Macular Degeneration: Danis RP

Whitehead AJ, Mares JA, Danis RP. · Department of Ophthalmology, University of Wisconsin-Madison, 406 Science Drive, Madison, WI 53711, USA. · Arch Ophthalmol. · Pubmed #16832030 links to  free full text

Abstract: The existence of the macula lutea of the human retina has been known for more than 200 years. It is established that the xanthophylls lutein and zeaxanthin are responsible for the yellow color. The effect of macular photopigments on blue-light filtration and color perception is well established. It has been postulated that the pigment might serve to reduce chromatic aberration and to improve visual acuity. The antioxidant capabilities of these xanthophylls combined with their ability to trap short-wavelength light may serve to protect the outer retina, retinal pigment epithelium, and choriocapillaris from oxidative damage. Current ideas on the pathophysiology of age-related macular degeneration may be compatible with the proposed function of lutein and zeaxanthin. This review will summarize our knowledge about macular pigment regarding current efforts in research and the epidemiology of age-related eye disease.

Hubbard LD, Danis RP, Neider MW, Thayer DW, Wabers HD, White JK, Pugliese AJ, Pugliese MF, Anonymous00012. · Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711-1068, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18421079 links to  free full text

Abstract: PURPOSE: To analyze brightness, contrast, and color balance of digital versus film retinal images in a multicenter clinical trial, to propose a model image from exemplars, and to optimize both image types for evaluation of age-related macular degeneration (AMD). METHODS: The Age-Related Eye Disease Study 2 (AREDS2) is enrolling subjects from 90 clinics, with three quarters of them using digital and one quarter using film cameras. Image brightness (B), contrast (C), and color balance (CB) were measured with three-color luminance histograms. First, the exemplars (film and digital) from expert groups were analyzed, and an AMD-oriented model was constructed. Second, the impact of B/C/CB on the appearance of typical AMD abnormalities was analyzed. Third, B/C/CB in AREDS2 images were compared between film (156 eyes) and digital (605 eyes), and against the model. Fourth, suboptimal images were enhanced by adjusting B/C/CB to bring them into accord with model parameters. RESULTS: Exemplar images had similar brightness, contrast, and color balance, supporting an image model. Varying a specimen image through a wide range of B/C/CB revealed greatest contrast of drusen and pigment abnormalities against normal retinal pigment epithelium with the model parameters. AREDS2 digital images were more variable than film, with lower correspondence to our model. Ten percent of digital were too dim and 19% too bright (oversaturated), versus 1% and 4% of film, respectively. On average, digital had lower green channel contrast (giving less retinal detail) than film. Overly red color balance (weaker green) was observed in 23% of digital versus 8% of film. About half of digital (but fewer film) images required enhancement before AMD grading. After optimization of both image types, AREDS2 image quality was judged as good as that in AREDS (all film). CONCLUSIONS: A histogram-based model, derived from exemplars, provides a pragmatic guide for image analysis and enhancement. In AREDS2, the best digital images matched the best film. Overall, however, digital provided lower contrast of retinal detail. Digital images taken with higher G-to-R ratio showed better brightness and contrast management. Optimization of images in the multicenter study helps standardize documentation of AMD (ClinicalTrials.gov NCT00345176).

Scott IU, Bressler NM, Bressler SB, Browning DJ, Chan CK, Danis RP, Davis MD, Kollman C, Qin H, Anonymous00398. · Pennsylvania State University College of Medicine, Hershey, PA, USA. · Retina. · Pubmed #18185135 links to  free full text

Abstract: PURPOSE: To evaluate agreement in diabetic retinopathy severity classification by retina specialists performing ophthalmoscopy versus reading center (RC) grading of seven-field stereoscopic fundus photographs in a phase 2 clinical trial of intravitreal bevacizumab for center-involved diabetic macular edema. METHODS: Clinicians' grading scale used four levels: microaneurysms only, mild/moderate nonproliferative diabetic retinopathy (NPDR), severe NPDR, and proliferative diabetic retinopathy (PDR) or prior panretinal photocoagulation (PRP) or both. The RC scale used eight levels: microaneurysms only, mild NPDR, moderate NPDR, moderately severe NPDR, severe NPDR, mild PDR, moderate PDR, and high-risk PDR. Percent agreement and kappa statistic were defined by collapsing RC categories to match those used by clinicians. RESULTS: There was agreement in 89/118 eyes (75%) with kappa = 0.55 (95% confidence interval [0.41, 0.68]). In six eyes, disagreements were of potential substantial clinical importance: five eyes with subtle retinal neovascularization and one with a small preretinal hemorrhage identified only in photographs. CONCLUSIONS: Clinician grading of retinopathy severity had moderate agreement with RC grading and might be useful for placing eyes into broad baseline categories.

Ciulla TA, Danis RP, Klein SB, Malinovsky VE, Soni PS, Pratt LM, Pugh NO, Morphis JG, Bloch C, Cameron J. · Retina Service, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Am J Ophthalmol. · Pubmed #12470761 No free full text.

