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Clinicopathologic Reports, Case Reports, and Small Case Series
December 2002

Bilateral Multifocal Chorioretinopathy in a Woman With Cutaneous Malignant Melanoma

Arch Ophthalmol. 2002;120(12):1756-1761. doi:

Melanoma-associated retinopathy (MAR) is a paraneoplastic retinopathy that occurs predominantly in males as a distal effect induced by the immune system's response to a cutaneous malignant melanoma (CMM).1 Onset and survival differ markedly, with associated vision problems occurring, on average, 3.6 years (range, 2 months to 19 years) following the diagnosis of CMM, and 1.9 years (range, 1 month to 15 years) subsequent to the finding of metastases. Survival time following the diagnosis of CMM is 5.9 years on average, ranging from 1 to 19.5 years.1 The MAR syndrome typically manifests as a sudden onset of disabling glare or night blindness that is thought to result from the production of autoantibodies reactive with retinal depolarizing bipolar cells.2 While the physical appearance of the retina is frequently normal, changes in the retinal pigment epithelium (RPE), such as a slight mottling, have been reported1,3 together with optic disc pallor, retinal vessel attenuation, and the presence of vitreous cells.1 Melanoma-associated retinopathy with retinal periphlebitis has also been described in a patient,4 which further illustrates the diversity of findings that accompany this syndrome. Here we report a woman with MAR with unusual fundus findings not previously described to our knowledge.

Report of a Case

A 33-year-old white woman had a 4-week history of sudden-onset bilateral disabling glare and night blindness in June 2000. While she could still make out her surroundings she described a white, central scotoma, and experienced photopsias on closing her eyes.

The patient had a history of familial dysplastic nevus syndrome. She was first diagnosed with CMM (nodular malignant melanoma; tumor thickness, 2.0 mm; Clark level III) in 1996. In 1997, the right ovary had to be removed due to metastasis. At this time, she received immunotherapy with anti-idiotypic melanoma–specific mouse antibodies, interleukin 2, and granulocyte macrophage colony stimulating factor.5 Her tumor status at that time was stage IV, pT3, N0, M1b (Union Internationale Contre le Cancer classification). The patient had not been taking systemic steroids and did not experience hypertension or renal problems.

On examination, visual acuity was 20/20 OU. The intraocular pressure was 8 mm Hg OU. A nevus was observed on the right lower eyelid. Results of slitlamp examination of the anterior segment were otherwise unremarkable. On ophthalmoscopy, lesions suggestive of multiple well-circumscribed detachments of the RPE were seen on the posterior pole of both eyes (Figure 1). Each detachment contained a small yellow-orange lesion.

Figure 1.
June 2000. Color photographs of
the posterior pole, showing multiple well-circumscribed detachments of the
retinal pigment epithelium in both eyes (A, right eye; B, left eye), each
of which contains a small yellow-orange lesion.

June 2000. Color photographs of the posterior pole, showing multiple well-circumscribed detachments of the retinal pigment epithelium in both eyes (A, right eye; B, left eye), each of which contains a small yellow-orange lesion.

Fluorescein angiography showed stable hyperfluorescent spots in some of the small yellow-orange lesions, as well as a stable, mild hyperfluorescence in the areas of the RPE detachment. Indocyanine green angiography showed multifocal staining, extending the areas of the RPE detachments (Figure 2).

Figure 2.
Early-phase (A) and late-phase
(B) fluorescein angiography of the left eye, depicting a mild hyperfluorescence
that did not increase in leakage. C, indocyanine green angiography of the
left eye, with staining extending the area of the retinal pigment epithelium
detachments.

Early-phase (A) and late-phase (B) fluorescein angiography of the left eye, depicting a mild hyperfluorescence that did not increase in leakage. C, indocyanine green angiography of the left eye, with staining extending the area of the retinal pigment epithelium detachments.

Testing of the visual fields failed to reveal any corresponding dysfunction. On kinetic perimetry (Goldmann III/4; Haag Streit, Bern, Switzerland), the visual field of either eye extended to 70° caudally, 50° cranially, 80° temporally, and 50° nasally. Testing of the central 30° using static perimetry (Octopus d32; Interzeag AG, Schlieren, Switzerland) revealed the following: mean defect (MD), 2.8 dB; loss variance (LV), 5.4 dB2 OD, and MD, 4.4 dB; LV, 7.1 dB2 OS. At a follow-up 2 months later, these values were as follows: MD, 0.9 dB; LV, 4.1 dB2 OD, and MD, 1.7 dB; LV, 3.8 dB2 OS. The MD and LV are comparative measures that represent the difference between the age-corrected normal data and the actual measured results. The MD is an index related to global damage whereby a loss of 1 dB corresponds to approximately a 10% loss of visual function. The tolerance for normality lies between −2 dB and +2 dB. The LV indicates localized damage. It is calculated from the individual deviation of all measured locations from the MD value. In combination with a normal MD, a value greater than 6 dB2 signifies a localized defect.

