Quantitative OCT analysis of idiopathic perifoveal telangiectasia

PURPOSE: To identify and quantitate specific changes in optical coherence tomography (OCT) images of patients with type 2 idiopathic perifoveal telangiectasia (IPT). METHODS: In a prospectively designed, observational, case-control study, 28 eyes of 14 consecutive patients with IPT were examined with OCT and compared with eyes of 14 unaffected control subjects. Light reflectivity profiles of raw scan data of OCT images were quantitatively analyzed for differences in distance between different retinal reflectivity layers and their respective reflectivities. Maculae were examined in four separate regions: (1) central fovea, (2) nasal perifovea, (3) temporal perifovea, and (4) outside the fovea. RESULTS: Retinal thinning, shortening of the photoreceptor outer segments and loss of reflectivity of the photoreceptor ellipsoid region were found in the central foveal region as well as the nasal and temporal perifoveal regions in eyes with IPT. In addition, increased reflectivity of the outer nuclear layer was found in a sharply demarcated area of the inferotemporal perifoveal region in all affected eyes. Retinal tissue located more than 2000 mum away from the foveola was indistinguishable from that in normal eyes. CONCLUSIONS: Quantitative OCT analysis shows unique and specific changes in the photoreceptors of the central macula in IPT which can be detected from first clinical presentation. These changes may be of use as an additional diagnostic tool. Correlation of the findings in the outer nuclear layer with histologic studies may help identify the nature of the reflectivity increase and define more clearly the type of damage sustained by the photoreceptors in this condition.

Comparison between intravitreal and orbital floor triamcinolone acetonide after phacoemulsification in patients with endogenous uveitis

PURPOSE: To compare the effect of intravitreal and orbital floor triamcinolone acetonide (TA) on macular edema, visual outcome, and course of postoperative inflammation after cataract surgery in uveitis patients. DESIGN: Prospective, randomized clinical trial. METHODS: Monocenter study (40 patients) with chronic endogenous uveitis who underwent phacoemulsification with intraocular lens implantation with either 4 mg intravitreal TA (n = 20) or 40 mg orbital floor TA (n = 20). The primary outcome was influence on cystoid macular edema (CME). Secondary outcome measures were best-corrected visual acuity (BCVA), anterior chamber cell grade, laser flare photometry, giant cell deposition, posterior capsule opacification (PCO), and intraocular pressure. RESULTS: Mean central foveal thickness decreased in the intravitreal TA group and increased in the orbital floor TA group (P < .001 at one and three months). CME improved in 50% of patients after intravitreal TA, whereas it was unchanged after orbital floor TA (difference between the groups at three months, P = .049). Mean BCVA (logarithm of the minimal angle of resolution) improved postoperatively (P < .001) from 0.76 and 0.74 to 0.22 and 0.23 in the intravitreal TA and orbital floor TA group, respectively. Anterior chamber cell count at one month was lower in the intravitreal TA than in the orbital floor TA group (P = .02). Laser flare photometry values and giant cell numbers were slightly higher after orbital floor TA than after intravitreal TA. The groups did not differ with respect to PCO rate and ocular hypertension. CONCLUSIONS: The CME improvement and anti-inflammatory effect after intravitreal TA was better than after orbital floor TA injection in cataract surgery in uveitis patients.

Reproducibility of retinal thickness measurements in healthy subjects using spectralis optical coherence tomography

PURPOSE: To test the reproducibility of retinal thickness measurements in healthy volunteers of a new Frequency-domain optical coherence tomography (OCT) device (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). DESIGN: Prospective, observational study. METHODS: Forty-one eyes of 41 healthy subjects were included into the study. Intraobserver reproducibility was tested with 20 x 15 degree raster scans consisting of 37 high-resolution line scans that were repeated three times by one examiner (M.N.M.). Mean retinal thickness was calculated for nine areas corresponding to the Early Treatment Diabetic Retinopathy Study (ETDRS) areas. Coefficients of variation (COV) were calculated. RESULTS: Retinal thickness measurements were highly reproducible for all ETDRS areas. Mean total retinal thickness was 342 +/- 15 microm. Mean foveal thickness was 286 +/- 17 microm. COVs ranged from 0.38% to 0.86%. Lowest COV was found for the temporal outer ETDRS area (area 7; COV, 0.38%). Highest COV was found for the temporal inner ETDRS area (area 3; COV, 0.86%). Mean difference between measurement 1 and 2, measurement 1 and 3, and measurement 2 and 3 for all ETDRS areas was 1.01 microm, 0.98 microm, and 0.99 microm, respectively. CONCLUSION: Spectralis OCT retinal thickness measurements in healthy volunteers showed excellent intraobserver reproducibility with virtually identical results between retinal thickness measurements performed by one operator.

Structure-function analyses of {\it PAX6\/} and the molecular bases of aniridia

PAX6 is a transcription activator that regulates eye development in animals ranging from Drosophila to human. The C-terminal region of PAX6 is proline/serine/threonine-rich (PST) and functions as a potent transactivation domain when attached to a heterologous DNA-binding domain of the yeast transcription factor, GAL4. The PST region comprises 152 amino acids encoded by four exons. The transactivation function of the PST region has not been defined and characterized in detail by in vitro mutagenesis. I dissected the PST domain in two independent systems, a heterologous system using a GAL4 DNA-binding site and the native system of PAX6. In both systems, the results show consistently that all four constituent exons of the PST domain are responsible for the transactivation function. The four exon fragments act cooperatively to stimulate transcription, although none of them can function individually as an independent transactivation domain. Combinations of two or more exon fragments can reconstitute substantial transactivation activity when fused to the DNA-binding domain of GAL4, but they surprisingly do not produce much activity in the context of native PAX6 even though the mutant PAX6 proteins are stable and their DNA-binding function remains unaffected. I conclude that the PAX6 protein contains an unusually large transactivation domain that is evolutionarily conserved to a high degree, and that its full transactivation activity relies on the cooperative action of the four exon fragments.^ Most PAX6 mutations detected in patients with aniridia result in truncations of the protein. Some of the truncation mutations occur in the PST region of PAX6, resulting in mutant proteins that retain their DNA-binding ability but have no significant transactivation activity. It is not clear whether such mutants are true loss-of-function or dominant-negative mutants. I show that these mutants are dominant-negative if they are coexpressed with wild-type PAX6 in cultured cells and that the dominant-negative effects result from enhanced DNA-binding ability of these mutants due to removal of the PST domain. These mutants are able to repress the wild-type PAX6 activity not only at target genes with paired domain binding sites but also at target genes with homeodomain binding sites.^ Mutations in the human PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, autosomal dominant keratitis, and familial foveal dysplasia. The various phenotypes may arise from different mutations in the same gene. To test this theory, I performed a functional analysis of two missense mutations in the paired domain: the R26G mutation reported in a case of Peters' anomaly, and the I87R mutation identified in a patient with aniridia. While both the R26 and the I87 positions are conserved in the paired boxes of all known PAX genes, X-ray crystallography has shown that only R26 makes contact with DNA. I found that the R26G mutant failed to bind a subset of paired domain binding sites but, surprisingly, bound other sites and successfully transactivated promoters containing those sites. In contrast, the I87R mutant had lost the ability to bind DNA at all tested sites and failed to transactivate promoters. My data support the haploinsufficiency hypothesis of aniridia, and the hypothesis that R26G is a hypomorphic allele. ^

Functional and anatomical outcome of eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab following an exit strategy regimen.

AIMS To assess the functional and morphological outcome of eyes with neovascular AMD treated with intravitreal ranbizumab following an exit strategy treatment regime. METHODS The Bern treatment regime for neovascular AMD has a fixed injection schedule, even in the non-active stage of the disease. The regimen has been adapted from the PIER study treatment protocol. Eyes with non-active AMD will receive 4 injections in the first year, and 2 injections in the second year of follow-up before treatment stops. Patients that received ranibizumab for treatment and reached the exit criteria were identified, and charts were reviewed to assess functional and morphological outcome. RESULTS Only 2.6% of all patients (15 out of 575 patients) reached the exit criteria. Mean change in best corrected ETDRS visual acuity (VA) was 4.5±16.9 letters when comparing baseline VA to 4 weeks after the last injection (p=0.32). OCT mean foveal thickness was significantly thinner after last treatment (247.9±43.0 µm) compared to baseline (332.5±83.1 µm, p=0.002). The mean total number of ranibizumab injections was 15.6±8.0, and the mean total treatment period was 40.9±18.3 months. Twenty percent of eyes had geographic atrophy present at baseline versus 46.6% at the end of treatment. CONCLUSIONS Even with a fixed treatment regime and a defined treatment exit strategy, only a small percentage of patients reach exit criteria. Retinal thickness has been significantly reduced by repeated intravitreal ranibizumab injections, and geographic atrophy became more frequent.

Natural History of Geographic Atrophy Progression Secondary to Age-Related Macular Degeneration (Geographic Atrophy Progression Study).

PURPOSE The Geographic Atrophy Progression (GAP) study was designed to assess the rate of geographic atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP). DESIGN Prospective, multicenter, noninterventional natural history study. PARTICIPANTS A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP. METHODS Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit). MAIN OUTCOME MEASURES The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity. RESULTS Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm(2) at 6 months, 1.85 (0.1) and 1.57 (0.1) mm(2) at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm(2) at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots (P < 0.001) and those with extrafoveal lesions compared with those with foveal lesions (P = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm(2)) or banded (mean 1.01 mm(2)) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm(2)) and focal (mean, 0.36 mm(2)) FAF patterns. CONCLUSIONS Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

Feature integration in pattern perception

The human visual system is able to effortlessly integrate local features to form our rich perception of patterns, despite the fact that visual information is discretely sampled by the retina and cortex. By using a novel perturbation technique, we show that the mechanisms by which features are integrated into coherent percepts are scale-invariant and nonlinear (phase and contrast polarity independent). They appear to operate by assigning position labels or “place tags” to each feature. Specifically, in the first series of experiments, we show that the positional tolerance of these place tags in foveal, and peripheral vision is about half the separation of the features, suggesting that the neural mechanisms that bind features into forms are quite robust to topographical jitter. In the second series of experiment, we asked how many stimulus samples are required for pattern identification by human and ideal observers. In human foveal vision, only about half the features are needed for reliable pattern interpolation. In this regard, human vision is quite efficient (ratio of ideal to real ≈ 0.75). Peripheral vision, on the other hand is rather inefficient, requiring more features, suggesting that the stimulus may be relatively underrepresented at the stage of feature integration.

Memory fields of neurons in the primate prefrontal cortex

Many prefrontal (PF) neurons convey information about both an object’s identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their “memory fields”) by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.

Decreased Perifoveal Sensitivity Detected by Microperimetry in Patients Using Hydroxychloroquine and without Visual Field and Fundoscopic Anomalies

Purpose. To evaluate the usefulness of microperimetry in the early detection of the ocular anomalies associated with the use of hydroxychloroquine. Methods. Prospective comparative case series study comprising 14 healthy eyes of 7 patients (group A) and 14 eyes of 7 patients under treatment with hydroxychloroquine for the treatment of rheumatologic diseases and without fundoscopic or perimetric anomalies (group B). A comprehensive ophthalmological examination including microperimetry (MP) and spectraldomain optical coherence tomography was performed in both groups. Results. No significant differences were found in mean MP foveal sensitivity between groups (P = 0.18). However, mean MP overall sensitivity was significantly higher in group A (29.05 ± 0.57 dB versus group B, 26.05 ± 2.75 dB; P < 0.001). Significantly higher sensitivity values were obtained in group A in comparison to group B for the three eccentric loci evaluated (P < 0.001). Conclusion. Microperimetry seems to be a useful tool for the early detection of retinal damage in patients treated with hydroxychloroquine.

On the decline of 1st and 2nd order sensitivity with eccentricity

We studied the relationship between the decline in sensitivity that occurs with eccentricity for stimuli of different spatial scale defined by either luminance (LM) or contrast (CM) modulation. We show that the detectability of CM stimuli declines with eccentricity in a spatial frequency-dependent manner, and that the rate of sensitivity decline for CM stimuli is roughly that expected from their 1st order carriers, except, possibly, at finer scales. Using an equivalent noise paradigm, we investigated the possible reasons for why the foveal sensitivity for detecting LM and CM stimuli differs as well as the reason why the detectability of 1st order stimuli declines with eccentricity. We show the former can be modeled by an increase in internal noise whereas the latter involves both an increase in internal noise and a loss of efficiency. To encompass both the threshold and suprathreshold transfer properties of peripheral vision, we propose a model in terms of the contrast gain of the underlying mechanisms.

Anisotropy for spatial summation of elongated patches of grating:A tale of two tails

Studies of spatial summation often use sinusoidal gratings with blurred edges. When the envelope is elongated (i) along the grating stripes and (ii) at right angles to the grating stripes, we refer to the stimuli as skunk-tails and tiger-tails respectively. Previous work [Polat & Tyler, 1999; Vision Research, 39, 887-895.] has found that sensitivity to skunk-tails is greater than for tiger-tails, but there have been several failures to replicate this result within a subset of the conditions. To address this we measured detection thresholds for skunk-tails, tiger-tails and squares of grating with sides matched to the lengths of the tails. For foveal viewing, we found a contrast sensitivity advantage in the order of 2 dB for skunk-tails over tiger-tails, but only for horizontal gratings. For vertical gratings, sensitivity was very similar for both tail-types. When the stimuli were presented parafoveally (upper right visual field), a small advantage was found for skunk-tails over tiger-tails at both orientations, and spatial summation slopes were close to that of the ideal observer. We did not replicate the findings of Polat & Tyler, but our results are consistent with (i) those of Foley et al. [Foley, J. M., Varadharajan, S., Koh, C. C., & Farias, C. Q. (2007) Vision Research, 47, 85-107.] who used only vertical gratings and (ii) those from modelfest, where only horizontal gratings were used. The small effect of tail-type here suggests an anisotropy in the underlying physiology. © 2007 Elsevier Ltd. All rights reserved.

Automated assessment of visual fields and their inter-relation to evoked potentials in visual disorders

The Octopus Automated Perimeter was validated in a comparative study and found to offer many advantages in the assessment of the visual field. The visual evoked potential was investigated in an extensive study using a variety of stimulus parameters to simulate hemianopia and central visual field defects. The scalp topography was recorded topographically and a technique to compute the source derivation of the scalp potential was developed. This enabled clarification of the expected scalp distribution to half field stimulation using different electrode montages. The visual evoked potential following full field stimulation was found to be asymmetrical around the midline with a bias over the left occiput particularly when the foveal polar projections of the occipital cortex were preferentially stimulated. The half field response reflected the distribution asymmetry. Masking of the central 3° resulted in a response which was approximately symmetrical around the midline but there was no evidence of the PNP-complex. A method for visual field quantification was developed based on the neural representation of visual space (Drasdo and Peaston 1982) in an attempt to relate visual field depravation with the resultant visual evoked potentials. There was no form of simple, diffuse summation between the scalp potential and the cortical generators. It was, however, possible to quantify the degree of scalp potential attenuation for M-scaled full field stimuli. The results obtained from patients exhibiting pre-chiasmal lesions suggested that the PNP-complex is not scotomatous in nature but confirmed that it is most likely to be related to specific diseases (Harding and Crews 1982). There was a strong correlation between the percentage information loss of the visual field and the diagnostic value of the visual evoked potential in patients exhibiting chiasmal lesions.