Abstract: PURPOSE: To examine the effect of proton beam irradiation on subfoveal choroidal neovascular membranes (CNVM) associated with age-related macular degeneration (AMD).Randomized, prospective, sham-controlled, double-masked treatment trial. METHODS: Thirty-seven subjects with subfoveal CNVM due to AMD were randomly assigned to 16-Gy proton irradiation delivered in two fractions 24 hours apart or to sham control treatment. Recruitment was halted at 37 subjects for ethical reasons regarding randomization to sham treatment when Food and Drug Administration approval of Visudyne was anticipated. RESULTS: Proton irradiation was associated with a trend toward stabilization of visual acuity, but this association did not reach statistical significance. No correlations were found within the fluorescein angiography data, including greatest linear dimension of CNVM total size, area of active leakage, area of associated subretinal hemorrhage, and intensity. CONCLUSIONS: With the acceptance of photodynamic therapy, future studies will require more complex design and larger sample size to determine whether radiation can play either a primary or adjunctive role in treating these lesions.

Danis RP, Ciulla TA, Pratt LM, Anliker W. · Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA. · Retina. · Pubmed #10872928 No free full text.

Abstract: PURPOSE: To examine the effects of intravitreal injection of 4.0 mg triamcinolone acetonide on the visual and clinical course of exudative age-related macular degeneration. METHODS: A randomized clinical trial of a single injection of triamcinolone acetonide into the vitreous cavity of experimental eyes at baseline versus observation of untreated subjects was performed in 27 patients followed up for 6 months. Inclusion criteria included exudative age-related macular degeneration with subfoveal or occult choroidal neovascularization, and visual acuity between 20/40 and 20/400. Examination, acuity assessment, fundus photography, and fluorescein angiography were performed at baseline and at 3 and 6 months after enrollment. LogMAR visual acuity was compared between groups by a repeated measures analysis of variance model. Masked assessment of photographic studies was performed and groups were compared with Fisher's exact test. RESULTS: Visual acuity was significantly better in the treated group compared with control subjects at 3 and 6 months (P < 0.005). Fundus photography and angiography were more likely to show stability or improvement at 3 and 6 months in the treated group (P = 0.05). Intraocular pressure elevation was seen in 25% of treated patients, but was controlled with topical medications. Progression of cataract was more frequently seen in the treated group. CONCLUSIONS: Intravitreal triamcinolone acetonide may provide short-term improvement in visual acuity and fundus findings in exudative macular degeneration. These findings must be considered preliminary and should be followed by multicenter, masked, placebo-controlled trials with long-term follow-up.

Domalpally A, Danis RP, Zhang B, Myers D, Kruse CN. · Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA. · Retina. · Pubmed #19373128 No free full text.

Abstract: PURPOSE: To analyze the scan characteristics associated with poor-quality Stratus optical coherence tomograms submitted to a reading center for multicenter clinical trials. METHODS: Data from evaluation of 6,741 fast macular thickness map reports from trials involving age-related macular degeneration (AMD), diabetic macular edema, and retinal vein occlusion were analyzed. Optical coherence tomograms with an erroneous centerpoint thickness needing manual remeasurement (MR) were categorized as being of poor quality. The frequency of MR and the artifacts associated were analyzed by disease type, underlying retinal morphology, and severity of retinal thickening. RESULTS: MR was performed in 2,027 (30%) optical coherence tomograms. AMD had the highest frequency of MR (54.9%), followed by retinal vein occlusion (23.9%) and diabetic macular edema (16.3%). Boundary line errors were the most common artifact across all disease types (61.3% of scans requiring MR) and increased with increasing retinal thickness. Decentration artifact was seen in 15.4% of scans requiring MR. The median absolute difference between machine and manually measured centerpoint thickness assessed in a subset of 84 scans was 75.5 microm. CONCLUSION: Artifacts causing erroneous reported centerpoint thickness are common. Identifying clues that indicate suboptimal quality of optical coherence tomography (OCT) images are important to avoid erroneous interpretation of OCT data in clinical trials.

Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin H, Anonymous00054. · Department of Ophthalmology and Public Health Sciences, Penn State Hershey Eye Center, Penn State College of Medicine, Hershey, Pennsylvania, USA. · Retina. · Pubmed #19373126 No free full text.

Abstract: PURPOSE: To report visual acuity and anatomic changes from baseline to 12 months after modified Early Treatment Diabetic Retinopathy Study (ETDRS)-style (focal/grid) photocoagulation in eyes with non-center-involved (non-CI) clinically significant macular edema. METHODS: Visual acuity, optical coherence tomography, fluorescein angiography, and fundus photography data were analyzed from eyes with non-CI clinically significant macular edema treated with modified ETDRS-style (focal/grid) photocoagulation in a Diabetic Retinopathy Clinical Research Network trial. RESULTS: Among the 22 eyes (of 22 patients) with 12-month follow-up, median visual acuity letter score remained within 1 letter of baseline over 12 months. The median central subfield retinal thickness decreased by 10 mum, median total macular volume decreased by 0.2 mm, and median fluorescein leakage area within the grid decreased by 0.7 disk areas. CONCLUSION: We are unaware of any other systematic evaluation of eyes with non-CI clinically significant macular edema since the ETDRS. Focal/grid laser in these non-CI eyes was associated with relatively stable visual acuity and retinal thickness measurements, and decreased fluorescein leakage area at 1 year. One-year visual acuity results are consistent with those published by the ETDRS, despite the intervening significant differences in the management of diabetes. Although this was a small study without a concurrent control group, the ETDRS recommendation to consider focal/grid laser in eyes with non-CI clinically significant macular edema still seems appropriate.

