Hannes Wildberger

Cancer-retina antigens as potential paraneoplastic antigens in melanoma-associated retinopathy

Melanoma‐associated retinopathy is a rare paraneoplastic neurological syndrome characterized by retinopathy in melanoma patients. The main photoreceptor proteins have been found to be expressed as cancer‐retina antigens in melanoma. Here we present evidence that these can function as paraneoplastic antigens in melanoma‐associated retinopathy. Sera and one tumor cell line of such patients were studied and ret‐transgenic mice spontaneously developing melanoma were used as a murine model for melanoma‐associated retinopathy. Splenocytes and sera were used for adoptive transfer from tumor‐bearing or control mice to wild‐type mice. Retinopathy was investigated in mice by funduscopy, electroretinography and eye histology. Expression of photoreceptor proteins and autoantibodies against arrestin and transducin were detected in melanoma‐associated retinopathy patients. In tumor‐bearing ret‐transgenic mice, retinopathy was frequently (13/15) detected by electroretinogram and eye histology. These pathological changes were manifested in degenerations of photoreceptors, bipolar cells and pigment epithelium as well as retinal detachment. Mostly these defects were combined. Cancer‐retina antigens were expressed in tumors of these mice, and autoantibodies against arrestin were revealed in some of their sera. Adoptive transfer of splenocytes and sera from tumor‐bearing into wild‐type mice led to the induction of retinopathy in 4/16 animals. We suggest that melanoma‐associated retinopathy can be mediated by humoral and/or cellular immune responses against a number of cancer‐retina antigens which may function as paraneoplastic antigens in melanoma‐associated retinopathy.

Cutaneous Ulceration after Injection of Polyethylene-Glycol-Modified Interferon Alpha Associated with Visual Disturbances in a Melanoma Patient

Interferons are used in the therapy of multiple sclerosis, Kaposi’s sarcoma, hepatitis and melanoma. Their short half-life that requires frequent injections can be increased by polyethylene glycol (PEG) modification. A 50-year-old patient was diagnosed as having an acrolentiginous melanoma (Breslow >5 mm, Clark level IV) and inguinal lymph node metastases. After surgical excision and lymphadenectomy, immune therapy with 6.0 μg pegylated interferon α2b/kg body weight, s.c., was started. Cutaneous ulcerations at the injection sites developed 9 months after treatment initiation. The patient also developed blurred vision and presented with binasal scotomas and pathological visually evoked potentials and electroretinogram. The cutaneous ulcerations slowly healed under local therapy and reduction of the concentration of the PEG-modified interferon from 0.86 to 0.43 mg/ml. The dosage was maintained. Two months later, the therapy was stopped due to disease progression. Vision subsequently recovered. Cutaneous reactions evolved at the sites of subcutaneous injections of PEG-modified interferon α2b. Changes in vision can probably be attributed to immunotherapy.

The influence of pattern size on amplitude, latency and wave form of retinal and cortical potentials elicited by checkerboard pattern reversal and stimulus onset-offset

Transient pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded with checkerboard pattern reversal and equiluminance stimulus onset-offset, elicited by a high quality moving mirror stimulator. Different sized checkerboard patterns (0.35-4.2 c/deg) were used as stimulus patterns. The wave forms of the equiluminance stimulus onset responses were similar to ERGs evoked with luminance decrease and the stimulus offset PERGs were like ERGs elicited by luminance increase. The PERG c wave and the VEP showed spatial frequency tuning with pattern reversal and stimulus offset. Spatial frequency tuning was not detectable with PERG a and b waves. Pattern reversal and stimulus onset evoked PERGs had no major spectral components above 40 Hz; stimulus offset evoked PERGs contained components up to 55.3 Hz. Retino-cortical time--measured as a latency difference of the PERG b wave to VEP P100--was identical with pattern reversal and stimulus onset and about 12 msec longer with stimulus offset. Our results suggest that the 3 stimulation modes, reversal, onset and offset induce different types of processing at the retinal and cortical levels. PERG a and b waves to our high luminance/contrast stimuli contain no pattern specific information and the c waves are the sum of luminance and pattern specific responses.

