Volume 4, Number 11

Monday, March 15, 2004

In this issue: (click heading to view article)
		Climatic Influence on Conjunctival Bacteria in Cataract Surgery Patients
		Using mfERGs to Predict Sites of Subsequent Diabetic Retinopathy
		Dry Eye in Women with Premature Ovarian Failure
		Significance of A-beta-containing Elements in Drusen Formation and AMD Pathogenesis
		Supplemental Oxygen May Improve Diabetic Macular Edema
		Briefly

Climatic Influence on Conjunctival Bacteria in Cataract Surgery Patients Conjunctival bacteria in patients undergoing cataract surgery may follow a seasonal prevalence pattern that could be considered a predisposing condition for having post-surgical endophthalmitis during certain months, according to investigators at Spain’s Gregorio Maranon University General Hospital in Madrid. Researchers cultured the lower conjunctival content sample of 4,432 consecutive patients awaiting cataract surgery from January 1994 to December 1996. They checked dates of surgeries and rehospitalization for post-surgical endophthalmitis (if it occurred), then grouped the isolated bacteria to study the statistical significance of the differences in the monthly prevalence differences (Chi 2 tests). They recorded temperature and relative humidity per month for area where patients lived. Results showed that the total frequency of conjunctival bacteria increased in April, May and June, when the average daily temperature rose from 12 to 22 degrees C (about 54 to 72 degrees Fahrenheit) and the relative humidity ranged between 45 and 60 percent. The frequency of bacteria groups was significantly higher in these months: frequency of Staphylococci coagulase negative was greater than 60 percent in April, May and June; frequency of Corynebacterium sp. was greater than 33 percent, Staphylococcus aureus greater than 8 percent and other Gram-positive bacteria greater than 2.5 percent in May; Streptococcus pneumoniae was greater than 3 percent in March, November and December; Haemophilus sp. was greater than 3 percent in January and April; Gram-negative Cocci was greater than 3 percent in April; and other Streptococcus sp. were greater than 6 percent in April, May and September. Incidence of rehospitalization for endophthalmitis after cataract extraction in May and June together was almost four times higher than in all other months.

SOURCE: Rubio EF. Climatic influence on conjunctival bacteria of patients undergoing cataract surgery. Eye 2004;Feb 27 [Epub ahead of print].

Using mfERGs to Predict Sites of Subsequent Diabetic Retinopathy A study by the University of California at Berkeley shows that localized functional abnormalities of the retina reflected by multifocal electroretinogram (mfERG) delays often precede the onset of new structural signs of diabetic retinopathy. These functional abnormalities, say the investigators, predicted local sites of new retinopathy observed one year later in diabetic retinopathy patients. In the study, one eye of 11 diabetic patients with nonproliferative diabetic retinopathy (NPDR) and 11 diabetic patients without retinopathy were retested 12 months after initial testing. At each time, mfERGs were recorded from 103 retinal locations, and fundus photographs were taken within one month of each recording. Researchers measured local mfERG implicit times and calculated their z-scores based on results obtained from 20 age-matched control subjects. mfERG abnormalities were defined as z-scores of 2 or more for implicit time and z-scores of -2 or less for amplitude. Researchers mapped mfERG z-scores onto fundus photographs and then examined the relationship between baseline abnormal z-scores and new retinopathy at follow-up. New retinopathy developed in seven of the eyes with NPDR after one year. In these eyes, 70 percent of the mfERGs in areas of new retinopathy had abnormal implicit times at baseline. In contrast, only 24 percent of the responses in regions that remained retinopathy-free were abnormal at baseline. Relative risk of development of new retinopathy over one year in the areas with abnormal baseline mfERG implicit times was approximately 21 times greater than that in the areas with normal baseline mfERGs. Eyes without initial retinopathy did not develop new retinopathy within the study period, although four of these 11 eyes had abnormal implicit times at baseline. mfERG implicit times tended to be more delayed at follow-up than at baseline in NPDR eyes, but not in eyes without retinopathy and control eyes. mfERG amplitudes had no predictive power.

SOURCE: Han Y, Bearse MA Jr, Schneck ME, et al. Multifocal electroretinogram delays predict sites of subsequent diabetic retinopathy. Invest Ophthalmol Vis Sci 2004;45(3):948-54.

