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Objective To characterize functional and anatomic sequelae of a bleb induced by subretinal injection. Methods Subretinal injections (100 μL) of balanced salt solution were placed in the superotemporal macula of 1 eye in 3 cynomolgus macaques. Fellow eyes received intravitreal injections (100 μL) of balanced salt solution. Fundus photography, ocular coherence tomography, and multifocal electroretinography were performed before and immediately after injection and again at intervals up to 3 months postinjection. Histopathologic analyses included transmission electron microscopy and immunohistochemistry for glial fibrillary acidic protein, rhodopsin, M/L-cone opsin, and S-cone opsin. Results Retinas were reattached by 2 days postinjection (seen by ocular coherence tomography). Multifocal electroretinography waveforms were suppressed post–subretinal injection within the subretinal injection bleb and, surprisingly, also in regions far peripheral to this area. Multifocal electroretinography amplitudes were nearly completely recovered by 90 days. The spectral-domain ocular coherence tomography inner segment–outer segment line had decreased reflectivity at 92 days. Glial fibrillary acidic protein and S-cone opsin staining were unaffected. Rhodopsin and M/L-cone opsins were partially displaced into the inner segments. Transmission electron microscopy revealed disorganization of the outer segment rod (but not cone) discs. At all postinjection intervals, eyes with intravitreal injection were similar to baseline. Conclusions Subretinal injection is a promising route for drug delivery to the eye. Three months post–subretinal injection, retinal function was nearly recovered, although reorganization of the outer segment rod disc remained disrupted. Understanding the functional and anatomic effects of subretinal injection is important for interpretation of the effects of compounds delivered to the subretinal space. Clinical Relevance Subretinal injection is a new potential route for drug delivery to the eye. Separating drug effects from the procedural effects is critical.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Presence and severity of age-related cataract was determined in adults 43 to 84 years of age in Beaver Dam, Wisconsin. Duplicate photograph gradings for nuclear sclerosis (n = 1160), cortical opacities (n = 1159), and posterior subcapsular cataract (n = 1137) were performed. There are five levels of nuclear sclerosis. Exact agreement occurred in 64.7% of the cases; agreement within one category in 99.8%. For cortical opacities, graders estimate involved area in nine segments of the lens. When the continuous scale is divided into 12 categories of severity, exact agreement varied between 73.5 and 82.4%; for agreement within one category, rates varied between 84.6 and 89.9%. For posterior subcapsular cataracts, exact agreement for involvement of the central circle occurred in 95.0% and agreement within one category occurred in 97.7%. Intraobserver comparisons disclosed similar concordance. These grading schemes are semiquantitative, reproducible, and can be performed for the large numbers of photographs from population-based studies.

Objective To compare gradings of lesions associated with age-related macular degeneration(AMD) from digital and stereoscopic film images. Design Instrument validation study. Participants Sixty-two subjects (124 eyes) with varying degrees of AMD, includingno AMD. Methods Images of the optic disc and macula were taken using a 45° digitalcamera (6.3 megapixels) through dark-adapted pupils and pharmacologicallydilated pupils. In addition, 30° stereoscopic retinal film images weretaken through pharmacologically dilated pupils of the same eyes. All imageswere graded for drusen size, type, and area; pigmentary abnormalities; geographicatrophy; and neovascular lesions using the modified Wisconsin Age-RelatedMaculopathy Grading System. Exact agreement and unweighted κ scores werecalculated for paired gradings resulting from digital and film images. Main Outcome Measure Agreement between gradings obtained from stereoscopic slide transparenciesand digital nonstereoscopic images. Results Exact agreement between gradings of digital and stereoscopic film imagestaken through pharmacologically dilated pupils was 91% (κ = 0.85)for the categories of none, early AMD, and late AMD. Exact agreement for gradingsof digital images taken through dark-adapted pupils compared with gradingsof film images was 80% (κ = 0.69). Exact agreement for gradingsof digital images captured through dark-adapted and pharmacologically dilatedpupils was 86% (κ = 0.78). In addition, κ scores for agreementbetween different approaches for individual lesions were moderate to almostperfect. Conclusions Gradings resulting from high-resolution digital images, especially whenthe pupil is pharmacologically dilated, are comparable with those resultingfrom film-based images. We conclude that digital imaging of the retina isuseful for epidemiological studies of AMD.

