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.
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.
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).
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
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
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.
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.
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
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
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.
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
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.
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
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).
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: email@example.com).
Palmowski AM, Haus AH, Pföhler C, Reinhold U, Allgayer R, Tilgen W, Ruprecht KW, Thirkill CE. Bilateral Multifocal Chorioretinopathy in a Woman With Cutaneous Malignant Melanoma. Arch Ophthalmol. 2002;120(12):1756-1761. doi: