American Academy of Ophthalmology Web Site: www.aao.org
New Findings from Ophthalmology, AJO and Archives
March’s American Journal of Ophthalmology:
February's Archives of Ophthalmology:
Round of Other Journals:
Researchers Find No Relationship Between Retinal Vessel Diameters and Incident AMD in the Elderly
Ikram et al. conducted a study focusing on the relationship between retinal vessel diameters and incident age-related macular disease to prove their hypothesis that smaller arteriolar or larger venular diameters are associated with an increased risk of incident AMD.
Using data involving persons 55 years and older from the Rotterdam Study, they could not find this association. The prospective population-based cohort study included 4,345 participants who were free of AMD at baseline and had gradable macular transparencies at both baseline and follow-up examination.
After a mean follow-up period of 5.2 years, 374 participants developed early and late incident AMD. Neither arteriolar nor venular diameters were related to the risk of incident AMD. However, after age stratification, smaller arteriolar diameters did predict AMD in individuals 75 years and older.
In conclusion, the authors did not find an association between retinal vessel diameters and incident AMD in this population.
Study of Postmortem Corneas Sheds Light on Wound-Healing Processes After LASIK
Using confocal microscopy on postmortem human LASIK corneas, Dawson et al. were able to correlate these findings directly to their respective histology and ultrastructure.
The researchers demonstrated that the biologic wound repair processes in the center of LASIK corneas resulted in focal areas of slightly thickened epithelium—the result of basal epithelial cell hypertropic modifications that occur over low points on the corneal surface. Other alterations included random undulations in Bowman’s layer over the flap surface, perhaps occurring because of a lack of compatibility of the flap to the laser stromal bed, and a variably thick hypocellular interface stromal scar containing primitive extracellular matrix material and variably reflective cellular structures.
The authors conclude that while vacuoles in keratocytes and implanted epithelial cells are organic in nature and seem to be present in all LASIK corneas, they appear to be nontoxic and functionally benign to the cornea.
Asymmetric IOP Fluctuations Affect Validity of Uniocular Trials In Glaucoma Management
Realini and Vickers issue a warning concerning the validity of uniocular drug trials in glaucoma management when assessing individual patient responses to topical IOP-lowering medications.
In a study to determine if fellow eyes exhibit symmetric IOP-lowering responses with bilateral treatment, they found spontaneous IOP fluctuations were not symmetric between fellow eyes.
Asymmetric spontaneous IOP fluctuations of 3 mmHg or more occurred in at least 50 percent of normal patients and in at least 63 percent of patients with glaucoma on stable IOP-lowering regimens. In the glaucoma patients, the average magnitude of an asymmetric IOP fluctuation was 4 mmHg.
The investigators assert these large spontaneous IOP fluctuations undermine the validity of the uniocular trial. Specifically, while therapeutic IOP responses to a given agent may be symmetric between fellow eyes, the magnitude of this therapeutic response cannot be determined using the uniocular trial because of these spontaneous interocular IOP fluctuations.
They call for the discontinuation of uniocular trials when initiating IOP-lowering therapy.
AREDS Identifies an Association Between Lifestyle Factors and Progression of AMD
Results from the Age-Related Eye Disease Study have shown that two modifiable lifestyle factors in patients with early or intermediate AMD —smoking and body mass index—are associated with progression to advanced AMD.
The original purpose of the AREDS was to study antioxidants and zinc supplementation prophylaxis for development of advanced AMD. The study included 788 participants at risk of developing advanced AMD in one eye (the fellow eye already had advanced AMD), and 2,506 participants at risk in both eyes.
In addition to the statistically significant association between smoking and BMI and progression to advanced AMD, the authors found a number of weaker associations including diabetes, use of nonsteroidal anti-inflammatory agents and hormone replacement therapy, and the incidence of either geographic atrophy or neovascular AMD.
They conclude that all of these associations warrant further investigation.
