Jeffrey M. Liebmann

Evolving guidelines for intravitreous injections.

Intravitreous (IVT) injection is increasingly being incorporated into the management of ocular diseases. While only fomivirsen sodium (Vitravene™) is currently approved by the Food and Drug Administration as an IVT injection, the number of approved IVT injections indications is anticipated to grow on the basis of promising results from ongoing clinical studies. Despite the potential benefits that may be derived from intraocular injections of different agents, no guidelines have been published previously for IVT injection. The purpose of this document is to identify specific strategies for the delivery of IVT injection that may reduce risks and improve outcomes. Consensus was sought among a panel of investigators, surgeons experienced with this technique, and industry representatives. Objective evidence was sought for all guidelines, but consensus was accepted where evidence remains incomplete. In the absence of either evidence or consensus, the current manuscript identifies outstanding issues in need of further investigation. It is anticipated that more complete guidelines will evolve over time, potentially altering some of the guidelines included here, based on new applications of IVT injection, additional clinical experience, and results of clinical trials.

Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive, and glaucomatous eyes

PURPOSE To evaluate the relationship between visual function and retinal nerve fiber layer measurements obtained with scanning laser polarimetry and optical coherence tomography in a masked, prospective trial. METHODS Consecutive normal, ocular hypertensive, and glaucomatous subjects who met inclusion and exclusion criteria were evaluated. Complete ophthalmologic examination, disk photography, scanning laser polarimetry, optical coherence tomography, and automated achromatic perimetry were performed. RESULTS Seventy-eight eyes of 78 patients (17 normal, 23 ocular hypertensive, and 38 glaucomatous) were enrolled (mean age, 56.8+/-11.5 years; range, 26 to 75 years). Eyes with glaucoma had significantly greater neural network scores on scanning laser polarimetry and lower maximum modulation, ellipse modulation, and mean retinal nerve fiber layer thickness measured with optical coherence tomography compared with normal and ocular hypertensive eyes, respectively (all P<.005). Significant associations were observed between neural network number (r = -.51, r = .03), maximum modulation (r = .39, r = -.32), ellipse modulation (r = .36, r = -.28), and optical coherence tomography-generated retinal nerve fiber layer thickness (r = .68, r = -.59) and visual field mean deviation and corrected pattern standard deviation, respectively. All scanning laser polarimetry parameters were significantly associated with optical coherence tomography-generated retinal nerve fiber layer thickness. CONCLUSION Optical coherence tomography and scanning laser polarimetry were capable of differentiating glaucomatous from nonglaucomatous populations in this cohort; however considerable measurement overlap was observed among normal, ocular hypertensive, and glaucomatous eyes. Retinal nerve fiber layer structural measurements demonstrated good correlation with visual function, and retinal nerve fiber layer thickness by optical coherence tomography correlated with retardation measurements by scanning laser polarimetry.

Late Bleb-related Endophthalmitis after Trabeculectomy with Adjunctive 5-Fluorouracil

The incidence of late-onset bleb-related endophthalmitis was evaluated retrospectively in 229 consecutive trabeculectomies performed with adjunctive 5-fluorouracil (5-FU) therapy. Mean follow-up was 23.7 +/- 16.3 months (range, 3 to 60 months). Thirteen eyes (5.7%) of 11 patients developed bleb-related endophthalmitis an average of 25.9 +/- 17.4 months (range, 5 to 58 months) after surgery. Infection occurred in 9 of 96 (9.4%) procedures performed from below and in 4 of 133 (3.0%) procedures performed superiorly (P = 0.05, Fishers exact test). The relative risk of bleb-related endophthalmitis in trabeculectomy from below versus above is 4.0 after adjustment for age and sex (95% confidence interval = 1.1, 14.8). Trabeculectomy with adjunctive 5-FU performed from below carries an increased risk of late bleb-related infection. The incidence of late bleb-related endophthalmitis after 5-FU trabeculectomy appears to be higher than that for trabeculectomy without adjunctive 5-FU injections.

Heidelberg retina tomography and optical coherence tomography in normal, ocular-hypertensive, and glaucomatous eyes

PURPOSE To evaluate optic disc and retinal nerve fiber layer (RNFL) appearance in normal, ocular-hypertensive, and glaucomatous eyes undergoing confocal scanning laser ophthalmoscopy and optical coherence tomography (OCT). DESIGN Prospective, cross-sectional study. PARTICIPANTS Seventy-eight eyes of 78 consecutive normal (n = 17), ocular-hypertensive (n = 23), and glaucomatous subjects (n = 38) were enrolled. METHODS Each patient underwent complete ophthalmic examination, achromatic automated perimetry, confocal scanning laser ophthalmoscopy (Heidelberg Retinal Tomography [HRT]), and OCT. Topographic HRT parameters (disc area, cup-disc ratio, rim area, rim volume, cup shape measure, mean RNFL thickness, and cross-sectional area) and mean OCT-generated RNFL thickness were evaluated in each group. MAIN OUTCOME MEASURES OCT and HRT assessment of optic disc and RNFL anatomy. RESULTS OCT RNFL thickness showed no difference between normal and ocular-hypertensive eyes (P = 0.15) but was significantly less in glaucomatous eyes (P < 0.001). HRT measurements of rim area, cup-disc ratio, cup shape measure, RNFL thickness, and RNFL cross-sectional area were significantly less in glaucomatous eyes (all P < 0.005) and were correlated with mean OCT RNFL thickness (all P < 0.02). RNFL thickness using OCT or HRT was highly correlated with visual field mean defect during achromatic perimetry (P < 0.0001). CONCLUSION Both HRT and OCT can differentiate glaucomatous from nonglaucomatous eyes. RNFL thickness measurements using OCT correspond to disc topographic parameters using HRT.

A Randomized Trial of Brimonidine Versus Timolol in Preserving Visual Function: Results From the Low-pressure Glaucoma Treatment Study

PURPOSE To compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma. DESIGN Randomized, double-masked, multicenter clinical trial. METHODS Exclusion criteria included untreated intraocular pressure (IOP) >21 mm Hg, visual field mean deviation worse than -16 decibels, or contraindications to study medications. Both eyes received twice-daily monotherapy randomized in blocks of 7 (4 brimonidine to 3 timolol). Standard automated perimetry and tonometry were performed at 4-month intervals. Main outcome measure was field progression in either eye, defined as the same 3 or more points with a negative slope ≥-1 dB/year at P<5%, on 3 consecutive tests, assessed by pointwise linear regression. Secondary outcome measures were progression based on glaucoma change probability maps (GCPM) of pattern deviation and the 3-omitting method for pointwise linear regression. RESULTS Ninety-nine patients were randomized to brimonidine and 79 to timolol. Mean (± SE) months of follow-up for all patients was 30.0 ± 2. Statistically fewer brimonidine-treated patients (9, 9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (31, 39.2%, log-rank 12.4, P=.001). Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. More brimonidine-treated (28, 28.3%) than timolol-treated (9, 11.4%) patients discontinued study participation because of drug-related adverse events (P=.008). Similar differences in progression were observed when analyzed by GCPM and the 3-omitting method. CONCLUSION Low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%.

Enhanced Depth Imaging Optical Coherence Tomography of Deep Optic Nerve Complex Structures in Glaucoma

