John C. Merriam

Reticular pseudodrusen in early age-related macular degeneration are associated with choroidal thinning.

PURPOSE To compare choroidal thickness (CT) measurements in early AMD between patients with and without reticular pseudodrusen (RPD) using spectral-domain optical coherence tomography (SD-OCT). METHODS This cross-sectional study examined 84 age- and sex-matched AMD patients (40 RPD [63 eyes], 44 non-RPD [75 eyes]). Fundus photographs and scanning laser ophthalmoscopy images were graded to identify RPD and non-RPD groups by three retinal specialists (MO, SY, SB) who were masked to corresponding SD-OCTs. CT at the fovea and 2400 to 3000 μm superior and inferior to the fovea was measured on SD-OCT by a grader (AG) and reviewed by a retinal specialist (SB). Only images with a clear posterior choroidal margin were analyzed (six eyes excluded due to poor image quality), and enhanced depth imaging SD-OCT was used when available (20 of 138 eyes). Greatest retinal thickness (RT) on horizontal foveal SD-OCT was also recorded. RESULTS Mean CTs in the superior, foveal, and inferior macula in RPD (191.3 μm ± 57.9 SD, 176.3 μm ± 60.5 SD, 179.7 μm ± 56.24 SD) were significantly less than that of non-RPD (228.0 μm ± 66.1 SD, 216.5 μm ± 70.3 SD, 224.4 μm ± 71.9 SD; P = 0.0010, P = 0.0005, P = 0.0001, respectively), as was greatest RT (P = 0.0301). CONCLUSIONS CT was thinner throughout the macula in the RPD group as compared with the non-RPD group. The current analysis supports an association between RPD and a thinned choroidal layer and is consistent with a choroidal etiology of RPD. CT may be integral to understanding RPD, and may be helpful in stratifying AMD progression risk.

Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1.

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruchs membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25–31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMD1 gene, HEMICENTIN-1, residing in the 1q25–31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

The effect of incisions for cataract on corneal curvature

PURPOSE To determine the magnitude and duration of change on the horizontal and vertical meridians of the cornea after five different incisions for cataract. DESIGN Retrospective comparative interventional study of five commonly used incisions for cataract surgery: extracapsular cataract extraction (ECCE), 6-mm superior scleral tunnel (6Sup), 3-mm superior scleral tunnel (3Sup), 3-mm temporal scleral tunnel (3Temp), and 3-mm temporal corneal incision (3Cor). PARTICIPANTS A total of 662 cases with preoperative regular astigmatism, measured with keratometry. METHODS The mean net change on each meridian was computed at 1 day, 1 week, 2 weeks, 1 month, 1.5 months, 2 months, 4 months, 6 months, and 12 months and at succeeding 6-month intervals after surgery. Best-fit parameters were calculated for the observed changes in the horizontal and vertical keratometry values after each incision. To determine when the cornea stabilized, average change on the horizontal and vertical meridians was compared with an estimate of the accuracy of keratometry measurement. MAIN OUTCOME MEASURES The pattern of change on the horizontal and vertical meridians and time for the cornea to stabilize after each incision. RESULTS The initial and final net changes after a superior incision decrease with length. A sigmoid equation describes the course of the changes on the horizontal and vertical meridians after the superior incisions. The changes after the temporal incisions depend linearly on time after surgery. Considering the uncertainty of keratometry, the corneal meridians stabilized 4.5 months after ECCE, 1.2 months after 6Sup, and 0.3 months after 3Sup. No significant change was detected on the horizontal and vertical meridians after 3Temp and 3Cor. CONCLUSIONS The magnitude and the duration of keratometric change on the horizontal and vertical meridians of the cornea depend on the length and location of the incision. Within the limits of measurement error, no significant change in corneal curvature was detected after either small temporal incision.