Accommodation, the mechanism by which the eye focuses on near objects, is lost with increasing age in humans and monkeys. This pathophysiology, called presbyopia, is poorly understood. We studied aging-related changes in the dynamics of accommodation in rhesus monkeys aged 4–24 yr after total iridectomy and midbrain implantation of an electrode to permit visualization and stimulation, respectively, of the eye’s accommodative apparatus. Real-time video techniques were used to capture and quantify images of the ciliary body and lens. During accommodation in youth, ciliary body movement was biphasic, lens movement was monophasic, and both slowed as the structures approached their new steady-state positions. Disaccommodation occurred more rapidly for both ciliary body and lens, but with longer latent period, and slowed near the end point. With increasing age, the amplitude of lens and ciliary body movement during accommodation declined, as did their velocities. The latent period of lens and ciliary body movements increased, and ciliary body movement became monophasic. The latent period of lens and ciliary body movement during disaccommodation was not significantly correlated with age, but their velocity declined significantly. The age-dependent decline in amplitude and velocity of ciliary body movements during accommodation suggests that ciliary body dysfunction plays a role in presbyopia. The age changes in lens movement could be a consequence of increasing inelasticity or hardening of the lens, or of age changes in ciliary body motility.

PURPOSE To analyze brightness, contrast, and color balance of digital versus film retinal images in a multicenter clinical trial, to propose a model image from exemplars, and to optimize both image types for evaluation of age-related macular degeneration (AMD). METHODS The Age-Related Eye Disease Study 2 (AREDS2) is enrolling subjects from 90 clinics, with three quarters of them using digital and one quarter using film cameras. Image brightness (B), contrast (C), and color balance (CB) were measured with three-color luminance histograms. First, the exemplars (film and digital) from expert groups were analyzed, and an AMD-oriented model was constructed. Second, the impact of B/C/CB on the appearance of typical AMD abnormalities was analyzed. Third, B/C/CB in AREDS2 images were compared between film (156 eyes) and digital (605 eyes), and against the model. Fourth, suboptimal images were enhanced by adjusting B/C/CB to bring them into accord with model parameters. RESULTS Exemplar images had similar brightness, contrast, and color balance, supporting an image model. Varying a specimen image through a wide range of B/C/CB revealed greatest contrast of drusen and pigment abnormalities against normal retinal pigment epithelium with the model parameters. AREDS2 digital images were more variable than film, with lower correspondence to our model. Ten percent of digital were too dim and 19% too bright (oversaturated), versus 1% and 4% of film, respectively. On average, digital had lower green channel contrast (giving less retinal detail) than film. Overly red color balance (weaker green) was observed in 23% of digital versus 8% of film. About half of digital (but fewer film) images required enhancement before AMD grading. After optimization of both image types, AREDS2 image quality was judged as good as that in AREDS (all film). CONCLUSIONS A histogram-based model, derived from exemplars, provides a pragmatic guide for image analysis and enhancement. In AREDS2, the best digital images matched the best film. Overall, however, digital provided lower contrast of retinal detail. Digital images taken with higher G-to-R ratio showed better brightness and contrast management. Optimization of images in the multicenter study helps standardize documentation of AMD (ClinicalTrials.gov NCT00345176).

• Fourteen rhesus monkeys, aged 1 to 24 years, underwent permanent implantation of a bipolar stimulating electrode into the Edinger-Westphal nucleus and complete unilateral or bilateral iridectomy. Slit-lamp Scheimpflug videography of the lens and slit-lamp goniovideography of the lens equator, zonule, and ciliary body allowed direct real-time observation and video recording of the movements of these structures during centrally stimulated accommodation and during disaccommodation. Scalloping of the lens capsule at the zonular insertion sites was clearly visible during disaccommodation and even during accommodation when the zonules were folded. During accommodation, the lens became axially thicker, the ciliary ring narrowed, and, at high levels of acommodation, the zonular fibers slackened and even folded and the lens moved downward. With increasing age and concomitantly decreasing accommodative amplitude, these excursions all diminished, so that in the oldest animals, they were very minimal or absent. Maximum centrally stimulated accommodative amplitude declined with age on a time scale similar to that for cholinomimetic drug-induced accommodation in the rhesus monkey and voluntary accommodation in the human.