OBJECTIVE To assess the usefulness of enhanced depth imaging (EDI) optical coherence tomography (OCT) for evaluating deep structures of the optic nerve complex (ONC; optic nerve head and peripapillary structures) in glaucoma. DESIGN Prospective, observational study. PARTICIPANTS Seventy-three established glaucoma patients (139 eyes) with a range of glaucomatous damage. METHODS Serial horizontal and vertical EDI OCT images of the ONC were obtained from both eyes of each participant. Deep ONC structures, including the lamina cribrosa (LC), short posterior ciliary artery (SPCA), central retinal artery (CRA), central retinal vein (CRV), peripapillary choroid and sclera, and subarachnoid space around the optic nerve, were investigated for their visibility and morphologic features. MAIN OUTCOME MEASURES Deep ONC structures identified in EDI OCT images. RESULTS Visual field mean deviation of 139 included eyes was -11.8 ± 8.6 dB (range, -28.70 to -2.01 dB). The anterior laminar surface was identified in all eyes in the central laminar area and in 91 (65%) eyes in the periphery beneath the neuroretinal and scleral rims or vascular structures. The LC pores with various shapes and sizes were visualized in 106 (76%) eyes, mainly in the central and temporal areas of the LC. Localized LC lesions seen on optic disc photographs were identified as focal LC defects (partial loss of LC tissue) in the EDI OCT images. The locations of the CRA and CRV were identified in all eyes. In the LC, the CRA maintained a straight shape with a consistent caliber, but the CRV (and tributaries) assumed a more irregular shape. The SPCAs, their branches through the emissary canals in the sclera, or both were visualized in 120 (86%) eyes. The subarachnoid space around the optic nerve was identified with varying degrees of clarity in 25 eyes (18%): 17 had high myopia and extensive parapapillary atrophy. Intrachoroidal cavitation or choroidal schisis, which had been unrecognized clinically, was identified in 2 eyes (1%) with high myopia. CONCLUSIONS Enhanced depth imaging OCT was able to visualize a wide variety of deep ONC structures in glaucoma patients and may be helpful in detecting, conceptualizing, and understanding basic and complicated in vivo anatomic and pathologic features of the ONC in glaucoma. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Increasing Sampling Density Improves Reproducibility of Optical Coherence Tomography Measurements

PURPOSE Published series of peripapillary retinal nerve fiber layer (RNFL) measurements using optical coherence tomography (OCT) have sampled 100 evenly distributed points on a 360 degrees peripapillary circular scan. The goal of this study was to determine whether a four-fold increase in sampling density improves the reproducibility of OCT measurements. METHODS Complete ophthalmic examinations, achromatic automated perimetry, and OCT imaging were performed in all patients. The OCT scanning consisted of three superior and inferior quadrantic scans (100 sampling points/quadrant) and three circular scans (25 points/quadrant). The RNFL thickness measurements and coefficient of variation (CV) were calculated for the superior and inferior quadrants for each sampling density technique. RESULTS The study included 22 eyes of 22 patients (3 control subjects; 2 patients with ocular hypertension; and 17 patients with glaucoma). Quadrants with associated glaucomatous visual field loss on automated achromatic perimetry had thinner RNFLs than quadrants without functional defects for both the 25- and 100-points/quadrant scans. For quadrants associated with normal visual hemifields (n = 22), there was no difference between the 25- and 100-points/quadrant scans in mean RNFL thickness and CV. Among quadrants with visual field defects (n = 22), RNFL thickness measurements were thinner in the 25-points/quadrant scans than in the 100-points/quadrant scans. The CV for the 25-points/quadrant scans (25.9%) was significantly higher than that for the 100-points/quadrant scans (11.9%). CONCLUSION Increasing the sampling density of OCT scans provides less variable representation of RNFL thickness. The optimal sampling density to achieve maximal reliability of OCT scans remains to be determined.

Reproducibility of Retinal Thickness Measurements in Normal Eyes Using Optical Coherence Tomography

BACKGROUND AND OBJECTIVE To determine the reproducibility of retinal thickness measurements in normal eyes using optical coherence tomography (OCT). PATIENTS AND METHODS Multiple 3.20-mm vertical cross-sectional images through the center of fixation of consecutive patients with normal results on ocular examinations were obtained. Each image was divided into seven 320-micron segments. Regional retinal thicknesses for each section were measured using both the manually assisted (requiring observer localization of reflectivity peaks) and the automated modes (observer-independent measurement) of the computer software. RESULTS Eighteen right eyes were studied. The mean coefficient of variation was less than 10% for all locations using the manually assisted method (average standard deviation less than 17 microns [range 9 to 16 microns]). The automated method was less reliable, with a coefficient of variation greater than 10% for locations within 500 microns of fixation. Automated measurements at fixation were the least reproducible because of poor internal limiting membrane reflectivity. CONCLUSION OCT is capable of reproducible measurement of retinal thickness in normal eyes. Computer-driven, automated measurement of retinal thickness within 500 microns of fixation needs to be refined and its reproducibility reassessed in this region.

The African descent and glaucoma evaluation study (ADAGES): Design and baseline data

OBJECTIVE To identify factors accounting for differences in glaucoma onset and rate of progression between individuals of African descent and European descent. DESIGN A prospective, multicenter observational cohort study of 1221 participants of African descent and European descent with no glaucoma (normal), suspected glaucoma, and glaucoma. Six hundred eighty-six patient participants in the African Descent and Glaucoma Evaluation Study will be followed up longitudinally. Four hundred thirty-six participants of European descent from the Diagnostic Innovations in Glaucoma Study (DIGS) were also included. Baseline demographics, visual function (standard automated perimetry, short-wavelength automated perimetry, frequency doubling technology perimetry), optic nerve structure (retina tomography, optical coherence tomography), clinical status, and risk factors were measured. RESULTS Individuals of African descent had (1) thinner corneas (P < .001) across all diagnostic groups, (2) a higher percentage of reported diabetes mellitus (P < .001) and high blood pressure (P < .001) and a lower percentage of reported heart disease (P = .001), and (3) worse pattern standard deviation for standard automated perimetry fields overall (P = .001) and within normal limits (P = .01) than individuals of European descent. No differences were present for mean intraocular pressure (P = .79). CONCLUSIONS Significant baseline differences were found in a number of clinical findings between persons of African descent compared with European descent. Longitudinal data from the African Descent and Glaucoma Evaluation Study will be important for determining which baseline features are important and predictive for accurate diagnosis and follow-up in this high-risk group. Trial Registration clinicaltrials.gov Identifier: NCT00221923.

Plasma homocysteine is elevated in patients with exfoliation syndrome

PURPOSE To compare plasma homocysteine concentrations among patients with exfoliation syndrome, exfoliative glaucoma, normal-tension glaucoma, and normal control subjects without vascular or inflammatory ocular disease or glaucoma. DESIGN Cross-sectional study. METHODS We tested 25 patients with exfoliation syndrome, 50 with exfoliative glaucoma, 25 with normal-tension glaucoma, and 24 control subjects. Fasting plasma homocysteine concentrations were measured by fluorescence polarization immunoassay. Patients using vitamin supplements or medications known to alter serum homocysteine were excluded. RESULTS Homocysteine levels were higher in both exfoliatin groups compared with controls (exfoliation syndrome: P =.003; exfoliative glaucoma: P =.009); levels in normal-tension glaucoma were higher than but not significantly different from those in controls (P =.2). Hyperhomocysteinemia was present in 16 of 25 (64%) exfoliation syndrome patients, 28 of 50 (56%) exfoliative glaucoma patients, 13 of 25 (52%) normal-tension glaucoma patients, and 7 of 24 (29.2%) controls (P =.005). Multiple logistic regression analyses comparing exfoliation syndrome and exfoliative glaucoma patients with controls indicated that elevated plasma homocysteine concentration was a significant risk factor for exfoliation syndrome, in both those patients (odds ratios per 1.0 micromol/l increase in plasma homocysteine concentrations = 1.47; 95% confidence interval [CI] = 1.08-2.0) and in exfoliative glaucoma patients (odds ratio = 1.3; 95% CI = 1.07-1.6). Although exfoliative glaucoma and normal-tension glaucoma patients were not significantly different with respect to hyperhomocysteinemia, logistic regression modeling of exfoliative glaucoma vs normal-tension glaucoma patients showed that an increased homocysteine concentration was a significant risk factor for exfoliation syndrome in the presence of glaucoma (odds ratio per 1.0 micromol/l increase in homocysteine = 1.2, 95% CI = 1.0-1.4). These relationships were not affected by adjustment for potential confounding due to sex, history of hypertension, or other factors. RESULTS Elevated plasma homocysteine, a risk factor for cardiovascular disease, is more common in exfoliation syndrome and exfoliative glaucoma patients than healthy controls. Patients with exfoliation syndrome may benefit from measurement of homocysteine levels.