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New Findings from Ophthalmology, AJO and Archives
February's American Journal of Ophthalmology:
December's Archives of Ophthalmology:
Roundup of Other Journals:
Results from the Beaver Dam Eye Study by Klein et al. describe a 15-year cumulative incidence of 14 percent for early age-related macular degeneration and 3 percent for late AMD in individuals 43 to 86 years of age at baseline.
The authors also report a high 15-year cumulative incidence of early (24 percent) and late (8 percent) AMD in individuals 75 years of age or older at baseline. The findings provide further evidence that the natural history of AMD follows a continuum from large numbers of small hard drusen to early stages of AMD.
In addition, eyes with soft, indistinct drusen or pigmentary abnormalities at baseline are more likely to develop late AMD 15 years later than those eyes without lesions.
The authors conclude the 15-year cumulative incidence of late AMD in people 75 years of age or older (8 percent) highlights a significant public health problem, especially given that the U.S. population this age is expected to increase by 54 percent from 2005 to 2025.
Intravitreal Triamcinolone Acetonide for Immune Recovery Uveitic Macular Edema
Morrison et al. have found the use of intravitreal triamcinolone acetonide improves vision, optical coherence tomography volume and thickness, and fluorescein angiography results in AIDS patients with macular edema secondary to immune recovery uveitis.
This prospective, consecutive, interventional case series involved seven patients (eight eyes) who underwent 13 intravitreal injections of 20 mg of decanted triamcinolone acetonide.
At one-month and three-month follow- up points, visual acuity improved, with an average visual improve-ment of 3 lines at three months. Retinal volume and thickness also demonstrated statistically significant improvement at all time points. The seven patients were followed for at least nine months, with no cases of cytomegalovirus reactivation.
The authors conclude that this treatment approach is an effective short-term alternative for AIDS patients with macular edema secondary to immune recovery uveitis. They call for extended follow-up to determine if the treatment effect is durable and whether there are any longer-term complications.
Intraoperative Triamcinolone Acetonide in Pars Plana Vitrectomy
Retinal breaks are one of the common intraoperative complications associated with pars plana vitrectomy (PPV). In a multicenter, prospective clinical trial, Yamakiri et al. found that the intraoperative use of triamcinolone acetonide (TA) reduced the incidence of retinal breaks and detachments in eyes undergoing PPV.
The investigators divided 774 patients from eight Japanese hospitals into two groups: 391 underwent TA-assisted PPV and 383 underwent conventional PPV. Retinal breaks were seen in 34 eyes (8.7 percent) undergoing TA-assisted PPV compared with 54 eyes (14.1 percent) undergoing conventional PPV. In addition, only three eyes (0.8 percent) in the TA group experienced retinal detachment, compared with 14 eyes (3.7 percent) in the control group. Neither group reported serious adverse events. While IOP was well-controlled in both groups, patients in the TA group were more likely to require antiglaucoma eye drops.
The investigators point out that the two patient groups continue to be followed, and follow-up observations may help establish the value of TA use in PPV.
IOP Fluctuations Not Independent Risk Factor for Glaucoma Progression
While findings from the Early Manifest Glaucoma Trial confirmed that elevated IOP is a strong risk factor for glaucoma progression, they also indicated that IOP fluctuation is not an independent risk factor for glaucoma progression.
The study by Bengtsson et al. involved 129 treated glaucoma patients and 126 control patients. Study visits were conducted every three months and included eye exams, IOP measurements and standard automated perimetry. The median follow-up was eight years, during which time 68 percent of patients progressed to glaucoma. Mean IOP was a significant risk factor in this progression, with the hazard ratio increasing by 11 percent for every mmHg of higher IOP. Yet fluctuations in these IOP levels did not appear to be related to glaucoma progression.
The authors note these findings are based on data from previously undiagnosed and untreated glaucoma patients identified by a population screening. Consequently, any conclusions would be more applicable to a general glaucoma population, as opposed to a highly selected subgroup.
Polymer-Coated Hydroxyapatite Implant Well-Tolerated
In 1989, the FDA approved hydroxyapatite orbital implants, which allowed fibrovascular ingrowth from the orbital tissues into the implant, theoretically minimizing infection and extrusion. While donor tissue wrapping to attach the implant has proven safe over the years, the hydroxyapatite implant was redesigned with a preplaced inorganic polymer wrap (coating) and made available in November 2003.
