September 2012

A new era of ocular imaging has recently begun with the advent of in vivo confocal microscopy (IVCM), shedding more light on the pathophysiology, diagnosis, and potential treatment strategies for dry eye disease. IVCM is a noninvasive and powerful tool that allows detection of changes in ocular surface epithelium, immune and inflammatory cells, corneal nerves, keratocytes, and meibomian gland structures on a cellular level. Ocular surface structures in dry eye-related conditions have been assessed and alterations have been quantified using IVCM. IVCM may aid in the assessment of dry eye disease prognosis and treatment, as well as lead to improved understanding of the pathophysiological mechanisms in this complex disease. Further, due to visualization of subclinical findings, IVCM may allow detection of disease at much earlier stages and allow stratification of patients for clinical trials. Finally, by providing an objective methodology to monitor treatment efficacy, image-guided therapy may allow the possibility of tailoring treatment based on cellular changes, rather than on clinical changes alone.

PURPOSE: Eyelid dysmotility may result from trauma, tumors, inflammation, infection, and a variety of other conditions. In these cases, a mechanical effect is disrupting a normal neuromuscular apparatus. Dysmotility can also be caused by paralytic eyelid disorders; included in this broad category are neurologic and myogenic disorders of eyelid opening and/or closure. Secondary effects include spastic eyelid closure and synkinesis syndromes. These conditions, by definition, are disorders of movement, and can only be studied adequately using dynamic imaging techniques. METHODS: A comprehensive literature search was performed on PubMed. Ninety abstracts were reviewed. RESULTS: Dynamic eyelid imaging has evolved dramatically over the past two decades, at least partially due to the rise of inexpensive digital technology. Magnetic search coil imaging, high- and low-speed videography, electromyography, and high-resolution microscopy coil magnetic resonance imaging each has its advantages and disadvantages, an understanding of which will guide appropriate selection of technology in any given clinical situation. CONCLUSIONS: Dynamic eyelid imaging is useful to study dysmotility. The optimal technique depends upon the clinical setting and the physiologic or pathologic topic of interest. To our knowledge, a report of this type has not been previously summarized.

Although the phenomenon of fundus autofluorescence has been known for decades, it has only recently been recognized as a measure of retinal pigment epithelial function and health. Characteristic fundus autofluorescence patterns have been described in eyes affected by inflammation of the posterior segment, and these patterns have provided insights into the pathogenesis of posterior uveitis entities. In addition, preliminary data indicate that fundus autofluorescence characteristics may serve as markers of disease activity, allow prediction of visual prognosis, and may help determine the adequacy of therapy. We provide an overview of the current state of fundus autofluorescence imaging technology and review our current knowledge of fundus autoflourescence findings and their clinical use in the posterior uveitis entities.

PURPOSE: Surgical treatment of myogenic ptosis usually requires a form of frontalis suspension. Complications can include entropion, headache, contour abnormalities, and poor eyelid excursion. The Levine palpebral spring has been used successfully to augment eyelid closure in more than 2,000 patients. The authors present a modified Levine spring to correct ptosis in a patient with poor levator function. METHODS: Interventional case report. A 55-year-old man with profound myogenic ptosis was treated with bilateral modified Levine palpebral springs. Eyelid position, contour and excursion, blink reflex, lagophthalmos, and ocular surface were evaluated. RESULTS: The Levine palpebral spring functioned well to open both eyelids. Margin reflex distance improved from -3 mm to 3 m postoperatively. Excellent contour and excursion were observed. Orbicularis action, including blink reflex, was preserved, and ocular surface was not compromised. CONCLUSION: The modified Levine palpebral spring is an alternative to frontalis suspension in treating select patients with eyelid ptosis with poor levator function.

The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy.

PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding.