Browning DJ, Apte RS, Bressler SB, Chalam KV, Danis RP, Davis MD, Kollman C, Qin H, Sadda S, Scott IU, Anonymous00031. · Charlotte Eye Ear Nose and Throat Assoc, PA, Charlotte, North Carolina, USA. · Retina. · Pubmed #19174719 No free full text.

Abstract: PURPOSE: To determine whether the extensiveness of diabetic macular edema using a 10-step scale based on optical coherence tomography explains pretreatment variation in visual acuity and predicts change in macular thickness or visual acuity after laser photocoagulation. METHODS: Three hundred twenty-three eyes from a randomized clinical trial of two methods of laser photocoagulation for diabetic macular edema were studied. Baseline number of thickened optical coherence tomography subfields was used to characterize diabetic macular edema on a 10-step scale from 0 to 9. Associations were explored between baseline number of thickened subfields and baseline fundus photographic variables, visual acuity, central subfield mean thickness (CSMT), and total macular volume. Associations were also examined between baseline number of thickened subfields and changes in visual acuity, CSMT, and total macular volume at 3.5 and 12 months after laser photocoagulation. RESULTS: For baseline visual acuity, the number of thickened subfields explained no more variation than did CSMT, age and fluorescein leakage. A greater number of thickened subfields was associated with a greater baseline CSMT, total macular volume, area of retinal thickening, and degree of thickening at the center of the macula (r = 0.64, 0.77, 0.61-0.63, and 0.45, respectively) and with a lower baseline visual acuity (r = 0.38). Baseline number of thickened subfields showed no association with change in visual acuity (r < or = 0.01-0.08) and weak associations with change in CSMT and total macular volume (r from 0.11 to 0.35). CONCLUSION: This optical coherence tomography based assessment of the extensiveness of diabetic macular edema did not explain additional variation in baseline visual acuity above that explained by other known important variables nor predict changes in macular thickness or visual acuity after laser photocoagulation.

Lujan BJ, Wang F, Gregori G, Rosenfeld PJ, Knighton RW, Puliafito CA, Danis RP, Hubbard LD, Chang RT, Budenz DL, Seider MI, Knight O. · Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. · Ophthalmic Surg Lasers Imaging. · Pubmed #18777875 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Measurements performed on fundus images using current software are not accurate. Accurate measurements can be obtained only by calibrating a fundus camera using measurements between fixed retinal landmarks, such as the dimensions of the optic nerve, or by relying on a calibrated model eye provided by a reading center. However, calibrated spectral domain OCT (SD-OCT) could offer a convenient alternative method for the calibration of any fundus image. PATIENTS AND METHODS: The ability to measure exact distances on SD-OCT fundus images was tested by measuring the distance between the center of the fovea and the optic nerve. Calibrated SD-OCT scans measuring 6 X 6 X 2 mm centered on the fovea and the optic nerve were analyzed in 50 healthy right eyes. The foveal center was identified using cross-sectional SD-OCT images, and the center of the optic nerve was identified manually. The SD-OCT scans were registered to each other, and the distances between the center of the optic nerve and fovea were calculated. The overlay of these SD-OCT fundus images on photographic fundus images was performed. RESULTS: Any image of the fundus could be calibrated by overlaying the SD-OCT fundus image, and the measurements were consistent with previously defined calibration methods. The mean distance between the center of the fovea and the center of the optic nerve was 4.32 +/-0.32 mm. The line from the center of the optic nerve to the foveal center had a mean declination of 7.67 +/- 3.88 degrees. Mean horizontal displacement and vertical displacement were 4.27 +/- 0.29 mm and 0.58 +/- 0.29 mm, respectively. CONCLUSIONS: The overlay of the SD-OCT fundus image provides a convenient method for calibrating any image of the fundus. This approach should provide a uniform standard when comparing images from different devices and from different reading centers.

Davis MD, Sheetz MJ, Aiello LP, Milton RC, Danis RP, Zhi X, Girach A, Jimenez MC, Vignati L, Anonymous00045. · Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18708615 No free full text.

Abstract: PURPOSE: To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters. METHODS: In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. RESULTS: Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). CONCLUSIONS: The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).

Browning DJ, Glassman AR, Aiello LP, Bressler NM, Bressler SB, Danis RP, Davis MD, Ferris FL, Huang SS, Kaiser PK, Kollman C, Sadda S, Scott IU, Qin H, Anonymous00193. · Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647, USA. · Ophthalmology. · Pubmed #18675696 No free full text.

Abstract: OBJECTIVE: To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME). DESIGN: Associations of pairs of OCT variables and results of 3 analysis methods using data from 2 studies of DME. PARTICIPANTS: Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME. METHODS: Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening. MAIN OUTCOME MEASURES: Concordance of results using different OCT variables and analysis methods. RESULTS: Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness. CONCLUSIONS: Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.

Glassman AR, Beck RW, Browning DJ, Danis RP, Kollman C, Anonymous00143. · Jaeb Center for Health Research, Tampa, Florida 33647, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18566462 No free full text.

Abstract: PURPOSE: To analyze the value of reading center error correction in automated optical coherence tomography (OCT; Stratus; Carl Zeiss Meditec, Inc., Dublin, CA) retinal thickness measurements in eyes with diabetic macular edema (DME). METHODS: OCT scans (n=6522) obtained in seven Diabetic Retinopathy Clinical Research Network (DRCR.net) studies were analyzed. The reading center evaluated whether the automated center point measurement appeared correct, and when it did not, measured it manually with calipers. Center point standard deviation (SD) as a percentage of thickness, center point thickness, signal strength, and analysis confidence were evaluated for their association with an automated measurement error (manual measurement needed and exceeded 12% of automated thickness). Curves were constructed for each factor by plotting the error rate against the proportion of scans sent to the reading center. The impact of measurement error on interpretation of clinical trial results and statistical power was also assessed. RESULTS: SD was the best predictor of an automated measurement error. The other three variables did not augment the ability to predict an error using SD alone. Based on SD, an error rate of 5% or less could be achieved by sending only 33% of scans to the reading center (those with an SD >or= 5%). Correcting automated errors had no appreciable effect on the interpretation of results from a completed randomized trial and had little impact on a trial's statistical power. CONCLUSIONS: In DME clinical trials, the error involved with using automated Stratus OCT center point measurements is sufficiently small that results are not likely to be affected if scans are not routinely sent to a reading center, provided adequate quality control measures are in place.

Danis RP, Fisher MR, Lambert E, Goulding A, Wu D, Lee LY. · Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53711, USA. · Arch Ophthalmol. · Pubmed #18195217 links to  free full text

Abstract: OBJECTIVES: To present the results for subgroups defined by center point (CP) measurement and to assess the repeatability of the Fast Retinal Thickness Map analysis results from the Stratus OCT3 machine. METHODS: Two hundred eighty-one replicate OCT3 scans from 134 operators' certification submissions to a reading center were analyzed, including scans from eyes that were reported to be normal and eyes with exudative age-related macular degeneration and with macular edema due to diabetic retinopathy or retinal vascular occlusion. RESULTS: The mean (SD) of the CP was 284 (150) microm and the center subfield (CC) was 301 (130) microm. The CP coefficient of repeatability (CR) was 49 microm and the CC CR was 27 microm. The CR increased by increasing retinal thickness for the CP and the CC within arbitrarily defined subgroups. For the 87 eyes with a session 1 CP of 175 microm or less, the CP CR was 17 microm and the CC CR was 10 microm. CONCLUSIONS: Among experienced operators, given the same operator, machine, and eye at the same sitting, OCT3 retinal thickness maps appear to have a CR that is likely to be less than the clinically important difference.

Rechtman E, Harris A, Siesky B, Kagemann L, Danis RP, Sines D, Ciulla TA. · Goldschleger Eye Institute, Tel-Hashomer, Israel. · Ophthalmic Surg Lasers Imaging. · Pubmed #17552388 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: To evaluate the relationship between retrobulbar and choroidal hemodynamics in non-neovascular age-related macular degeneration. PATIENTS AND METHODS: Thirteen patients with age-related macular degeneration were assessed by both color Doppler imaging and scanning laser ophthalmoscope indocyanine green (ICG) angiography. Color Doppler imaging was used to measure peak systolic and end diastolic velocity (from which the resistance index, a measure of the resistance to flow downstream, was calculated) in the retrobulbar vessels. Scanning laser ophthalmoscope ICG angiograms were analyzed by area dilution analysis for quantitative choroidal fluorescence intensity assessment. Color Doppler imaging parameters were correlated with scanning laser ophthalmoscope ICG area dilution analysis parameters. RESULTS: A good correlation was found between the posterior ciliary arteries resistance index and scanning laser ophthalmoscope ICG area dilution analysis fluorescence duration. CONCLUSIONS: Scanning laser ophthalmoscope ICG area dilution analysis "duration" may serve as an alternative to color Doppler imaging in assessing the resistance to blood flow in the posterior ciliary arteries.

Anonymous00133, Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP, Davis MD, Feman SS, Ferris F, Friedman SM, Garcia CA, Glassman AR, Han DP, Le D, Kollman C, Lauer AK, Recchia FM, Solomon SD. · No affiliation provided · Arch Ophthalmol. · Pubmed #17420366 links to  free full text

Abstract: OBJECTIVE: To compare 2 laser photocoagulation techniques for treatment of diabetic macular edema: the modified Early Treatment Diabetic Retinopathy Study (ETDRS) direct/grid photocoagulation technique and a potentially milder (but potentially more extensive) mild macular grid (MMG) laser technique in which microaneurysms are not treated directly and small mild burns are placed throughout the macula, whether or not edema is present. METHODS: Two hundred sixty-three subjects (mean age, 59 years) with previously untreated diabetic macular edema were randomly assigned to receive laser photocoagulation by either the modified ETDRS (162 eyes) or MMG (161 eyes) technique. Visual acuity, fundus photographs, and optical coherence tomography measurements were obtained at baseline and at 3.5, 8, and 12 months. Treatment was repeated if diabetic macular edema persisted. MAIN OUTCOME MEASURE: Change in optical coherence tomography measurements at 12-month follow-up. RESULTS: Among eyes with a baseline central subfield thickness of 250 microm or greater, central subfield thickening decreased by an average of 88 microm in the modified ETDRS group and by 49 microm in the MMG group at 12-month follow-up (adjusted mean difference, 33 microm; 95% confidence interval, 5-61 microm; P = .02). Weighted inner zone thickening by optical coherence tomography decreased by 42 microm in the modified ETDRS group and by 28 microm in the MMG group (adjusted mean difference, 14 microm; 95% confidence interval, 1-27 microm; P = .04); maximum retinal thickening (maximum thickening of the central and 4 inner subfields) decreased by 66 and 39 microm, respectively (adjusted mean difference, 27 microm; 95% confidence interval, 6-47 microm; P = .01), and retinal volume decreased by 0.8 and 0.4 mm3, respectively (adjusted mean difference, 0.3 mm3; 95% confidence interval, 0.02-0.53 mm3; P = .03). At 12 months, the mean change in visual acuity was 0 letters in the modified ETDRS group and 2 letters worse in the MMG group (adjusted mean difference, 2 letters; 95% confidence interval, -0.5 to 5 letters; P = .10). CONCLUSIONS: At 12 months after treatment, the MMG technique was less effective at reducing optical coherence tomography-measured retinal thickening than the more extensively evaluated current modified ETDRS laser photocoagulation approach. However, the visual acuity outcome with both approaches is not substantially different. Given these findings, a larger long-term trial of the MMG technique is not justified. APPLICATION TO CLINICAL PRACTICE: Modified ETDRS focal photocoagulation should continue to be a standard approach for treating diabetic macular edema. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00071773.

Anonymous00153, Krzystolik MG, Strauber SF, Aiello LP, Beck RW, Berger BB, Bressler NM, Browning DJ, Chambers RB, Danis RP, Davis MD, Glassman AR, Gonzalez VH, Greenberg PB, Gross JG, Kim JE, Kollman C. · Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647, USA. · Ophthalmology. · Pubmed #17353052 links to  free full text

Abstract: PURPOSE: To evaluate optical coherence tomography (OCT) reproducibility in patients with diabetic macular edema (DME). DESIGN: Prospective 1-day observational study. PARTICIPANTS: Two hundred twelve eyes of 107 patients with DME involving the macular center by clinical examination and OCT central subfield thickness of > or =225 microm. METHODS: Retinal thickness was measured with the OCT3 system, and scans were evaluated by a reading center. Reproducibility of retinal thickness measurements was assessed, and 95% confidence intervals (CIs) for a change in thickness were estimated. MAIN OUTCOME MEASURES: Reproducibility of OCT-measured central subfield thickness. RESULTS: Reproducibility was better for central subfield thickness than for center point thickness (half-width of the 95% CI for absolute change, 38 microm vs. 50 microm, and for relative change, 11% vs. 17%, respectively; P<0.001). The median absolute difference between replicate measurements of the central subfield was 7 microm (2%). Half-widths of the 95% CI for a change in central subfield thickness were 22, 23, 33, and 56 microm for scans with central subfield thicknesses of <200, 200 to <250, 250 to <400, and > or =400 microm, respectively. When expressed as percentage differences between 2 measurements, half-widths of the 95% CI for a change in central subfield thickness were 10%, 10%, 10%, and 13% for scans with central subfield thicknesses of <200, 200 to <250, 250 to <400, and > or =400 microm, respectively. We were unable to identify an effect on reproducibility of central subfield measurements with respect to the presence of cystoid abnormalities, subretinal fluid, vitreomacular traction, or reduced visual acuity. Reproducibility was better when both scans had a standard deviation (SD) of the center point of <10.0% (half-width of the 95% CI for change, 33 microm vs. 56 microm; P<0.001). CONCLUSIONS: Reproducibility is better for central subfield thickness measurements than for center point measurements, and variability is less with retinal thickness when expressed as a percent change than when expressed as an absolute change. A change in central subfield thickness exceeding 11% is likely to be real. Scans with an SD of the center point of > or =10.0% are less reproducible and should be viewed with caution when assessing the validity of an observed change in retinal thickness in patients with DME.

Anonymous00159, Danis RP, Glassman AR, Aiello LP, Antoszyk AN, Beck RW, Browning DJ, Ciardella AP, Kinyoun JL, Murtha TJ, Topping TM, Shami M, Sharuk GS, Wells JA. · Jaeb Center for Health Research, Tampa, FL 33647, USA. · Arch Ophthalmol. · Pubmed #17159029 links to  free full text

Abstract: OBJECTIVE: To evaluate diurnal variation in retinal thickness measured with optical coherence tomography (OCT) in patients with center-involved diabetic macular edema. METHODS: Serial OCT3 measurements were performed in 156 eyes of 96 subjects with clinically diagnosed diabetic macular edema and OCT central subfield retinal thickness of 225 microm or greater at 8 am. Central subfield thickness was measured from OCT3 retinal thickness maps at 6 points over a single day between 8 am and 4 pm. A change in central subfield thickening (observed thickness minus mean normal thickness) of at least 25% and of at least 50 microm at 2 consecutive points or between 8 am and 4 pm was considered to have met the composite outcome threshold. RESULTS: At 8 am, the mean central subfield thickness was 368 microm and the mean visual acuity was 66 letters (approximately 20/50). The mean change in relative central subfield retinal thickening between 8 am and 4 pm was a decrease of 6% (95% confidence interval, -9% to -3%) and the mean absolute change was a decrease of 13 microm (95% CI, -17 to -8). The absolute change was significantly greater in retinas that were thicker at 8 am (P<.001) but the relative change was not (P = .14). The composite threshold of reduction in central subfield thickening (as defined above) was observed in 5 eyes of 4 subjects (3% of eyes; 95% CI, 1% to 8%) while 2 eyes of 2 subjects (1%; 95% CI, 0% to 5%) had an increase in central subfield thickening of this same magnitude. The maximum decrease was observed at 4 pm in all 5 eyes. CONCLUSION: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening between 8 am and 4 pm.

Anonymous00052, Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, Bressler NM, Danis RP, Kinyoun JL, Nguyen QD, Bhavsar AR, Gottlieb J, Pieramici DJ, Rauser ME, Apte RS, Lim JI, Miskala PH. · Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647, USA. · Ophthalmology. · Pubmed #17123615 links to  free full text

Abstract: OBJECTIVE: To compare optical coherence tomography (OCT)-measured retinal thickness and visual acuity in eyes with diabetic macular edema (DME) both before and after macular laser photocoagulation. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: Two hundred ten patients (251 eyes) with DME enrolled in a randomized clinical trial of laser techniques. METHODS: Retinal thickness was measured with OCT and visual acuity was measured with the electronic Early Treatment of Diabetic Retinopathy procedure. MAIN OUTCOME MEASURES: Optical coherence tomography-measured center point thickness and visual acuity. RESULTS: The correlation coefficients for visual acuity versus OCT center point thickness were 0.52 at baseline and 0.49, 0.36, and 0.38 at 3.5, 8, and 12 months after laser photocoagulation. The slope of the best fit line to the baseline data was approximately 4.4 letters (95% confidence interval, 3.5-5.3) of better of visual acuity for every 100-mum decrease in center point thickness at baseline with no important difference at follow-up visits. Approximately one third of the variation in visual acuity could be predicted by a linear regression model that incorporated OCT center point thickness, age, hemoglobin A1C, and severity of fluorescein leakage. The correlation between change in visual acuity and change in OCT center point thickening 3.5 months after laser treatment was 0.44, with no important difference at the other follow-up times. A subset of eyes showed paradoxical improvements in visual acuity with increased center point thickening (7%-17% at the 3 time points) or paradoxical worsening of visual acuity with a decrease in center point thickening (18%-26% at the 3 time points). CONCLUSIONS: There is modest correlation between OCT-measured center point thickness and visual acuity, and modest correlation of changes in retinal thickening and visual acuity after focal laser treatment for DME. However, a wide range of visual acuity may be observed for a given degree of retinal edema. Thus, although OCT measurements of retinal thickness represent an important tool in clinical evaluation, they cannot substitute reliably as a surrogate for visual acuity at a given point in time. This study does not address whether short-term changes on OCT are predictive of long-term effects on visual acuity.

Henderson MA, Valluri S, Lo SS, Witt TC, Worth RM, Danis RP, Timmerman RD. · Department of Radiation Oncology, Indiana University Medical Center, Indianapolis, Ind., USA. · Stereotact Funct Neurosurg. · Pubmed #17077651 No free full text.

Abstract: We evaluated retrospectively our institutional experience in the treatment of macular degeneration with gamma knife radiosurgery (GKR). Treatment was delivered in a single shot of 12 Gy. Seven patients were treated between March of 1999 and May of 2000. The median duration of follow-up was 2.2 years. The majority of patients maintained stable visual acuity after treatment. Our series indicates that GKR may be useful as a salvage treatment for patients who have failed or are ineligible for other treatments for their macular degeneration. Further studies are needed to better define the role of GKR in the treatment of macular degeneration.

Hu W, Criswell MH, Ottlecz A, Cornell TL, Danis RP, Lambrou GN, Ciulla TA. · Retina Service Research Laboratories, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Retina. · Pubmed #16340537 No free full text.

Abstract: PURPOSE: To determine whether lumiracoxib, a highly selective cyclooxygenase-2 (COX-2) inhibitor that exhibits anti-inflammatory and antiangiogenic properties, can inhibit experimental choroidal neovascular membrane (CNVM) development induced by focal laser trauma in a well-characterized Brown Norway rat CNVM model. METHODS: Over a 35-day period, 24 rats received daily oral gavage dosages of 20 mg/kg lumiracoxib in a 0.5% (w/v) suspension of sodium carboxymethylcellulose (CMC), while a control group received the 0.5% CMC suspension only. After 7 days, eight laser photocoagulation sites were placed concentrically around the optic disk to induce CNVMs. Thirty-five days later, fundus photography and fluorescein angiography (FA) were performed and eyes were processed for histopathologic analysis. RESULTS: Masked FA grading of lesion sites revealed a small, but statistically significant difference (P<0.0001) in late stage staining intensity and leakage between the mean group scores of treated (1.4) and control (1.7) eyes. Histopathologic analysis demonstrated that the mean CNVM thickness +/- SD of 38 +/-19 microm (n=24 eyes, 175 photocoagulation sites) in the lumiracoxib-treated animals was reduced by 30% (P<0.001) compared to the CNVM mean thickness+/- SD of 54+/- 20 microm (n=24 eyes, 171 photocoagulation sites) in the control animals. CONCLUSION: Systemic administration of the selective COX-2 inhibitor lumiracoxib results in a partial but significant reduction in CNVM development in the rat laser-trauma model and thus may be clinically beneficial as a potential inhibitor of CNVM formation in exudative age-related macular degeneration.

Criswell MH, Ciulla TA, Lowseth LA, Small W, Danis RP, Carson DL. · Retina Service Research Laboratories, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, 46260, USA. · Invest Ophthalmol Vis Sci. · Pubmed #15914638 links to  free full text

Abstract: PURPOSE: Anastomotic vessels in exudative age-related macular degeneration (AMD) represent a serious clinical feature that reportedly does not respond well to either photocoagulation or photodynamic therapy (PDT). Anastomoses also occur in various animal models of choroidal neovascularization (CNV). In the present study, anastomotic vessels and their patency were evaluated in two primate CNV laser-trauma models after PDT, by using two novel photosensitizers. METHODS: In cynomolgus (Macaca fascicularis) and squirrel (Saimiri sciureus) monkey eyes (n = 20), matrix placement of laser photocoagulation sites elicited CNV as a component of the development of fibrovascular tissue (FVT). FVT sites received PDT according to specific drug infusion and laser light treatment parameters. FVTs and anastomoses were evaluated by fundus photography, fluorescein angiography, and histologic examination. RESULTS: Anastomoses averaged approximately 48% of FVT sites, with greatest occurrence in the macaque. Although PDT with each photosensitizer effectively produced FVT closure, both retinal vessels and anastomoses remained patent. CONCLUSIONS: Although PDT is effective in closing the choroidal neovascularization in FVT, this technique was ineffective in occluding anastomotic vessels and their associated tributaries within the mid- to proximal retina. Various factors (vascular diameter, composition, blood flow, orientation) may contribute to continued anastomotic patency. By convention, such vessels would typically be defined as chorioretinal anastomoses (CRAs); however, continuing studies suggest the possibility that these neovessels constitute dual-origin hybrids. Regardless of origin, viable anastomoses provide one potential mechanism for revascularization to occur after PDT and may help to explain why CRAs are considered a poor prognostic sign in patients with AMD.

Rechtman E, Danis RP, Pratt LM, Harris A. · Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA. · Br J Ophthalmol. · Pubmed #14977766 links to  free full text

Abstract: AIMS: To report the effects of intravitreal triamcinolone acetonide (iTAAC) injections as an adjunctive treatment to photodynamic therapy (PDT) with verteporfin for new subfoveal choroidal neovascularisation (CNV) in age related macular degeneration (AMD). METHODS: We retrospectively reviewed the records of all AMD patients who had iTAAC within 6 weeks of their first PDT and had a follow up of one year or longer. The proportion of eyes after one year follow up that lost or gained >or=15 and >or=30 ETDRS letters, baseline and one year lesion greatest linear dimension (GLD), number of PDTs, and side effects were assessed. RESULTS: Fourteen patients were evaluated. Eleven received one initial combined treatment and three received an additional combined treatment after 6 months. Median follow up was 18 months (range 12 to 25 months). Overall, 7% gained >or=30 letters, 50% maintained stable vision, 14% lost 15-29 letters, and 29% lost >or=30 letters. Overall, mean GLD increased from 2580 (SD 1088) microm to 3946 (SD 1503) micro m (p = 0.01). The mean number of PDTs during the first year was 2.57. Side effects were mild intraocular pressure elevation in 28.5% and cataract progression in 50% of phakic eyes. CONCLUSIONS: iTAAC with PDT in AMD was found to be relatively safe and had reasonable results for lesions with some classic component.

Ciulla TA, Criswell MH, Danis RP, Fronheiser M, Yuan P, Cox TA, Csaky KG, Robinson MR. · Retina Service Research Laboratories, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA. · Br J Ophthalmol. · Pubmed #12881350 links to  free full text

Abstract: AIM: To determine if intravitreal microimplants containing triamcinolone acetonide (TAAC) inhibit experimental fibrovascular proliferation (FVP) induced by laser trauma in a rat as a model of choroidal neovascular membranes (CNVMs). METHODS: 20 anaesthetised male Brown Norway rats received a series of eight krypton red laser lesions per eye (647 nm, 0.05 s, 50 micro m, 150 mW). Three types of sterilised TAAC microimplant designs were evaluated: implant A consisting of 8.62% TAAC/20% polyvinyl alcohol (PVA) matrix (by dry weight); implant B consisting of 3.62% TAAC/20% PVA matrix; and implant C consisting of a dual 8.62% TAAC/20% PVA matrix design combined with a central core (0.5 mm) of compressed TAAC to extend the implant release time. For each animal studied, one eye received one of the three aforementioned TAAC implant designs, while the fellow eye received a control implant consisting of PVA but without TAAC. The animals were sacrificed at day 35 and ocular tissues were processed for histological analysis. Serial histological specimens were methodically assessed in a masked fashion to analyse each laser lesion for the presence or absence of FVP; maximum FVP thickness for each lesion was measured from the choriocapillaris. RESULTS: All three types of TAAC implants inhibited FVP relative to controls in a statistically significant fashion. In the eyes that received implant A (n = 8), the mean thickness of the recovered lesions (n = 36) measured 32 (SD 22) micro m, compared to 52 (30) micro m (p <0.005) for the recovered lesions (n = 40) from the fellow control eyes. In the eyes that received implant B (n = 6), the mean thickness of the recovered lesions (n = 31) measured 28 (15) micro m, compared to 50 (29) micro m (p <0.001) for the lesions (n = 19) recovered from the fellow control eyes. In the eyes that received implant C (n = 6), the mean thickness of the recovered lesions (n = 21) measured 39 (24) micro m, compared to 65 (30) micro m (p <0.001) for the lesions (n = 39) recovered from the fellow control eyes. CONCLUSIONS: All three of the tested TAAC microimplant designs produced potent inhibition of FVP in a rat model of CNVMs. There were no differences in inhibition of FVP between the three different types of implants evaluated. This study provides evidence that: (1) corroborates previous investigations that propose TAAC as a potential treatment for CNVMs in humans, and (2) demonstrates TAAC can be effectively delivered via long acting sustained release intraocular microimplants. It should be noted, however, that the FVP observed in this rat laser trauma may not reflect the CNVM observed in human with exudative age related macular degeneration (AMD).

Ranson NT, Danis RP, Ciulla TA, Pratt L. · Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA. · Br J Ophthalmol. · Pubmed #11973247 links to  free full text

Abstract: BACKGROUND: Laser treatment of extrafoveal well delineated choroidal neovascularisation in exudative age related macular degeneration has a high rate of failure with subsequent severe vision loss from subfoveal involvement. Laser treatment may limit scotoma size, but is unpalatable because of early persistent vision loss. Intravitreal triamacinolone injection may be an acceptable alternative therapy in such disparate cases. METHODS: 14 consecutive patients with recurrent neovascularisation were treated with a single 4.0 mg injection of triamacinolone and followed for up to 1 year. Visual results were compared with published data from the Macular Photocoagulation Study of recurrent neovascularisation. RESULTS: Mean visual acuity remained stable at about 20/200 throughout the study period in the treated patients. This is comparable to the outcomes in the Macular Photocoagulation Study for laser retreated patients, and better than the observation group. CONCLUSIONS: Intravitreal triamcinolone may be an acceptable treatment of subfoveal recurrent neovascularisation while avoiding early persistent vision loss from laser retreatment.

Ciulla TA, Harris A, Kagemann L, Danis RP, Pratt LM, Chung HS, Weinberger D, Garzozi HJ. · Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA. · Br J Ophthalmol. · Pubmed #11815349 links to  free full text

Abstract: AIM: Choroidal perfusion, affected in age related macular degeneration (AMD), is difficult to objectively assess given the overlying retinal circulation. This study more objectively compared choroidal perfusion parameters in a group with non-neovascular AMD to an unaffected age matched control group. METHODS: 21 non-neovascular AMD subjects and 21 age matched control subjects without evidence of AMD underwent assessment of their choroidal blood flow in a case-control study. Scanning laser ophthalmoscope indocyanine green (ICG) angiograms were analysed by a new area dilution analysis technique. Four areas in the perifoveal region and two areas in the temporal peripapillary retina were evaluated by producing a graph of intensity of fluorescence of each area over time. The mean of the filling times and the heterogeneity of the filling times were assessed. RESULTS: The means of the filling times within the perifoveal regions and the hetereogeneity of the filling times between regions within the same eyes were significantly greater in the AMD patients compared with the control subjects. CONCLUSIONS: Delayed and heterogeneous filling of the choroid was objectively demonstrated in eyes with non-neovascular AMD compared with age matched controls without evidence of AMD, using an area dilution analysis technique applied to ICG angiography.