Transmission Spectra of Light to the Mammalian Retina

A simple method has been developed to determine the optical properties of the anterior segment of the intact eye. This consists of a probe that is inserted into the posterior sclera and detects light passing through the anterior segment. The probe is connected to a charge‐coupled device spectrophotometer via a fiber optic bundle. It was determined that the young rat anterior segment transmits light down to 300 nm, whereas calf and rabbit eyes transmit no UVB and only part of the UVA to the posterior segment. The absorbing species in these animals is most likely NAD(P)H, which has an absorption maximum at ∼345 nm and is associated with ζ‐crystallin. A young primate anterior segment transmits almost no UV with a steep increase in transmission at CA 400 nm. Because some experiments employed a light tube that is used to illuminate the retina during vitrectomies, this method can be used to determine the transmission spectra of the anterior segment of humans in vivo.

Iris hooks for phacoemulsification of the subluxated lens

Abstract Phacoemulsification of the lens in eyes with zonular loss risks dislocation of the lens into the vitreous cavity. We describe the use of iris hooks after capsulorhexis to support the lens during surgery. With iris hooks, the lens can be stabilized, helping prevent additional loss of zonules and permitting retention of the capsule to support an intraocular lens.

Cadherin 5 is Regulated by Corticosteroids and Associated with Central Serous Chorioretinopathy

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell–cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47–0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruchs membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruchs membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Transmission of light to the young primate retina: possible implications for the formation of lipofuscin.

The purpose of this study was to determine the transmission properties of the anterior segment of young primate eyes and potentially relate those changes to photochemical processes in the retina that lead to the early, rapid formation of lipofuscin. A simple method has been developed to determine the optical properties of the anterior segment of the intact eye. Using this technique, the transmission/absorption properties of primate cadaver eyes were determined. A young primate anterior segment has a maximum absorption at 365 nm due to the presence of the O‐β‐glucoside of 3‐hydroxykynurenine in the lens. This is synthesized in the last trimester of gestation. Although this compound filters out most of the UV light from reaching the retina, there is a small window of transmission centered on an absorption minimum at 320 nm. This closes by the second decade of life. The window of transmission of UV light to the primate retina may explain the initial accelerated formation of lipofuscin in the young human retina by a photochemical process. This would be exacerbated by any decrease in the ozone layer with concomitant increase in UV‐B reaching the earth’s surface.

Extracapsular cataract extraction and posterior-lip sclerectomy with viscoelastic

A review of 15 cases suggests that posterior-lip sclerectomy can be performed safely with extracapsular cataract extraction (ECCE) and posterior chamber lens implantation. The anterior chamber was filled with viscoelastic at the end of each procedure; no case required reoperation for shallow chamber or hypotony. The mean intraocular pressure after 1 year was 12.1 mm Hg. The astigmatism induced by the triple procedure did not differ significantly from that caused by ECCE alone during the initial 2 postoperative years. A new mathematical model that describes the change over time of postoperative astigmatism associated with these procedures is described.

Intracellular Position of Centrioles and the Direction of Homeostatic Epithelial Cell Movements in the Mouse Cornea

Corneal epithelial cells exhibit continuous centripetal movements at a rate of about 30 µm per day, but neither the driving force nor the mechanism that determines the direction of movements is known. To facilitate the investigation of homeostatic cell movement, we examined if the intracellular position of a centriole can be used as a directional marker of epithelial cell movements in the mouse cornea. A direction of cell movements was estimated in fixed specimens from a pattern of underlying subepithelial nerve fibers. Intracellular position of centrioles was determined by gamma-tubulin immunohistology and plotted in a narrow strip along the entire diameter of a cornea from limbus to limbus. When we determined the position of centrioles in the peripheral cornea where cell movements proceed generally along a radial path, about 55% of basal epithelial cells contained a centriole in the front half of a cell. However, in the central cornea where cells exhibit a spiral pattern of movements, centrioles were distributed randomly. These results suggest that centrioles tend to be positioned toward the direction of movement in corneal basal epithelial cells when they are moving centripetally at a steady rate.