Nyctometry (Rodenstock, Munich, Germany) provides information on vision in dim light and thus can be seen as an indicator for the quality of night vision. Increasingly weaker contrasts are presented at a particular adaptation level; thus, sensitivity to different illumination is tested. In our patient, on nyctometry, stimuli with a decreasing contrast of 1:23.5, 1:5.0, 1:2.7, 1:2.0, 1:1.66, and 1:1.46 were presented, first without glare (surrounding luminance: 0.032 candela [cd]/m2) and then with glare (surrounding luminance: 0.1 cd/m2, glare source with a diameter of ˜15 minutes of arc, a 3° angle of glare, and a corneal luminance of 0.35 lux). While most healthy young people can easily see a contrast of 1:2.7 with or without glare, our patient could not detect any stimulus either with or without glare.

Electrophysiologic testing (pattern electroretinogram [P-ERG], Ganzfeld ERG [Haag Streit], and electro-oculogram [Medelec, Surrey, England]) was performed according to the standard of the International Society for Clinical Electrophysiology of Vision. The electro-oculogram results were within the normal range, with an Arden ratio of 1.9 OD and 2.4 OS.

The P-ERG showed normal amplitudes for N35P50 (3.05 µV OD, 1.7 µV OS [normal range, 1.46-4.9 µV]) and for P50N95 (7.1 µV OD, 4.9 µV OS [normal range, 2.0-8.6 µV]) as well as normal latencies (eg, P50: 53.9 ms OD, 51.6 ms OS [normal range, 49-59 ms]).

The Ganzfeld ERG showed a selective reduction of the isolated rod scotopic b-wave amplitude (luminance: 0.0025 cd/m2; 16.5 µV OD, 20.7 µV OS [normal, >110 µV]) (Figure 3A). The a wave was normal with a maximal response amplitude of 35.4 µV OD and 45.9 µV OS (normal range, 33-48 µV; luminance, 2.8 cd/m2). Retinal function evaluation by multifocal ERG (mfERG) (VERIS; Electro-Diagnostic Imaging, San Mateo, Calif) (Lmax 200 cd, Lmean 100 cd) showed reduced amplitudes in the central 4° OU where the mean amplitude N1P1 (first negative to first positive peak) was 24.1 nV/degrees2 (deg2) OD and 24.4 nV/deg2 OS (Figure 4A). This contrasts with the mean (SD) response of 69.0 (22.1) nV/degrees2 (deg2) in the central 4° of a normal reference control group of 15 individuals of similar age.

Figure 3.
Ganzfeld electroretinogram (ERG)
(Haag Streit, Bern, Switzerland) showing isolated rod scotopic b-wave. A,
June 30, 2000. Initial selective reduction of the isolated rod scotopic b-wave
amplitude: 16.5 µV OD, 20.7 µV OS (normal, >110 µV). One
scaling unit depicts 20 µV. B, July 3, 2001. The isolated rod scotopic
ERG b-wave amplitude recovered to 164 µV OD and 204 µV OS (normal,
>110 µV). One scaling unit depicts 100 µV.

Ganzfeld electroretinogram (ERG) (Haag Streit, Bern, Switzerland) showing isolated rod scotopic b-wave. A, June 30, 2000. Initial selective reduction of the isolated rod scotopic b-wave amplitude: 16.5 µV OD, 20.7 µV OS (normal, >110 µV). One scaling unit depicts 20 µV. B, July 3, 2001. The isolated rod scotopic ERG b-wave amplitude recovered to 164 µV OD and 204 µV OS (normal, >110 µV). One scaling unit depicts 100 µV.

Figure 4.
Testing of the central retinal
cone function with the multifocal electroretinogram (VERIS; Electrodiagnostic
Imaging, San Mateo, Calif, Lmax 200 candela (cd), Lmean 100 cd, stimulation
of the central 50° of the retina). A, The top shows a normal first-order
trace array (left eye) for comparison. The bottom shows the patient's recordings
(June 2000) show reduced amplitudes in the central 4°(central 7 waveforms).
B, The top shows a normal first-order trace array (left eye) for comparison.
The bottom shows the patient's recordings obtained 6 months later (December
2000) show improved response amplitudes in the central 4°(central 7 waveforms).
However, amplitudes in the central 4° are still reduced when compared
with the normal trace array.

