improve after treatment with IVIg. CASE REPORT A 56- year- old man with malignant melanoma of the right temporal forehead area underwent wide excision and lymph node dissection in 2001. The Breslow thickness of the tumor was 0.8 mm, and the Clark level of invasion was 4. Lymph nodes were negative for tumor metastases. Four years later, in September 2005, the patient complained of blurred vision and flickering lights in the left eye only. The patient reported no night blindness. There were no other medical problems or family history of retinal disorders. Best- corrected visual acuities were 20/ 25 in both eyes. Visual field testing revealed constriction in the left eye J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 23 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Subhadra et al only. Pupillary examination showed a left relative afferent pupillary defect. Dilated fundus examination showed no evidence of vitreous cells, vessel attenuation, pigmentary changes, or optic disc pallor. Results of ERG in the left eye were consistent with MAR, in that ERG showed an abolished rod- specific response, a negative maximal response, and a photopic response with a broadened a- wave trough and a sharply rising b- wave peak. There was complete loss of the ON bipolar activity in the left eye. ERG findings for the right eye were essentially normal, although there was a slight decrease in the b- wave/ a- wave ratio of the maximal response and a slight decrease in the ON bipolar ERG findings compared with normal values ( Fig. 1). Dark adaptation studies were not performed. An enlarged right preauricular lymph node ( 1.3 cm) was then found on physical examination. An excisional biopsy sample indicated recurrent melanoma. CT of the chest, abdomen, and pelvis performed in September 2005 did not show other metastatic disease. In October 2005, to complete optimal treatment for local recurrence, the patient underwent superficial parotidectomy, right modified radical neck dissection, and regional flap reconstruction. Whole body positron emission tomography and CT in December 2005 showed no suggestion of other sites of melanoma. The patient then received 6,000 cGy of external beam irradiation to the right neck including a 1,000- cGy boost to the preauricular region. Results of a paraneoplastic antibody profile were negative, including the following antibodies: anti- neuronal nuclear type 1, 2, and 3, Purkinje cell cytoplasmic type 1, 2, and Tr, amphiphysin, collapsin response- mediating protein- 5 ( CRMP- 5), striational, calcium channel binding P/ Q, acetylcholine receptor, and potassium channel. Three months after reporting blurred vision and flickering lights in his left eye, the patient reported the same symptoms in his right eye. Best- corrected visual acuities were 20/ 25 in the right eye and 20/ 40 in the left eye. ERG demonstrated nearly absent scotopic amplitudes, negative maximal responses, and a broadened photopic a- wave trough with a sharply rising b- wave peak in both eyes, consistent with a diagnosis of MAR. Visual field analysis demonstrated significant defects in both eyes ( Fig. 2). Dilated fundus examination remained unchanged with no evidence of vitreous cells, vessel attenuation, pigmentary changes, or optic disc pallor. The patient received 100 g IVIg for 2 consecutive days and then monthly thereafter. Four weeks after the initiation of IVIg therapy, best- corrected visual acuities had improved to 20/ 20 in the right eye and 20/ 30 in the left eye. The visual field improved significantly in the right eye but Right Eye 6 0 0 M V • 4 0 0 M V • 200JJV • - 2 0 0 I J V - rod . . / ~ \ max 30 Hz photopic on/ off Left Eye Normal Subject 20° nv 400JJV • 200MV • OV • - 200pV • « 400pV • 0 400pV • 200pV • 0V • - 200MV • - 400MV • 0 400| JV • 200| JV • 0V • - 200pV • - 4 0 0 | J V - M -" j S 100mS \. \ AJ^>^^^ S 100mS 2 vy 200pV • 150MV • 100jiV • 50pV • OV • 1 A 150MV - 100pV - 50pV • OV - - 50pV - 2 \ \ y/ W \ j| \ | V ^ 75pV • 50| jV - 25pV • - OnV - - 25JJV - - 50pV • - 75pV • 100( JV • 2 4 J 6 FIG. 1 . Electroretinography ( ERG) performed before treatment with intravenous immunoglobulin ( IVIg). Results of ERG of the right eye are normal except for reduced maximal response ( max) and slightly reduced ON bipolar response ( on/ off). ERG of the left eye reveals an abolished rod response, a negative maximal response, and photopic responses with a broadened trough and a sharply rising b- wave peak and complete loss of the ON bipolar response. Results from a normal subject ( bottom panel) are shown for comparison. 