Jackson Memorial Lecture: AMD—A 35-Year Perspective
Stuart L. Fine, MD, from the University of Pennsylvania gave the Jackson Memorial Lecture at last year’s Joint Meeting of the Academy and the European Society of Ophthalmology. In his written manuscript, Dr. Fine provides his personal perspective concerning diagnosis, treatment and evaluation of treatment for early and late stages of AMD over a 35-year period.
Using a literature review, personal recollections and conversations with investigators who participated in trials to evaluate treatments for AMD, Dr. Fine assesses new and existing treatments.
In 1969, patients with AMD constituted a small part of a typical ophthalmic practice.
From 1969 to 2004, the prevalence of AMD increased, and the methods of evaluation and treatment changed dramatically. The emergence of fluorescein angiography and the development of laser photocoagulation and photodynamic therapy substantially altered clinical practice. Several promising pharmacologic interventions are now being assessed in clinical trials. Nevertheless, AMD remains the leading cause of severe and irreversible vision loss in the United States because there are no highly effective treatments available for most patients.
Extensive research is being conducted with support from NEI and industry sources. There is a great interest in prevention trials and the author is optimistic that over the next 35 years there will be significant improvements in our ability to prevent severe vision loss from late AMD.
A Suspect Safety Profile of Long-Term, High-Dose Intraocular Corticosteroid Delivery
Intraocular steroids are now frequently used for a number of retinal disorders. Holekamp et al. report on the feasibility and safety profile of 2-milligram and 6-mg fluocinolone acetonide implants after long-term follow-up in eyes with CNV.
In a prospective, noncomparative, interventional case series, patients with non-age-related subfoveal CNV were enrolled in a compassionate use protocol. Sustained drug delivery devices containing either 2 mg (eight eyes) or 6 mg (six eyes) of fluocinolone acetonide were implanted through the pars plana into the vitreous cavity of 14 patients with predominantly classic, subfoveal CNV. The main outcome measures were complications related to the device. Secondary outcome measures were involution of established CNV, inhibition of recurrent CNV and visual acuity.
Patients entered the study with a diagnosis of ocular histoplasmosis (seven), myopic degeneration (four), angioid streaks (two) and punctate inner choroidopathy (one). Patients were followed for an average of 33 months (range 16 to 40 months).
All 14 eyes developed elevated IOP and cataract. Four eyes developed nonischemic central retinal vein occlusion. Complications required implant removal in eight eyes. Ten of 14 eyes demonstrated involution of CNV or inhibition of recurrent CNV. Ten eyes had stable or improved visual acuity. Median initial visual acuity was 20/64. Median final visual acuity was 20/40.
The authors conclude that this long-term follow-up demonstrates a significant complication rate with the sustained release of high-dose intraocular corticosteroids. The complications are treatable and eyes can retain good vision. This therapeutic approach warrants further study to identify whether lower doses of corticosteroids may reduce the complication rate yet still be effective in treating ocular disease.
Overnight orthokeratology remains a controversial treatment modality for myopia. Hiraoka et al. evaluated corneal higher-order aberrations induced by overnight orthokeratology for myopia in a prospective, noncomparative, consecutive, interventional case series.
The study was conducted in 64 eyes of 39 patients. Patients were followed up for at least three months and attained uncorrected visual acuity of 20/20 or better. Corneal height data were obtained with computerized videokeratography (TMS-2N, Tomey), and wavefront aberration was derived using Zernike polynomials. Higher-order aberrations of the cornea were calculated for 3-millimeter and 6-mm pupils.
Orthokeratology significantly reduced manifest refraction from –2.60 D to –0.17 D (P < 0.0001). Root-mean-square (RMS) of third-order (coma-like) aberrations was significantly increased by orthokeratology for both 3-mm (P < 0.0001) and 6-mm (P < 0.0001) pupils. Fourth-order RMS (spherical-like) aberrations increased significantly by the treatment for both 3-mm and 6-mm pupils. Vertical coma significantly changed from positive to negative for both 3-mm and 6-mm pupils. Horizontal coma significantly increased to the positive direction for both 3-mm and 6-mm pupils. Increases in the third- and fourth-order RMS showed significant positive correlations with the amount of myopic correction for 3-mm and 6-mm pupils.