Saine and Tyler have assembled a book that may be the most comprehensive textbook on ophthalmic photography; it is certainly the most up to date regarding electronic imaging of the fundus. It is creatively illustrated and contains several hundred images, both color and black and white. The book is divided into 9 main chapters, each with a title page containing an outline of the topics to be discussed. Many chapters make use of sidebars, shaded boxes containing helpful hints and practical suggestions. They provide additional detail to the text with, for example, tips for dilating the difficult patient and suggestions for determining the correct film exposure for young children. Three appendixes provide a list of helpful abbreviations used in ophthalmic photography, a list of professional societies and companies of general interest to the photographer, including manufacturers of stereo equipment, digital cameras, and software useful in ophthalmic photography. A comprehensive index

Macular edema and collateral vessels were examined clinically and histopathologically up to 48 months after branch retinal vein occlusion in six eyes of five cynomolgus monkeys. In all six, central macular swelling and fluorescein leakage from the retinal vasculature were confined to the acute stage. However, histopathologically, at the chronic stage, only two maculas were completely recovered and unremarkable, whereas the other four showed variable degrees of cystoid degeneration and photoreceptor cell loss. In the two recovered maculas, six to eight normal-sized capillaries separated the fovea from the nearest cluster of capillary collaterals. In three maculas with cystic degeneration, collaterals incorporated the circumfoveal capillaries. In the fourth macula with cystic degeneration, collaterals were separated from the center by two normal-sized capillaries but were also associated with large areas of capillary nonperfusion partially due to occlusion of the macular arteriole.

Slit-lamp photographic studies of 144 caged rhesus monkeys, aged 2 months to 35 years, show age-related changes in anterior-chamber depth, lens thickness, anterior and posterior curvatures of the lens, and location of the posterior lens surface relative to the anterior corneal surface. For these parameters, as well as for those measured by other techniques, a difference in slope magnitude and (or) slope sign was found between the growth phase which lasts for 5–6 years, and the adult phase (greater than 5–6 years). Age-related changes in the adult rhesus eye are qualitatively similar in almost all aspects to those observed in the human eye, indicating that the rhesus is a good animal model for the study of human loss of accommodative amplitude.

The rhesus monkey lens exhibits two zones of discontinuity, one anteriorly and one posteriorly. They are first discernible by slit-lamp photography as performed in this study at around age 7 years in iridectomized eyes, and become more distinct with increasing age. Their thickness and distance from each other along the polar axis are independent of lens age, but their distance from the lens surface increases with increasing age. Upon accommodation, the distance between the two zones increases while all other distances along the polar axis remain unchanged, indicating that, as in the human, overall alterations in rhesus lenticular shape and thickness with accommodation primarily reflect changes in the shape of the central region. The curvature of each zone becomes sharper in a linear fashion with accommodation, with the slope of the relationship being similar to those for lens surfaces.

Changes in crystalline lens shape and axial thickness, anterior chamber depth and anterior cornea-posterior lens distance during accommodation induced by corneal iontophoresis of carbachol or electrical stimulation of the Edinger-Westphal nucleus were studied in 25 living, surgically aniridic rhesus monkey eyes, aged 1-25 years. Intraocular distances and anterior and posterior lens surface curvatures were evaluated from slit-lamp Scheimpflug photographs; distances were also determined by A-scan ultrasonography. With increasing accommodation, both lens surfaces become more sharply curved, the lens thickens and the anterior chamber shallows, while the posterior lens surface remains fixed relative to the cornea. Within statistical limits, the respective curvature and distance changes are the same for a given dioptric accommodation induced by either stimulation technique. The respective intraocular distance-accommodation relationships are identical whether derived from photographic or ultrasonographic measurements. Temporal and contralateral reproducibility of all measurements is excellent. Each parameter-accommodation relationship is strikingly linear in all eyes, although above 20 D the slopes of the lens surface curvature-accommodation relationships may have decreased. The curvature change per D of accommodation averages approximately 20% more for the posterior than for the anterior lens surface. There is relatively little interindividual variation in the slope of each relationship despite the significant interindividual differences in age and accommodative amplitude, indicating that the relationships are independent of age. However, when extrapolated back to the non-accommodated resting state, the data indicate that the lens thickens, both its surfaces become more sharply curved, and the anterior chamber shallows with age in adult greater than 5 years, while opposite trends are seen in younger animals.