Dry Eye in Women with Premature Ovarian Failure The role of sex hormones in dry eye has been investigated in several studies, but it remains unclear what role estrogen excess, androgen deficiency and/or estrogen-androgen imbalance play in association with dry eye. Androgen deficiency, as seen in congenital androgen insensitivity syndrome and antiandrogen therapy, has been associated with dry eye. Androgen deficiency is also seen in Sjögren’s syndrome, and it has been proposed to lead to evaporative tear deficiency in affected women. Since women with premature ovarian failure (defined as cessation of normal ovarian function in women younger than 40 years) also suffer from androgen deficiency, researchers at the National Eye Institute (NIH) hypothesized that these women would exhibit signs or symptoms of dry eye more frequently than age-matched controls with normal ovarian status. Investigators examined 65 patients with premature ovarian failure and 36 age-matched healthy controls for signs and symptoms of dry eye. They administered the Ocular Surface Disease Index questionnaire and the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) to the participants. They also assessed ocular surface damage (Oxford and van Bijsterveld scores of vital dye staining) and tear status (Schirmer tests 1 [without anesthesia] and 2 [with anesthesia] and tear break-up time). Women with premature ovarian failure scored significantly worse than control subjects on all ocular surface damage parameters: Oxford score (3.2 vs 1.7), conjunctival lissamine green (2.1 vs 1.3), corneal fluorescein staining (1.2 vs 0.4) and van Bijsterveld score (2.1 vs 1.3). In addition, the proportion of patients with premature ovarian failure meeting the dry eye diagnostic criterion of a van Bijsterveld score greater than or equal to 4 was significantly greater among women with premature ovarian failure than among controls (20 percent vs. 3 percent). The group with premature ovarian failure also tended to have worse scores than controls on self-reported symptoms, as measured by the overall Ocular Surface Disease Index (12.5 vs 2.1) and the overall NEI-VFQ (94 vs 98) after adjustment for age and race. Schirmer test scores and tear break-up time did not differ. The study’s authors believe that this association between ocular surface disease and premature ovarian failure has not been previously reported.

SOURCE: Smith JA, Vitale S, Reed GF, et al. Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol 2004;122:151-6.

Significance of A-beta-containing Elements in Drusen Formation and AMD Pathogenesis Recent studies strongly suggest that drusen, the extracellular deposits associated with age-related macular degeneration (AMD), are a manifestation of local inflammatory events. New evidence indicates that substructural elements within drusen contain activated complement components as well as amyloid-beta (A-beta), a major pro-inflammatory component of Alzheimer"s disease plaques. Investigators at California’s Center for the Study of Macular Degeneration and the Doheny Eye Institute used differential interference contrast optics, laser scanning confocal immunofluorescence and immunogold electron microscopy to further assess the structural properties and molecular composition of A-beta-containing elements in drusen. They obtained estimates of their frequency from montages of electron micrographs gathered from 152 human donor eyes aged 9 to 91 years. Spherical A-beta-containing elements, which are typically organized as concentric ring-like structures, are common substructural components of drusen. They stain with thioflavin T but are not stained by Congo red; nor do they bind cationic, lipophilic or nucleic acid-binding fluorescent dyes. Ultrastructurally, they are composed of a central core, one or more concentric inner rings with intervening electron lucent layers and an electron-dense outer shell. Immunogold labeling indicated that most A-beta immunoreactivity was associated with the outer layers that consist of densely-packed spherical subunits. No longitudinally-oriented fibril arrays, characteristic of aggregated amyloid fibrils in the brain, were evident. Other prominent drusen-associated proteins, including the terminal complement complex C5b-9, vitronectin, apolipoprotein E, serum amyloid P component and ubiquitin were excluded from the spheres. The study’s authors concluded that these structures embedded in drusen may be represent a new type of macromolecular assembly that contains A-beta as well as activated complement components. The presence of A-beta in these extracellular deposits is an additional indication that some of the pathogenic pathways that give rise to drusen and AMD may be shared with other neurodegenerative diseases characterized by misfolded protein deposition and aggregation.

SOURCE: Anderson DH, Talaga KC, Rivest AJ, et al. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exper Eye Res 2004;78(2):243-56.