Psychophysical investigations of human peripheral vision

This thesis investigates various aspects of peripheral vision, which is known not to be as acute as vision at the point of fixation. Differences between foveal and peripheral vision are generally thought to be of a quantitative rather than a qualitative nature. However, the rate of decline in sensitivity between foveal and peripheral vision is known to be task dependent and the mechanisms underlying the differences are not yet well understood. Several experiments described here have employed a psychophysical technique referred to as 'spatial scaling'. Thresholds are determined at several eccentricities for ranges of stimuli which are magnified versions of one another. Using this methodology a parameter called the E2 value is determined, which defines the eccentricity at which stimulus size must double in order to maintain performance equivalent to that at the fovea. Experiments of this type have evaluated the eccentricity dependencies of detection tasks (kinetic and static presentation of a differential light stimulus), resolution tasks (bar orientation discrimination in the presence of flanking stimuli, word recognition and reading performance), and relative localisation tasks (curvature detection and discrimination). Most tasks could be made equal across the visual field by appropriate magnification. E2 values are found to vary widely dependent on the task, and possible reasons for such variations are discussed. The dependence of positional acuity thresholds on stimulus eccentricity, separation and spatial scale parameters is also examined. The relevance of each factor in producing 'Weber's law' for position can be determined from the results.

Spatial scaling in human peripheral vision

The observation that performance in many visual tasks can be made independent of eccentricity by increasing the size of peripheral stimuli according to the cortical magnification factor has dominated studies of peripheral vision for many years. However, it has become evident that the cortical magnification factor cannot be successfully applied to all tasks. To find out why, several tasks were studied using spatial scaling, a method which requires no pre-determined scaling factors (such as those predicted from cortical magnification) to magnify the stimulus at any eccentricity. Instead, thresholds are measured at the fovea and in the periphery using a series of stimuli, all of which are simply magnified versions of one another. Analysis of the data obtained in this way reveals the value of the parameter E2, the eccentricity at which foveal stimulus size must double in order to maintain performance equivalent to that at the fovea. The tasks investigated include hyperacuities (vernier acuity, bisection acuity, spatial interval discrimination, referenced displacement detection, and orientation discrimination), unreferenced instantaneous and gradual movement, flicker sensitivity, and face discrimination. In all cases tasks obeyed the principle of spatial scaling since performance in the periphery could be equated to that at the fovea by appropriate magnification. However, E2 values found for different spatial tasks varied over a 200-fold range. In spatial tasks (e.g. bisection acuity and spatial interval discrimination) E2 values were low, reaching about 0.075 deg, whereas in movement tasks the values could be as high as 16 deg. Using a method of spatial scaling it has been possible to equate foveal and peripheral perfonnance in many diverse visual tasks. The rate at which peripheral stimulus size had to be increased as a function of eccentricity was dependent upon the stimulus conditions and the task itself. Possible reasons for these findings are discussed.

Topographic studies of scalp potentials evoked by pattern presentation

The waveform and scalp distribution of the visual evoked potentials elicited by stimuli in the foveal and parafoveal regions have been investigated in a group of normal humans using a 16-channel `brain mapping' system. The waveform and topography of the responses to pattern onset and pattern reversal stimulation were investigated, using 4 x 4o full field and 4 x 2o lateral and altitudinal half-field stimuli. The responses were composed of several successive peaks which are in some respects consistent with those demonstrated by other workers using larger field sizes. The differences in the behaviour of these components with respect to the position of the stimulus in the visual field were suggestive of origins in different areas of the visual cortex and/or different visual mechanism. Of particular interest were the major early positive components `P90' and `P95' of the responses to pattern onset and pattern reversal stimulation respectively. More detailed exploration of the behaviour of these major early positive components was carried out using `M-scaled' stimuli selected to activate one square centimetre patches of striate cortex and associated extrastriate re-projections, positioned at different points in the foveal and parafoveal area of the visual field. The inter- and intra-subject variability in amplitude and localisation of the signals elicited by these targets was considered to be a reflection of the individual variations in relationship of visual field projections with the pattern of gyri and fissures on the proximal surface of the occipital lobe. The behaviour of component P90 of the onset response is consistent with a lateral origin in extrastriate visual cortex; that of P95 of the pattern reversal response is consistent in some respects with a striate cortical origin, but in others with a partial origin in extrastriate cortex.