Ocular biometric parameters and accommodative amplitude were measured by various techniques in 100 normal emmetropic human subjects age 18-70 yr. Anterior chamber depth decreased and lens thickness increased linearly over the entire age group. Accommodative amplitude declined linearly until a stable nadir was reached at about age 50 yr. The respective slopes and intercepts of the age-dependent decline in anterior chamber depth were essentially the same for measurements made independently by optical pachmetry, A-scan ultrasonography, and slit-lamp Scheimpflug photography. The age-dependent increase in lens thickness differed in slope and intercept for measurements made by photography and ultrasonography if the generally accepted lenticular sound velocity was assumed for all subjects. However, if putative lenticular sound velocity was adjusted for age, the relationships given by the two techniques were essentially identical. Total anterior segment length (defined as the distance between the anterior corneal and posterior lens surfaces), vitreous cavity length (distance between the posterior lens and anterior retinal surfaces), and total globe length were all independent of age. This constellation of findings indicates that the human lens grows throughout adult life while the globe does not, that thickening of the lens completely accounts for shallowing of the anterior chamber with age, but that the posterior surface of the lens remains fixed in position relative to the cornea and retina.

Accommodation is a dynamic visual process involving the controlled deformation of the crystalline lens by the ciliary muscle. In the unaccommodated state (focus on infinity), the lens is stretched to its thinnest along the visual axis, and its curvature is at its flattest. The accommodative process, which increases the refractive contribution of the lens to the overall system, occurs through a controlled elastic recovery by the lens, resulting in increased axial lens thickness and sharpness of curvature. With increasing age, the closest focus obtainable through this process recedes, resulting eventually in the condition termed presbyopia.

As part of a cross-sectional study of aging of the human accommodative apparatus, unaccommodated anterior chamber depth, unaccommodated lens thickness, and accommodative amplitude were each determined by two or more independent techniques in 100 normal emmetropic subjects, age 18-70 yr. For anterior chamber depth, the order of accuracy seemed to be: optical pachymetry > slit-lamp Scheimpflug photography > Ascan ultrasonography, although there was good agreement among all three methods. For lens thickness, slitlamp Scheimpflug photography seemed more accurate than A-scan ultrasonography when the generally accepted lenticular sound velocity of 1641 m . s(-1) was used for the ultrasonographic calculation. The agedependent divergence allowed calculation of a putative relationship between lenticular sound velocity and age, indicating that velocity decreased by ~3 m . s(-1) . yr(-1). Accommodative amplitude declined with age, reaching a minimum, by age 50 yr, of 0.5 diopters as measured by coincidence refractometry. This residual 0.5 diopters may represent the inherent focal depth of the eye's optical system, rather than active accommodation. Maximum accommodative amplitude based on the subject's ability to clearly visualize a target through minus lenses was always 1.50 diopters greater than the refractometrically measured maximum, regardless of age. This difference presumably represents increased depth of field provided by pupillary constriction, rather than active accommodation.

• A universally adjustable slitlamp mount has been developed for use with the four-mirror gonioscopy lens (Zeiss). The device frees both of the examiner's hands and allows leisurely examination of the anterior chamber angle and posterior pole, simultaneous manipulation of the slitlamp illumination and observation systems, dynamic indentation gonioscopy, and high-quality goniophotography.

Five cynomolgi underwent unilateral 360 degrees ciliary muscle retrodisplacement. Beginning several months later, they received 150 to 210 micrograms of echothiophate iodine topically once daily in both eyes for five months. In all eyes anterior and posterior subcapsular lens opacities developed that were characteristic of those caused by echothiophate. There were no apparent differences in biomicroscopic appearance or time course of the cataracts between eyes with or without retrodisplaced ciliary muscles. Since eyes with retrodisplaced ciliary muscles accommodate only minimally in response to echothiophate, possible mechanical stress on the lens due to sustained, intense accommodation cannot explain echothiophate cataractogenesis.