Testing of the central retinal cone function with the multifocal electroretinogram (VERIS; Electrodiagnostic Imaging, San Mateo, Calif, Lmax 200 candela (cd), Lmean 100 cd, stimulation of the central 50° of the retina). A, The top shows a normal first-order trace array (left eye) for comparison. The bottom shows the patient's recordings (June 2000) show reduced amplitudes in the central 4°(central 7 waveforms). B, The top shows a normal first-order trace array (left eye) for comparison. The bottom shows the patient's recordings obtained 6 months later (December 2000) show improved response amplitudes in the central 4°(central 7 waveforms). However, amplitudes in the central 4° are still reduced when compared with the normal trace array.

The central distribution of the reduced amplitudes observed in the multifocal ERG of our patient are comparable with the reduced central amplitudes observed in the multifocal ERG of patients with MAR,6 but reduced amplitudes (Figure 4) were not found in all areas of retinal lesions (Figure 1).

The patient's serum was evaluated by indirect immunohistochemical analysis on 6-µm sections of rhesus monkey at a dilution of 1:100. Antibody reactions were visualized using fluorescein-isothiocyanate conjugated rabbit-antihuman polyvalent γ-globulins (Sigma F4637; Sigma, St Louis, Mo) at a dilution of 1:500. Serologic examination revealed abnormal immunologic activity consistent with MAR, showing a focus of antibody reactions within the inner nuclear layer, where the nuclei of the bipolar cells are located. Western blot reactions on an extract of rhesus optic nerve revealed additional abnormal antibody activity with myelin basic protein.

Intensive examination in October 2000 led to the recognition and removal of a metastasis in the lymph nodes of the right axilla (radical lymph node dissection, 3 of 7 lymph nodes were positive) followed by chemotherapy with vindesine.

In December 2000, the mfERG recordings showed an improvement of the central amplitudes, with the mean amplitude N1P1 (first negative to first positive peak) improving to 33 nV/deg2 OD and 28.3 nV/deg2 OS, in contrast with a response mean (SD) of 69.0 (22.1) nV/deg2 in the control group (Figure 4B).

In April 2001, the patient was able to see the bright background disc on which the stimulus was presented during nyctometry for the first time, although she still could not detect the stimulus itself.

At a follow-up nyctometry in July 2001, vision in the right eye had improved to where it could resolve a contrast of 1:2.7 without glare; with glare, however, no contrast stimulus was seen. The left eye was still unable to detect any stimulus, either with or without glare. Visual acuity and visual fields had remained stable.

The isolated rod scotopic ERG b-wave amplitude also recovered to 164 µV OD and 204 µV OS, respectively. The P-ERG continued to show normal amplitudes for N35P50 (2.91 µV OD, 1.66 µV OS [normal range, 1.46-4.9 µV]) as well as for P50N95 (7.02 µV OD, 4.89 µV OS [normal range, 2.0-8.6 µV]). The latencies of P50 also remained within the normal range (53.3 ms OD, 52.1 ms OS [normal range, 49-59 ms]).

On ophthalmoscopy, the detachments of the RPE had resolved while the yellow-orange lesions appeared to have increased in size and density (Figure 5). These lesions showed autofluorescence, which may indicate lipid deposits in the RPE or inner choroid (Figure 6). Fluorescein angiography showed a marked blocking of the choroidal filling, with intact filling of the retinal vessels (Figure 6). The clinically apparent lesions therefore appeared to predominate in the RPE and/or inner choroid. The patient was aware of a negative scotoma in the area of the lesions when she closed her eyes. This effect indicated choroidal malfunction.

Figure 5.
July 2001. Color photographs show
the detachment to have resolved, while the yellow-orange lesions appear to
have consolidated continuously. A, Right eye; B, left eye.

July 2001. Color photographs show the detachment to have resolved, while the yellow-orange lesions appear to have consolidated continuously. A, Right eye; B, left eye.

Figure 6.
Autofluorescence in the lesions
of the left eye (A) and fluorescein angiography of the left eye (B). There
is a marked blocking of the choroidal filling, with intact filling of the
retinal vessels.

Autofluorescence in the lesions of the left eye (A) and fluorescein angiography of the left eye (B). There is a marked blocking of the choroidal filling, with intact filling of the retinal vessels.

On further follow-up in February 2002, the patient reported improved night vision and a lessened sensitivity to glare. However, she complained of a recent onset of central metamorphopsia in the left eye. Visual acuity was 20/16 OD and 20/40 OS. When examined by nyctometry, it was found that the right eye could now resolve a contrast of 1:2.7 without glare and of 1:5 with glare, but the left eye was still unable to detect any stimulus either with or without glare.