The authors conclude that corneal higher-order aberrations significantly increased even in clinically successful orthokeratology cases. The increases in the higher-order aberrations correlated with the magnitude of myopic correction.
Quantitative Assessment of Atypical Birefringence Images
Corneal compensation remains an important topic in scanning laser polarimetry. Bagga et al. define the clinical characteristics of atypical birefringence images and describe a quantitative method for their identification in a prospective, comparative, clinical observational study.
Normal and glaucomatous eyes underwent complete examination, standard automated perimetry, scanning laser polarimetry with variable corneal compensation (GDx-VCC) and optical coherence tomography of the macula, peripapillary retinal nerve fiber layer and optic disc. Eyes were classified into two groups: normal birefringence pattern and atypical birefringence pattern. Clinical, functional and structural characteristics were assessed separately. A multiple logistic regression model was used to predict eyes with atypical birefringence pattern on the basis of a quantitative scan score generated by a support vector machine with GDx-VCC.
Sixty-five eyes of 65 patients were enrolled. Atypical birefringence pattern images were observed in five of 20 (25 percent) normal eyes and 23 of 45 (51 percent) glaucomatous eyes. Compared with eyes with a normal birefringence pattern, glaucomatous eyes with an atypical pattern demonstrated significantly lower scores on the support vector machine and greater temporal, mean, inferior and nasal retinal nerve fiber layer thickness using GDx-VCC; there was a weaker correlation with OCT-generated retinal nerve fiber layer thickness. Atypical birefringence pattern images were significantly correlated with older age. The support vector machine score was the only significant predictor of atypical birefringence pattern images. It provided high discriminating power between eyes with normal and atypical birefringence pattern.
The authors conclude that atypical birefringence pattern images exist in a subset of normal and glaucomatous eyes, are associated with older patient age and produce an artifactual increase in retinal nerve fiber layer thickness using GDx-VCC. The support vector machine score is highly predictive of atypical birefringence pattern images.
The Gambian Eye Care Program: An Analysis of Costs and Benefits
The Gambian Eye Care Program began in 1986. Frick et al. estimated the program’s net benefits using a limited definition of benefits from a societal perspective.
Through 1996, the program was associated with a significant decrease in the prevalence of blindness in the Gambia. The researchers projected changes in lifetime productivity of individuals who avoided blindness through 1996 both as a function of avoiding blindness and as a function of a longer life expectancy, using previously reported results on the link between blindness and mortality. They compared the dollar value of the benefits of reduced blindness with the costs of the program to determine whether the program appeared to be a good investment based on economic criteria. The results were favorable.
In summary, the authors showed that in one sub-Saharan African country, a national eye care program could bring about substantial economic return (10 percent per year over the lifetime of the individuals affected) that would compare favorably with the return on other potential investments of the limited resources available to the government.
Povidone-Iodine Applications for Anterior Segment Intraocular Surgery: Two Methods Compared
De Kaspar et al. compared two different methods of povidone-iodine application in 200 patients undergoing anterior segment surgery: vigorous irrigation of the conjunctival fornix vs. two drops of povidone-iodine on the ocular surface. Both groups also received topical ofloxacin one hour prior to surgery and periorbital scrub with povidone-iodine.
This prospective randomized study demonstrated that irrigation of the fornix with povidone-iodine resulted in significantly fewer positive conjunctival cultures (26 percent) at the time of the surgery compared with the application of two drops of povidone-iodine (43 percent) onto the ocular surface (P = 0.02). There were no adverse effects of the povidone-iodine.
