Faculty Bibliography

PURPOSE/OBJECTIVE:To describe cases of unilateral cone-rod dysfunction presenting in two middle-aged females. METHODS:This case series highlights two middle-aged female patients with progressive visual decline in one eye. Fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), multi-focal electroretinogram (mfERG), full-field electroretinogram(ffERG), and genetic testing were obtained. RESULTS:In the first patient, mfERG showed an extinguished response and ffERG demonstrated markedly reduced a-wave and b-wave amplitudes (more pronounced under photopic conditions) in the right eye. SD-OCT showed attenuation of the ellipsoid zone of the right eye. Similar findings were appreciated in the second patient. Genetic testing in the first patient identified three heterozygous variants in PRPH2, RCBTB1, and USH2A. The second patient was found to have heterozygous variants in BBS1 and ABCA4. CONCLUSION/CONCLUSIONS:These two cases add to the literature of case reports of unilateral cone-rod and rod-cone dystrophies. However, the underlying etiology of the unilateral pattern of cone-rod dysfunction and the significance of the heterozygous mutations found in both cases remains uncertain.

PURPOSE/OBJECTIVE:Traditional ERGs recorded using corneal electrodes can be difficult for some patients to tolerate. In the last several years, adhesive skin electrodes have gained in acceptance. In this report we present a qualitative comparison of waveforms as well as a quantitative analysis of correlation of amplitudes and implicit times of simultaneous ERG recordings using contact lens and skin electrodes. METHODS:89 subjects were included; all were referred for full-field ERG testing for multiple indications. ERGs (obtained according to ISCEV standards) were recorded simultaneously from both eyes with ERG-jet corneal contact lens electrodes and LKC Technologies Sensor Strip adhesive skin electrodes using multi-channel instrumentation (Diagnosys LLC, Espion3). Waveforms, a-wave and b-wave amplitudes and implicit times were compared. RESULTS:Waveform morphologies were similar between electrode types. Regression coefficients (conversion factors) for a-wave and b-wave amplitudes under both photopic and scotopic conditions were tightly clustered. Regression coefficients for implicit times were nearly equal to 1.0. The regression coefficient for the entire amplitude dataset was 0.349, with an overall correlation of 0. 869 between amplitude recorded with skin and contact lens electrodes. The regression coefficient for the entire implicit time dataset was 0.967, with an overall correlation of 0.964 between skin and contact lens electrodes. CONCLUSIONS:Our best estimate for the conversion factor between ERG amplitudes recorded with adhesive skin electrodes and contact lens electrodes is 0.349-amplitudes with skin electrodes are about 1/3 the amplitudes recorded simultaneously from the same eyes with contact lens electrodes, with a high correlation. Implicit times are nearly identical for the two electrode types.

Purpose/UNASSIGNED:To increase our understanding of the mechanisms underlying hydroxychloroquine (HCQ) retinopathy, analyses by quantitative fundus autofluorescence (qAF) and near-infrared fundus autofluorescence (NIR-AF) were compared to results obtained by recommended screening tests. Methods/UNASSIGNED:Thirty-one patients (28 females, 3 males) were evaluated with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT); 28 also had multifocal electroretinography (mfERG). Measurement of short-wavelength fundus autofluorescence (SW-AF) by qAF involved the use of an internal fluorescent reference and intensity measurements in eight concentric segments at 7° to 9° eccentricity. For semiquantitative analysis of NIR-AF, intensities were acquired along a vertical axis through the fovea. Results/UNASSIGNED:Four of 15 high-dose (total dose >1000 g, daily dose >5.0 mg/kg) patients and one of 16 low-dose (total dose <1000 g, daily dose 4.4 mg/kg) patients were diagnosed with HCQ-associated retinopathy based on abnormal 10-2 visual fields, SD-OCT, and SW-AF imaging. Three of the high-dose patients also had abnormal mfERG results. Of the five patients exhibiting retinopathy, two had qAF color-coded images revealing higher intensities inferior, nasal, and lateral to the fovea. The abnormal visual fields also exhibited superior-inferior differences. Mean NIR-AF gray-level intensities were increased in four high-dose patients with no evidence of retinopathy. In two patients with retinopathy, NIR-AF intensity within the parafovea was below the normal range. One high-dose patient (6.25 mg/kg) had only abnormal mfERG results. Conclusions/UNASSIGNED:These findings indicate that screening for HCQ retinopathy should take into consideration superior-inferior differences in susceptibility to HCQ retinopathy.

Purpose : To compare rod and cone sensitivity loss to structural changes on en-face optical coherence tomography (OCT) and fundus autofluorescence (AF) in patients with Stargardt disease (STGD1). Methods : Eight patients aged 16-70 yrs. with genetically confirmed STGD1 were enrolled. Spectral domain (SD)-OCT cube scans (9x6mm, 97 B-scans), short-wavelength (SW)-AF, and near-infrared (NIR)-AF images (30 and 55degree) were obtained from the better eye. For the OCT, the automated segmentation of the inner/outer segment (IS/OS) junction and RPE/BM boundaries were manually corrected, and en-face images were generated with these boundaries as references using commercial software. RPE atrophy (a central hyperr effective area on the subRPE slab) and IS/OS junction loss (an abnormal reffective area on the IS/OS slab) were measured using ImageJ. The areas of hypoSW-AF, hyper+hypoSW-AF, and hypoNIR-AF were also measured. Rod and cone system sensitivities were assessed with two-color dark-adapted fundus perimetry (Nidek MP-1S) using a 10-2 grid centered on the fovea (size 3 stimulus, 200-ms duration, 68 points). The rod and cone sensitivity maps were superimposed on SW-AF (Fig.), NIR-AF, and en-face images. Scotopic visual fields were measured in 5 eyes using a Medmont dark-adapted chromatic perimeter (size 5 stimulus, 200-ms duration, 505 nm, 103 points, 144degreex72degree). Results : Five eyes had foveal sparing. For 7 eyes, the area of IS/OS junction loss was larger than that of RPE atrophy (p=0.03), and the hyper+hypoSW-AF area was larger than the hyperreffective area on the subRPE slab (p=0.003). Agreement between the area of IS/OS junction loss and the hyper+hypoSW-AF area was good. For 5 eyes, the hypoNIR area was larger than the hypoSW-AF, but the hyper+hypoSW-AF area was larger than the hypoNIRAF area (p=0.01). Rod sensitivity was more affected than cone sensitivity (p<0.001) adjacent to areas of RPE atrophy, IS/OS junction loss, and surrounding the hypo-AF areas (Fig.) Rod visual fields for 5 eyes showed rod sensitivity was markedly decreased within the central 20degree, but comparable to normal in the periphery. Conclusions : Decreased rod and cone sensitivities are associated with photoreceptor and RPE structural changes that extend beyond atrophy in STGD1