On ophthalmoscopy, the yellow-orange deposits appeared to be reduced in size and density (Figure 7). Fluorescein angiography continued to show a blocking of the choroidal filling, with intact filling of the retinal vessels in the area of these lesions. Small filling defects were seen by indocyanine green angiography. Neither fluorescein angiography nor indocyanine green angiography revealed a choroidal neovascular membrane or macular edema. The reduced central vision in the left eye was thought to be secondary to the observed central pigment epithelial changes.

Figure 7.
February 2002. A, Color photographs
show the yellow-orange lesions, which appear reduced in size. B, Corresponding
fluorescein angiography. C, Indocyanine green angiography. Right eye, top
row; left eye, bottom row.

February 2002. A, Color photographs show the yellow-orange lesions, which appear reduced in size. B, Corresponding fluorescein angiography. C, Indocyanine green angiography. Right eye, top row; left eye, bottom row.

At the latest follow-up in June 2002, the patient reported improved central metamorphopsia in the left eye. Visual acuity was stable (20/16 OD 20/40 OS). When examined by nyctometry, it was found that the right eye could resolve a contrast of 1:1.46 without glare and of 1:5 with glare. The left eye was now able to detect a contrast of 1:5 without glare. With glare, the left eye still could not resolve the stimulus. On ophthalmoscopy, the yellow-orange deposits appeared further reduced in size and density (Figure 8). To date, further electrophysiologic examinations were not performed.

Figure 8.
June 2002. Right (A and B) and
left (C and D) eyes. A and C, Color photographs depict the yellow-orange lesions,
which appear even more reduced in size than in Figure 7. This can be appreciated
more when their autofluorescence is viewed (B and D).

June 2002. Right (A and B) and left (C and D) eyes. A and C, Color photographs depict the yellow-orange lesions, which appear even more reduced in size than in Figure 7. This can be appreciated more when their autofluorescence is viewed (B and D).

Comment

We describe a patient with MAR who experienced subjective improvement of her night vision and of her glare sensitivity following removal of metastasis and treatment with chemotherapy. This recuperation could also be observed in the normalization of a previously abnormal rod-isolated scotopic b-wave response as well as in the improvement of nyctometry results. This recovery is consistent with the recent experimental findings of Lei et al,7 who found electrophysiologic dysfunction typical of MAR to be a transient effect following intravitreal injection of MAR serum into the eye of a monkey.

Furthermore, our patient's case is remarkable in that she had unusual fundus findings on initial examination, the origin of which remains unclear at present. The findings in our patient may be compared with those of Best disease, where multifocal vitelliform lesions of various size, similar to those we describe, may also occur. Multifocal vitelliform Best disease may also occur sporadically and may show normal electro-oculogram results, as were found in our patient. In Best disease, vitelliform RPE detachments can show a marked symmetry between the left and right eye and may develop over several years.8,9 Our patient had no familial history of Best disease; in contrast, she experienced a regression of RPE detachments in association with the removal of secondary melanoma metastases.

The vitelliform detachments of the RPE in Best disease have been described as acquiring a yellow discoloration and blocking choroidal fluorescence on fluorescein angiography.10 We found no "egg yolk" or "scrambled lesion" typical of Best disease in our patient.8 In addition, the vitelliform stage of her RPE detachments did not block choroidal fluorescence on fluorescein angiography; blocking only occurred following resolution of the RPE detachments and following the deposition of lipids. It is unlikely that our patient suffers from multifocal vitelliform Best disease. The combination of MAR and bilateral multifocal chorioretinopathy we described represents an additional example of the pathologic and immunologic heterogeneity that continues to emerge in descriptions of the MAR syndrome.

This research was supported by grants DFG Pa 609/2 from the Deutsche Forschungsgemeinschaft, Bonn (Dr Palmowski); 1P30 EY12576-01 from the National Eye Institute, Washington, DC (Dr Thirkill); and Research to Prevent Blindness, New York, NY (Dr Thirkill).

This research was presented in part at the International Society for Clinical Electrophysiology of Vision at the meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla, April 28, 2001, and at the meeting of the European Neuro-Ophthalmological Society, Tübingen, Germany, July 22, 2001.

We thank Anita Leys, MD, PhD, and Mary van Schooneveld, MD, PhD, for their helpful comments.

We have no proprietary interest in any of the products mentioned.

Corresponding author: Anja M. Palmowski, MD, Department of Ophthalmology, Saarland University Hospital, D-66421 Homburg/Saar, Germany (e-mail: auapal@med-rz.uni-sb.de).

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