Supplemental Oxygen May Improve Diabetic Macular Edema Supplemental inspired oxygen may decrease macular thickness due to diabetic macular edema (DME), according to a study by Johns Hopkins University School of Medicine and the National Eye Institute. This suggests that retinal hypoxia is involved in the development and maintenance of DME. Five patients with chronic DME despite at least one focal laser photocoagulation treatment (nine eyes) received 4 L/min of inspired oxygen by nasal cannula for three months. Best-corrected visual acuity and retinal thickness, assessed by optical coherence tomography, were measured at baseline, during three months of oxygen treatment, and for three months after stopping oxygen. After three months of oxygen therapy, nine of nine eyes with DME at baseline showed a reduction in thickness of the center of the macula. Foveal thickness above the normal range was reduced by an average of 43.5 percent (range 14 to 100 percent), excess foveolar thickness was reduced by an average of 42.1 percent (range 13 to 100 percent), and excess macular volume was reduced by an average of 54 percent (range 35 to 100 percent). Statistical analyses suggested that these changes were unlikely to be the result of chance. Three eyes showed improvement in VA by at least two lines, one by slightly less than two lines, and five eyes showed no change. Three months after discontinuation of oxygen, five of the nine eyes showed increased thickening of the macula compared with when oxygen was discontinued.

SOURCE: Nguyen QD, Shah SM, Van Anden E, et al. Supplemental oxygen improves diabetic macular edema: a pilot study. Invest Ophthalmol Vis Sci 2004;45:617-24.

BRIEFLY INVESTIGATIONAL TREATMENT FOR UVEITIS SHOWS PROMISE. Researchers at the National Institutes of Health (NIH) have found in a preliminary trial that an investigational treatment for uveitis appears to have far fewer side effects than existing therapies. The trial results, published in the Journal of Autoimmunity, show that monthly intravenous infusion of a drug called daclizumab, which has been approved by the FDA for preventing organ rejection in kidney transplant patients, controlled uveitis and was well tolerated in seven of 10 patients over four years. The authors of the study also presented some evidence that a formulation of daclizumab injected under the skin may provide similar results; such a formulation might allow uveitis patients to self-administer the drug. The NIH intends to launch a larger clinical trial to test standard treatments for uveitis compared with daclizumab. REFERENCE: Nussenblatt RB, Thompson DJ, Li Z, et al. Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration. J Autoimmun 2003;21(3):283-93. TUMOR-SUPPRESSOR PROTEIN MAY BE KEY TO RETINOBLASTOMA TREATMENT. Investigators studying the tumor-suppressing retinoblastoma protein (Rb) in mice at St. Jude Children’s Research Hospital in Memphis, TN, may have discovered how some children develop retinoblastoma, which could in turn lead to an improved treatment for the disease. Results of the study, which appeared in Nature Genetics, show that Rb is required for proper development of the mouse retina; it prompts rod development and limits the proliferation of immature retinal cells so that the retina develops normally. The authors of the study believe that they have taken the first step toward understanding what Rb does during normal mouse development by using several new genetic techniques to study the mutation in lab dishes and single retinal progenitor cells rather than in Rb "knockout" mice, as is commonly the case. Using these methods, the investigators believe that they can better determine how to block the signals that trigger retinoblastoma in children. REFERENCE: Zhang J, Gray J, Wu L, et al. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet 2004;Feb 29 [Epub ahead of print]. NEW STUDY RESULTS PRESENTED FOR EYETECH’S MACUGEN. Eyetech Pharmaceuticals recently presented additional data from the VEGF Inhibition Study in Ocular Neovascularization (VISION) at the Aspen Retinal Detachment Society Meeting in Colorado. Previous study data on Eyetech’s investigational drug Macugen, a selective inhibitor of vascular endothelial growth factor (VEGF) in the treatment of wet age-related macular degeneration (AMD), showed that among the patients receiving 0.3 mg of Macugen, 70 percent lost less than three lines of vision on the eye chart, compared with 55 percent of patients who received sham injection. The new data suggest that the overall efficacy of Macugen is independent of lesion size and patient age. Specifically statistical interaction tests indicate that efficacy is similar in small and large lesions (>4 Disc Areas vs. <4 Disc Areas) as well as in younger and older patients (older than 75 vs. younger than 75). The new data was the result of two pivotal Phase II/III randomized, multicenter double-masked studies in patients with all subtypes of wet AMD, in which 1,186 patients were randomized to receive one of three doses of intravitreous Macugen or a sham (control) injection every six weeks for 54 weeks. The VISION trial was sponsored by Eyetech and Pfizer, Inc., which have partnered to develop and market Macugen.

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