Retinitis pigmentosa (RP), a genetically heterogeneous group of retinopathies which occur in both non-syndromic and syndromic forms, is caused by mutations in about 100 genes. Although recent advances in next-generation sequencing have aided in the discovery of novel RP genes, a number of the underlying contributing genes and loci remain to be identified. We investigated three siblings, born to asymptomatic parents of Italian-American descent, who each presented with atypical RP with systemic features, including facial dysmorphologies, psychomotor developmental delays recognized since early childhood, learning disabilities, and short stature. RP-associated ophthalmological findings included salt-and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction as determined by almost extinguished electroretinogram in 2 of 3 siblings. Atypical for RP features included mottled macula at an early age and peripapillary sparing of the RPE. Whole exome sequencing (WES) data, queried under a recessive model of inheritance, identified compound heterozygous stop mutations, c.C199T:p.R67* and c.C322T:p.R108*, in the retinol dehydrogenase 11 (RDH11) gene, resulting in a non-functional protein, in all affected children. In summary, deleterious mutations in RDH11, an important enzyme for vision-related and systemic retinoic acid metabolism, cause a new syndrome with RP.

Fundus-driven perimetry, commonly known as microperimetry, is a technique for measuring visual field sensitivity, whilst simultaneously viewing the fundus. In this article, we review the technique, focusing on the MP-1 microperimeter (Nidek Instruments, Inc, Padua, Italy); we compare it with conventional static automated perimetry, emphasizing the importance of understanding the effects of the different stimulus conditions and data analyses on the interpretation of microperimetry data. The clinical applications of the technique, in the evaluation of functional and structural changes that accompany retinal diseases, are illustrated by its use in patients with age-related macular degeneration, Stargardt disease, and retinitis pigmentosa. In addition, the advantages and limitations of the technique are summarized.

The aim of this study was to investigate visualization of the tapetal-like reflex using current imaging modalities and evaluate SD-OCT changes in known carriers of X-linked retinitis pigmentosa (XLRP); the objective being the development of an optimal protocol for clinicians to identify carriers. Ten XLRP carriers (19 eyes) were examined using color fundus photography, 488 nm reflectance (488-R), near-infrared reflectance (NIR-R), autofluorescence (AF) and spectral domain optical coherence tomography (SD-OCT) imaging (Spectralis SLO-OCT, Heidelberg). Horizontal line scans through the fovea were acquired in all subjects and in a group of 10 age-similar controls. Peripheral SD-OCT scans (extending to 27.5 degrees eccentricity) were also acquired in both eyes of 7 carriers. MP-1 microperimetery (10-2 pattern; Nidek) was performed in one eye of each carrier. For the XLRP carriers, a tapetal reflex was observed with all imaging modalities in 8 of 19 eyes. It had the same retinal location on color fundus, 488-R and NIR-R imaging but a different location on AF. The tapetal reflex was most easily detected in 488-R images. The horizontal foveal SD-OCT scans were qualitatively normal, but measurements showed significant outer retinal layer thinning in all eyes. Additionally, the 14 eyes with peripheral SD-OCTs demonstrated patchy loss of the inner segment ellipsoid band. Microperimetry exhibited patchy visual sensitivity loss in 9 eyes. Full field ERGs were variable, ranging from normal to severely abnormal rod and cone responses. Our findings suggest that an optimal protocol for identifying carriers of XLRP should include 488-R imaging in a multimodal approach. Peripheral SD-OCT imaging and central retinal layer quantification revealed significant structural abnormalities.

To investigate the variation in human cone photoreceptor packing density with various demographic or clinical factors, cone packing density was measured using a Canon prototype adaptive optics scanning laser ophthalmoscope and compared as a function of retinal eccentricity, refractive error, axial length, age, gender, race/ethnicity and ocular dominance. We enrolled 192 eyes of 192 subjects with no ocular pathology. Cone packing density was measured at three different retinal eccentricities (0.5 mm, 1.0 mm, and 1.5 mm from the foveal center) along four meridians. Cone density decreased from 32,200 to 11,600 cells/mm(2) with retinal eccentricity (0.5 mm to 1.5 mm from the fovea, P < 0.001). A trend towards a slightly negative correlation was observed between age and density (r = -0.117, P = 0.14). There was, however, a statistically significant negative correlation (r = -0.367, P = 0.003) between axial length and cone density. Gender, ocular dominance, and race/ethnicity were not important determinants of cone density (all, P > 0.05). In addition, to assess the spatial arrangement of the cone mosaics, the nearest-neighbor distances (NNDs) and the Voronoi domains were analyzed. The results of NND and Voronoi analysis were significantly correlated with the variation of the cone density. Average NND and Voronoi area were gradually increased (all, P