24 © 2008 Lippincott Williams & Wilkins Melanoma- Associated Retinopathy J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 FIG. 2. Humphrey visual fields before intravenous immunoglobulin treatment demonstrate severe bilateral visual field loss ( A) and gradual improvement 1 month ( B), 2 months ( C), and 8 months ( D) after treatment was started. Four months after treatment was stopped, visual fields had not worsened ( E). remained poor in the left eye. Over the next 4 months, the patient's visual acuities remained stable, ranging from 20/ 20 to 20/ 40 in the right eye and from 20/ 25 to 20/ 40 in the left eye. Visual fields continued to improve steadily ( Fig. 2). There was no improvement in the ERG ( Fig. 3). The IVIg dosing schedule was changed to once every 6 weeks in May 2006. This schedule was again extended to once every 8 weeks in August 2006 because of continued stability of visual acuities and visual fields. The patient received the last dose of IVIg in December 2006. At the last follow- up visit in April 2007, best- corrected visual acuities were 20/ 20 in the right eye and 20/ 25 in the left eye. Visual fields continued to show improvement. ( Fig. 2) Over the course of treatment, the patient noted progressive improvement in night vision, peripheral vision, and photopsias. He described his visual function as nearly normal with the exception of mild intermittent flickering in his visual field. During the last 18 months of postoperative follow- up, no evidence of melanoma recurrence or metastatic disease has been found. DISCUSSION Our patient is noteworthy because his visual fields improved after IVIg treatment, and although metastasec-tomy in our patient also could have played a role in this improvement, the recovery in visual fields occurred only after IVIg was started. In previously described patients ( 2), only one patient showed improved visual function after IVIg treatment alone. MAR can be caused by antibody production against melanoma- associated antigens that cross- react with analogous epitopes on retinal rod bipolar cells. Neuronal retinal antigen ( 2), transducin ( 6), and photoreceptor cell- specific nuclear receptor ( 7) are documented examples of epitopes recognized by these antibodies. Gold et al ( 8) have proposed several mechanisms of IVIg action, including an anti- idiotype reaction against membrane- bound B- cell receptor, neutralization of autoantibodies by anti- idiotypes, binding of complement components CI, inhibition of maturation of dendritic cells with consecutive inhibition of T- cell activation, and modulation of the expression of intercellular adhesion molecules. We hypothesize that once IVIg- mediated modulation of the immune system occurs, a permanent cessation of the production of autoantibodies may occur. Because of the rarity of MAR, it is difficult to evaluate treatments by using prospective, randomized studies. Still, it is widely agreed that decreasing the melanoma tumor burden in MAR with metastasectomy or radiation is an important first- line treatment. In our patient, however, visual function continued to decline for 2 months after surgical removal of the metastatic tumor mass and subsequent radiation therapy. Only after the initiation of IVIg therapy were improvements in visual fields observed in our patient, suggesting that the production of autoantibodies 25 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Subhadra et al rod max 30 Hz photopic on/ off Right Eye Left Eye Normal Subject 200, jV FIG. 3. Electroretinography ( ERG) performed 2 months after initiation of intravenous gammaglobulin treatment. In the right eye, results of ERG worsened and were identical to those of the left eye, which are unchanged. Results from a normal subject ( bottom panel) are shown for comparison. may continue even after a reduction or elimination of tumor burden. REFERENCES 1. Pfohler C, Preuss KD, Tilgen W, et al. Mitofilin and titin as target antigens in melanoma- associated retinopathy. Int J Cancer 2007; 120: 788- 95. 2. 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. 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Drug insight: The use of intravenous immunoglobulin in neurology- therapeutic considerations and practical issues. Nat Clin Pract Neurol 2007; 3: 36- 44. 26 © 2008 Lippincott Williams & Wilkins |