In summary, a combination of topical ofloxacin, scrubbing of the periorbital area and irrigation of the conjunctival fornix with povidone-iodine appears to be safe and effective in eliminating bacteria from the conjunctiva and may reduce the risk of postoperative endophthalmitis.
Atropine vs. Patching for Treatment of Moderate Amblyopia
In a randomized trial, the Pediatric Eye Disease Investigator Group compared the effectiveness at two years of an initial six-month treatment with occlusive eye patches followed by best clinical care with an initial six-month treatment with daily topical atropine sulfate 1 percent followed by best clinical care.
The patient cohort included children younger than 7 years of age at randomization with moderate amblyopia (visual acuity 20/40 to 20/100) from strabismus, anisometropia or both. The two-year outcome examination was completed for 363 (87 percent) of the 419 patients enrolled.
The actual treatment regimens prescribed beyond six months were related to the initial treatment assignment at randomization. Patching was prescribed at some time during this 18-month period for 84 percent of children who had been treated with patching during the initial six months, while atropine was prescribed for 78 percent of children who had been treated with atropine during the initial six months.
Similar percentages of patients were switched to the opposite treatment (28 percent in the patching group and 25 percent in the atropine group). At the two-year visit, visual acuity had improved from baseline by an average of 3.7 lines in the patching group and 3.6 lines in the atropine group.
In summary, atropine or patching for six months followed by best clinical care until two years after enrollment produced similar improvement of moderate amblyopia in children between 3 and 7 years of age at enrollment. However, on average the amblyopic eye remained about 2 lines worse than the sound eye in both groups.
Ophthalmology summaries are written by Lori Baker Schena and edited by John Kerrison, MD. American Journal of Ophthalmology summaries are edited by Thomas J. Liesegang, MD. Archives summaries are written by the lead authors.
Roundup of Other Journals
Pegaptanib for Neovascular AMD
Gragoudas et al. have found that pegaptanib (Macugen), an antivascular endothelial growth factor therapy, produces a “statistically significant and clinically meaningful benefit” in the treatment of neovascular AMD.
Pegaptanib was designed to bind and block the activity of an extracellular vascular endothelial growth factor—specifically the 165-amino-acid isoform ( VEGF165). The authors hypothesized that targeting VEGF165 would effect the underlying conditions common to choroidal neovascularization.
They conducted two concurrent clinical trials, with patients receiving intravitreous injection into one eye of pegaptanib (at a dose of 0.3 milligrams, 1 mg or 3 mg) or sham injections administered every six weeks over a period of 48 weeks.
They observed a reduced risk of visual-acuity loss with all doses of the drug as early as six weeks after treatment was started, with evidence of an increasing benefit over time up to week 54.
The authors advocate vigilance to avoid injection-related adverse events including endophthalmitis (1.3 percent), and call for long-term data to determine the safety and efficacy of pegaptanib therapy.
Investigative Ophthalmology & Visual Science
Recent advances in stem cell research have increased hopes for the development of cellular therapies for age-related degenerative diseases. Specifically, embryonic stem cells have shown an unlimited self-renewal capacity, offering potential in the realm of regenerative medicine.
However, Arnhold et al. have found one potential technical hurdle on the mouse level that needs to be overcome before bench studies of ES-cell transplantation can be moved to the clinical setting.
The researchers used mouse ES-cell-derived neural precursor cells that carried the sequence for the green fluorescent protein gene. They engrafted these cells subretinally into the eyes of rhodopsin knockout mice; control animals underwent sham surgery. While analysis of eyes at two and four weeks after engraftment showed no morphologic alterations, at eight weeks the researchers detected tumors consistent with teratomas in 50 percent of engrafted eyes. The resultant tumor formation affected almost all layers of the eye, including the retina, the vitreous and the choroid.
The authors conclude that the risk of tumor formation must be addressed before any clinical studies of these cells to treat degenerative eye disease take place.
Roundup of Other Journals is written by Lori Baker Schena and edited by Deepak P. Edward, MD.