Pattern electroretinogram and visual evoked potential amplitudes are influenced by different stimulus field sizes and scotomata

The pattern electroretinogram and the visual evoked potential were recorded simultaneously with various stimulus fields and artificial scotomata of increasing sizes. In contrast to an earlier study, a smaller check size (20′) and two stimulus field sizes (20° × 20° and 10° × 10°) for the scotomata were used. With a concentric decreasing stimulus field, a reduction of both the pattern electroretinogram and visual evoked potential was found. Both showed a simultaneous reduction of amplitudes, but, compared with the amplitude in the full field, the reduction was more extensive for the pattern electroretinogram at each test field size. This implies a greater contribution to the pattern electroretinogram from more eccentric retinal parts. An artificial central scotoma of increasing size in the 20° × 20° field had less influence on the pattern electroretinogram than on the visual evoked potential. The percentage amplitude loss of the visual evoked potential was more pronounced. The visual evoked potential was eventually abolished by a scotoma size from 10° × 10° upward, while the pattern electroretinogram was still registrable. When scotomata of similar size were introduced in a smaller (10° × 10°) field, percentage pattern electroretinogram and visual evoked potential amplitude losses were less separated than in a larger (20° × 20°) test field.

Pattern electroretinogram, visual evoked potential and psychophysical functions in maculopathy

To compare pattern electroretinograms and visual evoked potentials with psychophysical examinations, such as visual acuity, static (automated) perimetry and color vision in unilateral maculopathies of various origins, 20 patients with unilateral retinal diseases within the macula and the posterior pole were tested. Pattern electroretinography, visual evoked potential testing and static perimetry (Octopus program M1) were performed with three different test field sizes (20° × 20°, 10° × 10° and 6° × 6°). The best correlation in all three test field sizes was found between visual acuity, static perimetry and visual evoked potential. This result is surprising, since central area defined functions (visual evoked potentials, visual acuity) correlated well with a total area integrating function (mean defect in static perimetry). The pattern electroretinogram, which seems to reflect an area-related function as well, showed a correlation to static perimetry only in the smaller 10° × 10° and 6° × 6° fields and not a significant correlation in the 20° × 20° field. Smaller stimulation fields may therefore produce sharper results in pattern electroretinographic testing. There was no correlation between pattern electroretinograms and visual evoked potentials or visual acuity. The pattern electroretinogram was recorded under monocular and binocular viewing conditions. In 60% of the patients, the amplitude of the affected eye was more reduced in the monocular than the binocular viewing condition; the healthy fellow eye controlled stable fixation of the affected eye more readily during binocular pattern electroretinogram registration. The degree of the color vision disturbance (C-index, desaturated panel D-15 test) did not correlate to any of the other examinations.

Subjective critical flicker fusion (CFF) helps to separate amblyopia from organic disease

The examination of the critical flicker fusion (CFF) in the visual field center is a helpful tool in order to differentiate amblyopia from organic diseases such as maculopathies and neuropathies. A newly developed apparatus (4F) offers a simple and fast examination: ascending as well as descending thresholds of the foveal CFF can be determined. If central fixation is maintained, the test results are well reproducible. Different conditions show different results: normal thresholds or thresholds above normal are obtained in amblyopias, whereas they are below normal in maculopathies and neuropathies. In optic neuritis, CFF depends on the stage of the disease. There is no correlation between visual acuity and CFF in different conditions.

Optic disc doubling or pseudo-optic disc in colobomatous retinal abnormality?

I n their Photo Essay, Padhi et al (1) described a patient with optic disc doubling. We examined a similar case (Fig. 1) and believe that the case reported by Padhi et al, like ours, has a coloboma located inferiorly to the true optic disc. First, the optical coherence tomography (OCT) image in the report by Padhi et al shows naso-temporal asymmetry of the nerve fiber characteristic of a true optic disc, but convergence of the inner retinal layers toward the second disc. This finding is typical of retinal coloboma (2). Second, inferior retinal colobomas often are associated with abnormal retinal vasculature. Third, on OCT imaging, typically there is a discontinuation of the IS/OS junction near a coloboma (3). This finding may be present in the patient of Padhi et al, although it is difficult to assess due to the quality and angulation of the scan. Christina Gerth-Kahlert, MD Hannes Wildberger, MD Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland christina.gerth-kahlert@usz.ch

A comparative study of visual evoked potentials and of retinal nerve fiber layer photography in neuropathies of the optic nerve

The degree of retinal nerve fiber loss within the papillomacular bundle in optic-neuropathies was evaluated from red-free fundus photographs. Visual evoked potentials were obtained from pattern reversal with variable check sizes. A semiquantitative scale was used for the estimation of nerve fiber loss and amplitude reduction of the visual evoked potentials. A significant correlation was found between both. However, a few patients showed rather well-preserved visual evoked potentials with an atrophic nerve fiber layer. Possibly a small number of invisible remaining fibers are able to sustain nearly normal visual evoked potentials. On the other hand, some patients had abnormal visual evoked potentials in the presence of a normal nerve fiber layer. We conclude that evaluation of the nerve fiber layer of the papillomacular bundle without functional testing of the optic nerve is not sufficient to predict degree of foveal integrity.