PURPOSE: To analyze the morphologic features of corneal epithelial cells and keratocytes by in vivo confocal microscopy in patients with herpes simplex keratitis (HSK) as associated with corneal innervation. DESIGN: Prospective, cross-sectional, controlled, single-center study. PARTICIPANTS: Thirty-one eyes with the diagnosis HSK and their contralateral clinically unaffected eyes were studied and compared with normal controls (n = 15). METHODS: In vivo confocal microscopy (Confoscan 4; Nidek Technologies, Gamagori, Japan) and corneal esthesiometry (Cochet-Bonnet; Luneau Ophthalmologie, Chartres, France) of the central cornea were performed bilaterally in all patients and controls. Patients were grouped into normal (>5.5 cm), mild (>2.5-5.5 cm), and severe (<2.5 cm) loss of sensation. MAIN OUTCOME MEASURES: Changes in morphologic features and density of the superficial and basal epithelial cells, as well as stromal keratocytes, were assessed by 2 masked observers. Changes were correlated to corneal sensation, number of nerves, and total length of nerves. RESULTS: There was a significant and gradual decrease in the density of superficial epithelial cells in HSK eyes, with 852.50 ± 24.4 cells/mm(2) in eyes with severe sensation loss and 2435.23 ± 224.3 cells/mm(2) in control eyes (P = 0.008). Superficial epithelial cell size was 2.5-fold larger in HSK eyes (835.3 μm(2)) compared with contralateral or normal eyes (407.4 μm(2); P = 0.003). A significant number of hyperreflective desquamating superficial epithelial cells were present in HSK eyes with normal (6.4%), mild (29.1%), and severe (52.2%) loss of sensation, but were absent in controls. The density of basal epithelial cells, anterior keratocytes, and posterior keratocytes did not show statistical significance between patients and controls. Changes in superficial epithelial cell density and morphologic features correlated strongly with total nerve length, number, and corneal sensation. Scans of contralateral eyes did not show any significant epithelial or stromal changes compared with controls. CONCLUSIONS: In vivo confocal microscopy reveals profound HSK-induced changes in the superficial epithelium, as demonstrated by increase in cell size, decrease in cell density, and squamous metaplasia. This study demonstrated that these changes correlate strongly with changes in corneal innervation.

More than 98% of a typical vertebrate genome does not code for proteins. Although non-coding regions are sprinkled with short (<200 bp) islands of evolutionarily conserved sequences, the function of most of these unannotated conserved islands remains unknown. One possibility is that unannotated conserved islands could encode non-coding RNAs (ncRNAs); alternatively, unannotated conserved islands could serve as promoter-distal regulatory factor binding sites (RFBSs) like enhancers. Here we assess these possibilities by comparing unannotated conserved islands in the human and mouse genomes to transcribed regions and to RFBSs, relying on a detailed case study of one human and one mouse cell type. We define transcribed regions by applying a novel transcript-calling algorithm to RNA-Seq data obtained from total cellular RNA, and we define RFBSs using ChIP-Seq and DNAse-hypersensitivity assays. We find that unannotated conserved islands are four times more likely to coincide with RFBSs than with unannotated ncRNAs. Thousands of conserved RFBSs can be categorized as insulators based on the presence of CTCF or as enhancers based on the presence of p300/CBP and H3K4me1. While many unannotated conserved RFBSs are transcriptionally active to some extent, the transcripts produced tend to be unspliced, non-polyadenylated and expressed at levels 10 to 100-fold lower than annotated coding or ncRNAs. Extending these findings across multiple cell types and tissues, we propose that most conserved non-coding genomic DNA in vertebrate genomes corresponds to promoter-distal regulatory elements.

Intraoperative wavefront aberrometry is a relatively new technology that aims to improve refractive outcomes following cataract surgery by optimizing the spherical power of the intraocular lens implant or calculating the appropriate axis and power of toric lenses during cataract surgery in an aphakic state. This article reviews the literature on intraoperative wavefront aberrometry and provides a critical assessment of the benefits and shortcomings of that technology.

Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema.

PURPOSE: The purpose of this study is to report the use of intravitreal triamcinolone for treatment of cancer-associated retinopathy (CAR) refractory to systemic therapy. METHODS: This was a retrospective chart review study. RESULTS: A 67-year-old man presented with cancer-associated retinopathy with antibodies against a 46-kDa retinal protein, alpha enolase. There was disease progression despite therapy with mycophenolate and intravenous immunoglobulin. Serial intravitreal injections of triamcinolone resulted in restoration of photoreceptor anatomy on optical coherence tomography and visual improvement. The patient's vision was preserved at 20/40 OD and 20/32 OS until his death from lung cancer 31 months after CAR diagnosis. CONCLUSIONS: Intravitreal triamcinolone may be beneficial for maintenance of vision in patients with CAR.

In a 58-year-old woman with blepharospasm, a slowly enlarging left inferomedial eyelid lesion developed. It measured 3 × 5 mm and was nonulcerated, well-circumscribed, whitish, upraised, and firm. An initial incomplete excision followed by a total repeated excision revealed small squamous microcysts, often exhibiting calcifications and cords of nonclefting basaloid cells embedded in a scirrhous stroma characteristic of desmoplastic trichoepithelioma (DTE). Immunohistochemical investigations disclosed CD34-positive stromal fibroblasts and many CK20-positive Merkel cells located among the epithelial cells, features absent in mimicking sclerosing basal cell carcinoma (BCC). The tumor has not recurred during 6 months of follow up. Besides BCC, the differential diagnosis chiefly concerns syringoma and microcystic adnexal carcinoma. Surgical therapy should aim at complete excision but does not have to be as extensive or aggressive as that used for morpheic or sclerosing BCC because of its lack of diffusely infiltrating margins.

Assessment of patients with infectious endophthalmitis is frequently limited by media opacities, and ocular ultrasonography is routinely performed in this setting. We examined the literature to assess the level of evidence for the utility of ocular ultrasonography in these patients. Common ultrasonographic findings reported include low amplitude mobile echoes, vitreous membranes, and thickening of the retina and choroid. Based on the available evidence, we conclude that ocular ultrasound may be a useful adjunct in guiding treatment and minimizing complications. While positive findings may be confirmatory in cases in which the clinical suspicion is high, ocular ultrasound alone cannot be used to prove or to exclude the diagnosis of infectious endophthalmitis.

The diagnosis of many neuro-ophthalmic conditions is facilitated with neuro-imaging. The two main modalities are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Clinicians who refer patients for either of these techniques must not only know which of them to choose, but also where the imaging should be performed (e.g. brain, orbit), whether or not contrast is indicated, and if angiography should be supplemented. These complexities often result in imaging studies that are either unneeded or unhelpful. The goal of this manuscript is to provide a practical set of guidelines for the general ophthalmologist of how to choose the correct parameters for neuro-imaging studies.

Epiphora is a common problem seen by the ophthalmologist. There are numerous etiologies of a watering eye, and the underlying diagnosis is not always clear. A variety of in-office examination techniques and procedures exist to aid with diagnosis and determination of appropriate therapy, but sometimes the diagnosis remains elusive, or an instituted therapy fails. Lacrimal imaging, particularly in these cases, can be helpful in assessing the function and anatomy of the lacrimal drainage system. This review serves to examine the literature of the last 10 years concerning imaging of the lacrimal drainage system.