Shields et al. conducted a retrospective, single-center case series involving 126 patients managed with enucleation and the new polymer-coated hydroxyapatite implant to determine ease of placement, motility outcome, tissue complications and patient satisfaction.
They found that implant preparation and placement was uncomplicated, without adhesion to surrounding tissue; socket motility was good; complications were minimal, with no reports of implant extrusion or allergic reaction to the polymer; and patient satisfaction was high.
The authors conclude that with proper placement, this implant is well-tolerated and allows the surgeon to avoid use of donor tissue wraps— permitting attachment of the muscles directly to the implant.
American Journal of Ophthalmology
Long-Term Follow-Up of Intacs in Keratoconus
Intacs corneal inserts are one option among several for treatment of keratoconus. Longer-term results are now available for this procedure. Kymionis et al. performed a five-year, retrospective, follow-up study in 17 eyes of 15 patients aged 24 to 52 with keratoconus. Two Intacs segments of 0.45-mm thickness were inserted in the cornea of each eye, encircling the keratoconus area in an attempt to achieve maximal flattening.
At five years, the spherical equivalent error was statistically significantly reduced (pre-Intacs mean of –5.54 D and post-Intacs mean of –3.02 D) (P = 0.01). Pre-Intacs UCVA was 20/50 or worse in all eyes. At the last follow-up examination, 10 of 17 eyes (59 percent) had UCVA of 20/50 or better, and had experienced a gain of between 1 to 8 lines. Six eyes (35 percent) maintained the pre-Intacs BCVA and one eye lost 3 lines of BCVA. There were no late postop complications in this series of patients.
This small study demonstrated that, after five years, intracorneal ring segments implantation improved UCVA, BCVA and refraction in the majority of the keratoconus patients. There was no evidence of progressive sight-threatening complications in this study.
Deep Anterior Lamellar vs. Penetrating Corneal Allografts
Ardjomand et al. compared visual function after deep anterior lamellar keratoplasty (DALK) with visual function after penetrating keratoplasty (PK) for keratoconus and correlated this with corneal thickness.
Twenty-three patients (32 eyes) with unilateral or bilateral DALK or PK for keratoconus were analyzed for visual quality after suture removal in this retrospective case series.
Evaluation included measurement of visual acuity, contrast sensitivity and higher-order aberrations (HOAs). Readings were performed with both spectacle and rigid contact lens correction of refractive error. Total and residual stromal thickness after DALK was measured using optical coherence tomography and correlated to visual quality.
Eyes after PK had better visual acuity than eyes after DALK. Subgroup analysis of DALK eyes revealed that the level of visual acuity was related to the thickness of residual recipient corneal stroma. Eyes with a recipient corneal bed thickness of less than 20 µm had visual acuities similar to eyes with a PK, whereas those with a recipient thickness of greater than 80 µm had a significantly reduced visual acuity.
Contrast sensitivity was similar in DALK and PK eyes. There was no significant difference in HOAs between eyes with DALK or eyes with PK.
These data suggest that the main parameter for good visual function after DALK for keratoconus is the thickness of residual recipient stromal bed.
Successful Treatment of Resistant Ocular Fusariosis With Posaconazole
Tu et al. report on the successful treatment of a series of Fusarium ocular infections with the new agent posaconazole.
In this retrospective, interventional case series there were three patients from three different centers with Fusarium keratitis that failed to respond to maximal tolerated medical and surgical therapy, including multiple systemic, intracameral and topical antifungal agents, and yet responded to systemic posaconazole. Two patients were contact lens wearers, and two patients developed endophthalmitis. The infections of all three patients failed to respond to systemic and/or topical voriconazole treatment. One patient could not tolerate systemic voriconazole, one experienced no marked improvement and the third patient neither tolerated nor responded to it. All patients were then treated with oral posaconazole and experienced rapid reduction of intraocular inflammation and pain, as well as resolution of the infection without additional intervention.
Posaconazole, which exhibits excellent tissue penetration and demonstrates efficacy in the treatment of systemic Fusarium infection, was successful in treating three cases of Fusarium keratitis and/or endophthalmitis that failed prior therapy.