PURPOSE: To measure natural image search performance in patients with central vision impairment. To evaluate the performance effect for a JPEG based image enhancement technique using the visual search task. METHODS: One hundred and fifty JPEG images were presented on a touch screen monitor in either an enhanced or original version to 19 patients (visual acuity 0.4-1.2 logMAR, 6/15 to 6/90, 20/50 to 20/300) and seven normally sighted controls (visual acuity -0.12 to 0.1 logMAR, 6/4.5 to 6/7.5, 20/15 to 20/25). Each image fell into one of three categories: faces, indoors, and collections. The enhancement was realized by moderately boosting a mid-range spatial frequency band in the discrete cosine transform (DCT) coefficients of the image luminance component. Participants pointed to an object in a picture that matched a given target displayed at the upper-left corner of the monitor. Search performance was quantified by the percentage of correct responses, the median search time of correct responses, and an 'integrated performance' measure - the area under the curve of cumulative correct response rate over search time. RESULTS: Patients were able to perform the search tasks but their performance was substantially worse than the controls. Search performances for the three image categories were significantly different (p <= 0.001) for all the participants, with searching for faces being the most difficult. When search time and correct response were analyzed separately, the effect of enhancement led to increase in one measure but decrease in another for many patients. Using the integrated performance, it was found that search performance declined with decrease in acuity (p = 0.005). An improvement with enhancement was found mainly for the patients whose acuity ranged from 0.4 to 0.8 logMAR (6/15 to 6/38, 20/50 to 20/125). Enhancement conferred a small but significant improvement in integrated performance for indoor and collection images (p = 0.025) in the patients. CONCLUSION: Search performance for natural images can be measured in patients with impaired vision to evaluate the effect of image enhancement. Patients with moderate vision loss might benefit from the moderate level of enhancement used here.

PURPOSE: In performing search tasks, the visual system encodes information across the visual field at a resolution inversely related to eccentricity and deploys saccades to place visually interesting targets upon the fovea, where resolution is highest. The serial process of fixation, punctuated by saccadic eye movements, continues until the desired target has been located. Loss of central vision restricts the ability to resolve the high spatial information of a target, interfering with this visual search process. We investigate oculomotor adaptations to central visual field loss with gaze-contingent artificial scotomas. METHODS: Spatial distortions were placed at random locations in 25° square natural scenes. Gaze-contingent artificial central scotomas were updated at the screen rate (75 Hz) based on a 250 Hz eye tracker. Eight subjects searched the natural scene for the spatial distortion and indicated its location using a mouse-controlled cursor. RESULTS: As the central scotoma size increased, the mean search time increased [F(3,28) = 5.27, p = 0.05], and the spatial distribution of gaze points during fixation increased significantly along the x [F(3,28) = 6.33, p = 0.002] and y [F(3,28) = 3.32, p = 0.034] axes. Oculomotor patterns of fixation duration, saccade size, and saccade duration did not change significantly, regardless of scotoma size. CONCLUSIONS: There is limited automatic adaptation of the oculomotor system after simulated central vision loss.

Computer based video games are receiving great interest as a means to learn and acquire new skills. As a novel approach to teaching navigation skills in the blind, we have developed Audio-based Environment Simulator (AbES); a virtual reality environment set within the context of a video game metaphor. Despite the fact that participants were naïve to the overall purpose of the software, we found that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building using audio based cues alone. This was confirmed by a series of behavioral performance tests designed to assess the transfer of acquired spatial information to a large-scale, real-world indoor navigation task. Furthermore, learning the spatial layout through a goal directed gaming strategy allowed for the mental manipulation of spatial information as evidenced by enhanced navigation performance when compared to an explicit route learning strategy. We conclude that the immersive and highly interactive nature of the software greatly engages the blind user to actively explore the virtual environment. This in turn generates an accurate sense of a large-scale three-dimensional space and facilitates the learning and transfer of navigation skills to the physical world.

Proliferative vitreoretinopathy (PVR) is a vision-threatening disease and a common complication of surgery to correct rhegmatogenous retinal detachment (RRD). Several models of the pathogenesis of this disease have been described with some of these models focusing on the role of inflammatory cells and other models focusing on the role of growth factors and cytokines in the vitreous which come into contact with intraretinal and retinal pigment epithelial cells. New experiments have shed light on the pathogenesis of PVR and offer promising avenues for clinical intervention before PVR develops. One such target is the indirect pathway of activation of platelet-derived growth factor receptor alpha (PDGRα), which plays an important role in PVR. Clinical trials assessing the efficacy of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH), daunorubicin, and 13-cis-retinoic acid, among other therapies, have yielded mixed results. Here we review inflammatory and other mechanisms involved in the pathogenesis of PVR, we highlight important clinical trials, and we discuss how findings at the bench have the potential to be translated to the bedside.

Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.