Comparison of Frequency-Doubling Perimetry With Standard Automated Perimetry to Detect Glaucoma
Leeprechanon et al. compared second-generation frequency-doubling perimetry (FDP) with standard automated perimetry (SAP) to detect glaucomatous visual field abnormalities.
Fifty eyes of 50 patients with glaucoma and with confirmed SAP visual field abnormalities and 42 eyes from 42 normal control subjects were evaluated in a prospective, cross-sectional, controlled observational study. Swedish Interactive Thresholding Algorithm (SITA) standard 24-2 SAP and FDP visual fields were performed. The correlation of global indices and the number of defects on total deviation and pattern deviation plots were compared. The spatial concordance of FDP and SAP defect locations was determined.
Significant correlations of mean deviation and pattern standard deviation were found between SAP and FDP in patients with glaucoma, but not in the normal group. FDP had significantly greater defect scores than SAP on total deviation and pattern deviation plots in the glaucoma group. In comparison with SAP, sensitivity and specificity of FDP were 92 percent and 98 percent, respectively, with glaucoma hemifield test criteria, and 98 percent and 93 percent with pattern standard deviation less than 5 percent criteria, respectively. Similarly high diagnostic precision was found with mean deviation and pattern standard deviation. The location of defects within 12 hemifield clusters found with FDP agreed moderately well with those detected with SAP.
Archives of Ophthalmology
The Economic Burden of Major Adult Visual Disorders in the United States
Rein et al. estimated the economic burden and budgetary impact of major adult visual disorders in the United States in 2004. Major adult visual disorders were defined as age-related macular degeneration, cataracts, diabetic retinopathy, glaucoma, refractive error, visual impairment and blindness among people aged 40 and older. Economic burden was divided into direct medical costs, other direct costs (primarily the cost of nursing home care) and productivity losses. Budgetary impact was defined as those medical and other direct costs paid for by the federal government, the cost of government benefits for the visually impaired and blind, and associated tax losses that result from lost productivity.
The annual economic burden of major adult visual disorders was $35.4 billion ($16.2 billion in direct medical costs, $11.1 billion in other direct costs and $8 billion in productivity losses) and the annual governmental budgetary impact was $13.7 billion in 2004. Of the $16.2 billion in direct medical costs, cataracts accounted for $6.8 billion, refractive error for $5.5 billion, glaucoma for $2.9 billion, AMD for $575 million and diabetic retinopathy for $493 million.
Among Americans aged 65 or older, 16 percent of those who are visually impaired and 40 percent of those who are blind resided in nursing homes, compared with only 4.3 percent of those in the general population. This incremental difference accounted for $11 billion in nursing home costs. Direct medical costs accounted for $5.5 billion of the governmental budgetary impact, Medicaid reimbursement for nursing home costs accounted for $6.6 billion and tax losses, transfer payments and other government services accounted for $1.6 billion.
The authors conclude that major adult visual disorders impose a substantial economic burden on the United States that currently exceeds that of many other major medical conditions.
Taylor et al. have examined the need for and possible demand for cataract surgery. The Cataract Surgery Rate (CSR) is the number of cataract operations per million people per year. The authors used population-based data from the Melbourne Visual Impairment Project and data from the Australia Census.
The CSR is related to the threshold visual acuity at which cataract is operated, surgical coverage and the age structure of the population. There is almost a fivefold increase in the CSR when the threshold for surgery changes from vision of less than 20/200 (CSR = 2,110) to less than 20/60 (CSR = 9,070). In addition, there will be a threefold increase in the CSR between 1950 and 2020 due to increased life expectancy.
Perimacular Retinal Folds Simulating Nonaccidental Injury in an Infant
Lueder et al. reported a 4-month-old infant who sustained an accidental severe crush head injury with a large, displaced skull fracture. The patient’s ocular examination revealed bilateral diffuse retinal hemorrhages, a retinoschisis cavity and elevated perimacular folds. Histopathology confirmed retinoschisis and diffuse multilayered retinal hemorrhages.
Retinoschisis cavities in infants are almost always associated with nonaccidental shaking injuries. This case indicates that such abnormalities may also occur as a result of a severe crush head injury, as the history and associated physical findings clearly distinguished this case from a nonaccidental shaking injury. In the absence of a corroborated history, and particularly if there are no external head injuries, the presence of a retinoschisis cavity remains indicative of shaken baby syndrome.
Diurnal Variation in Retinal Thickening Measurement by OCT in Diabetic Macular Edema
The Diabetic Retinopathy Clinical Research Network evaluated serial optical coherence tomography measurements in a group of patients with center-involved diabetic macular edema to determine if diurnal variation in retinal thickening was important to take into account for interpreting OCT for clinical research and clinical care.
In a study of 156 eyes of 96 patients with center-involved DME, six OCT measurements were obtained between 8 a.m. and 4 p.m. Analysis of change in the center subfield measurement of retinal thickening was performed. The mean decrease in center subfield thickening was 13 µm. Five subjects had a decrease of at least 50 µm, while two had an increase of at least 50 µm.
While this study found evidence of diurnal variation in central retinal thickness in DME patients, the meaningful change was small.
Trial of Iodine 125 Brachytherapy for Choroidal Melanoma
From January 1987 through July 1998, patients with unilateral choroidal melanoma enrolled in the Collaborative Ocular Melanoma Study randomized clinical trial comparing iodine 125 brachytherapy and enucleation with respect to mortality. The primary exclusion criteria were clinically detectable melanoma metastasis or another cancer, or a history of cancer, and peripapillary location of the tumor.
The 1,317 patients who enrolled were followed for death, diagnosis of metastatic melanoma and other cancers, and other outcomes at twice-yearly examinations. Interim mortality findings were published in 2001. Findings from a parallel study of quality of life among patients who enrolled during the last 41 months of accrual were reported in February 2006.
The current report summarizes rates of death from all causes and from melanoma metastasis (as judged by an independent mortality coding committee) by treatment arm, overall through 12 years after treatment and within subgroups of patients through 10 years. The vital status after five years was unknown for only four of all 1,317 patients, and only seven of the 799 patients eligible for 10 years of follow-up exams.
Neither data already published nor the updated findings presented in this report favor one treatment over the other for either mortality outcome, overall or by patient subgroup. The findings from the two treatment arms were combined to permit precise estimation of mortality rates. Five- and 10-year rates, and their 95 percent confidence intervals, were 19 percent (17 percent to 21 percent) and 35 percent (32 percent to 38 percent), respectively. Adjustment for the only important predictors of either death from all causes or death with melanoma metastasis (age and maximum basal tumor diameter at treatment) had little effect on either treatment arm comparisons or pooled mortality rates. Of the 515 patients who enrolled by July 1991 and thus were eligible for 12 years of follow-up exams, 285 (55 percent) were alive 12 years after treatment and 231 (45 percent) were free of clinically detectable cancer.
Thus, physicians and patients who match the eligibility criteria for this clinical trial can select either iodine 125 brachytherapy or enucleation for treatment of choroidal melanoma based on personal values without reservations regarding survival. However, the COMS group cautions physicians and patients against extrapolation of these findings to patients with larger tumors or to those who have peripapillary choroidal melanoma.
Cataract Extraction in the Collaborative Initial Glaucoma Treatment Study
Musch et al. studied the incidence of and predictors for cataract extraction (CE) in 607 patients with newly diagnosed glaucoma. They also characterized the patients’ visual function before and after CE.
Patients were randomized to medical or surgical treatments for glaucoma at 14 centers and followed for a median of 7.7 years. Vision-specific quality of life (VS-QOL) data were collected by telephone interview. CE took place in 99 study eyes.
The researchers found that several factors conferred a higher risk of cataract: the hazard ratio (HR) for initial surgery (3.7), older age (e.g., 65 vs. 50 years; HR = 8.8), a more negative spherical equivalent (HR = 1.9 per –3 D) and a diagnosis of pseudoexfoliative glaucoma (HR = 2.1). Visual field testing pre- and post-CE showed the mean deviation improved (2.6 dB) but the pattern standard deviation worsened (0.9 dB). VS-QOL significantly worsened prior to CE and improved significantly after CE on most subscales.
The authors conclude that initial surgery, older age, myopia and a diagnosis of pseudoexfoliative glaucoma place a glaucoma patient at a higher risk of cataract. The impact of CE on visual field indices is mixed.
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 of Ophthalmology summaries are written by the lead authors.
In 1999, the American Society of Anesthesiologists (ASA) Committee on Professional Liability established the ASA Postoperative Visual Loss (POVL) Registry to collect detailed information on cases of POVL occurring following nonocular surgery. Lee et al. retrospectively reviewed 93 spine surgery cases in this registry and described the clinical characteristics of these patients.
More than two-thirds of these individuals underwent spine surgery in the prone position, and 89 percent of these cases were associated with ischemic optic neuropathy. ION may reflect a multifactorial etiology given that most of the spine surgery patients were healthy with a wide range of nadir hematocrits and blood pressure management. In addition, 96 percent of these individuals had an estimated blood loss of 1,000 ml or greater, or anesthetic duration of six hours or longer. Interestingly, ION occurred in the absence of vascular injury in other critical organs, such as the heart or brain—even in patients with preexisting coronary atherosclerosis, diabetes and hypertension.
These findings suggest that the optic nerve vasculature may be uniquely vulnerable to hemodynamic perturbations in the prone position in some patients. The authors recommend that patients undergoing lengthy spine surgery in the prone position be told about the risks of possible visual loss.
The phase 3 MARINA study—Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration—evaluated ranibizumab for the treatment of minimally classic or occult (with no classic lesions) choroidal neovascularization associated with AMD.
For this two-year, multicenter, double-blind study, Rosenfeld et al. randomly assigned patients with AMD to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. They found that during two years of follow-up, ranibizumab therapy was associated with clinically and statistically significant benefits with respect to visual acuity and angiographic lesions. Specifically, at 12 months, 94.5 percent of the group given 0.3 mg of ranibizumab and 94.6 percent of those given 0.5 mg lost fewer than 15 letters, compared with 62.2 percent of patients receiving the sham injections. In addition, visual acuity improved by 15 or more letters in 24.8 percent of the 0.3-mg group and 33.8 percent of the 0.5-mg group, compared with 5 percent of the sham injection group. This benefit was maintained at 24 months. These outcomes were achieved with a low rate of serious adverse events.
In a retrospective, cross-sectional study using a patient questionnaire, van Kooij et al. observed a strong association between advancing age and the presence of cystoid macular edema in patients with uveitis.They found a positive correlation between CME and papillary leakage on angiography.
The study involved 97 consecutive patients who filled in a questionnaire to determine the presence of cardiovascular disease and associated risk factors. The researchers then analyzed the data from the ophthalmologic records and questionnaire data. Forty-four percent of patients had CME. For individuals older than age 50, the risk of having CME was 3.8-fold larger than for younger patients. In addition, CME was most common in patients with panuveitis and was associated with papillary leakage on fluorescein angiography. The investigators also found that after adjustment for age, multivariate logistic regression demonstrated no association between cardiovascular disease and its risk factors, and the presence of CME.
They conclude that an earlier and more aggressive uveitis treatment course in elderly patients might postpone development of CME, thereby improving the visual prognosis of these individuals.
Vascular permeability was the first described function for VEGF, which has a central role in vasculogenesis and angiogenesis. Yet how VEGF induces vessel leakiness has remained poorly understood.
Gavard and Gutkind observed that VEGF regulates the availability of VE-cadherin at the cell surface by promoting its endocytosis through a VEGFR-2Src-Vav2-Rac-PAK signaling axis. The rapid endocytosis of VE-cadherin leads to disruption of the endothelial barrier function.
They also found that the VEGF-induced internalization of VE-cadherin involves the phosphorylation of a conserved motif within the VE-cadherin ICD and the consequent recruitment of beta-arrestin2, which is best known for its involvement in the GPCR ligand-dependent endocytosis.
Ultimately, these new insights into the basic molecular mechanisms by which VEGF induces vascular permeability through the endocytosis of VE-cadherin may result in broad spectrum clinical implications. They may help identify novel therapeutic targets for treatment of many human diseases involving vessel leakiness—including diabetic retinopathy and macular degeneration.
Roundup of Other Journals is written by Lori Baker Schena and edited by Deepak P. Edward, MD.