Young H. Kwon

Primary Open-Angle Glaucoma

Glaucoma is one of the leading causes of blindness worldwide. This review discusses the clinical features, genetics, molecular biology, and cell biology of glaucoma. The authors present a typical case of glaucoma, together with the ocular findings.

Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma.

PURPOSE To evaluate long-term visual field outcome in primary open-angle glaucoma. METHODS In this retrospective cohort study, 40 eyes of 40 patients with primary open-angle glaucoma with elevated intraocular pressure and a minimum of 8-year longitudinal series of visual fields were plotted with Goldmann perimeter. Eyes with any other ocular disease except cataract were excluded. Manual grid templates were used to quantify the visual fields. Linear regression was performed to estimate the rate of visual field decline. Pertinent clinical factors were evaluated for statistical association with the rate of decline. Long-term clinical outcome including visual acuity, rate of legal blindness, and rate of medical and surgical interventions was also measured. RESULTS In the 40 eyes studied, with a mean follow-up of 14 years, the visual field score decreased at the rate of -1.5% per year. Overall, 68% showed significant decrease, and the rate of decrease among these eyes was -2.1% per year. Five eyes became legally blind from glaucoma; the cumulative rate of blindness from glaucoma was 19% at 22 years. Higher intraocular pressure and greater number of antiglaucoma medications on initial presentation were associated with faster and slower deterioration of visual field (compared with the average), respectively. CONCLUSIONS With standard glaucoma therapy, the rate of visual field loss in primary open-angle glaucoma is slow. Lower intraocular pressure and more antiglaucoma medications are associated with slower visual field decline. Legal blindness from glaucoma is 19% over a follow-up of 22 years.

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma

PURPOSE To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN Prospective case control study. METHODS The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Segmentation of the Optic Disc in 3-D OCT Scans of the Optic Nerve Head

Glaucoma is the second leading ocular disease causing blindness due to gradual damage to the optic nerve and resultant visual field loss. Segmentations of the optic disc cup and neuroretinal rim can provide important parameters for detecting and tracking this disease. The purpose of this study is to describe and evaluate a method that can automatically segment the optic disc cup and rim in spectral-domain 3-D OCT (SD-OCT) volumes. Four intraretinal surfaces were segmented using a fast multiscale 3-D graph search algorithm. After surface segmentation, the retina in each 3-D OCT scan was flattened to ensure a consistent optic nerve head shape. A set of 15 features, derived from the segmented intraretinal surfaces and voxel intensities in the SD-OCT volume, were used to train a classifier that can determine which A-scans in the OCT volume belong to the background, optic disc cup and rim. Finally, prior knowledge about the shapes of the cup and rim was incorporated into the system using a convex hull-based approach. Two glaucoma experts annotated the cup and rim area using planimetry, and the annotations of the first expert were used as the reference standard. A leave-one-subject-out experiment on 27 optic nerve head-centered OCT volumes (14 right eye scans and 13 left eye scans from 14 patients) was performed. Two different types of classification methods were compared, and experimental results showed that the best performing method had an unsigned error for the optic disc cup of 2.52 ? 0.87 pixels (0.076 ? 0.026 mm) and for the neuroretinal rim of 2.04 ? 0.86 pixels (0.061 ? 0.026 mm). The interobserver variability as indicated by the unsigned border positioning difference between the second expert observer and the reference standard was 2.54 ? 1.03 pixels (0.076 ? 0.031 mm for the optic disc cup and 2.14 ? 0.80 pixels (0.064 ? 0.024 mm for the neuroretinal rim. The unsigned error of the best performing method was not significantly different (p > 0.2) from the interobserver variability.

Copy number variations on chromosome 12q14 in patients with normal tension glaucoma

We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reaction (PCR) experiments identified a 780 kbp duplication within the GLC1P locus that is co-inherited with NTG in the pedigree. Real-time PCR studies showed that the genes within this duplication [TBK1 (TANK-binding kinase 1), XPOT, RASSF3 and GNS] are all expressed in the human retina. Cohorts of 478 glaucoma patients (including 152 NTG patients), 100 normal control subjects and 400 age-related macular degeneration patients were subsequently tested for copy number variation in GLC1P. Overlapping duplications were detected in 2 (1.3%) of the 152 NTG subjects, one of which had a strong family history of glaucoma. These duplications defined a 300 kbp critical region of GLC1P that spans two genes (TBK1 and XPOT). Microarray expression experiments and northern blot analysis using RNA obtained from human skin fibroblast cells showed that duplication of chromosome 12q14 results in increased TBK1 and GNS transcription. Finally, immunohistochemistry studies showed that TBK1 is expressed in the ganglion cells, nerve fiber layer and microvasculature of the human retina. Together, these data link the duplication of genes on chromosome 12q14 with familial NTG and suggest that an extra copy of the encompassed TBK1 gene is likely responsible for these cases of glaucoma. However, animal studies will be necessary to rule out a role for the other duplicated or neighboring genes.

Long-term results of eyes with penetrating keratoplasty and glaucoma drainage tube implant.

PURPOSE To present long-term results of eyes with penetrating keratoplasty (PK) and glaucoma tube implant. DESIGN Retrospective, noncomparative, interventional case series. PARTICIPANTS We retrospectively reviewed medical records of all patients who underwent both PK and glaucoma tube implant (Baerveldt or Ahmed) at the University of Iowa between July of 1988 and December of 1997 (55 eyes). METHODS Success of the tube implant or PK was evaluated using Kaplan-Meier survival analysis. Association of relevant clinical factors with glaucoma or corneal graft outcome was evaluated using log-rank test or Cox proportional hazard regression analysis. The factors evaluated were glaucoma and cornea diagnoses; prior, simultaneous, and subsequent surgeries; type of tube implant; relative timing of surgeries; and postsurgical complications. MAIN OUTCOME MEASURES Glaucoma outcome was assessed by postoperative intraocular pressure (IOP), number of medications, and need for further glaucoma surgery. Corneal outcome was assessed by graft rejection, failure, and Snellen visual acuity. Surgical procedures before and during the study period, and their complications were evaluated. RESULTS The mean preoperative intraocular pressure was 29.8 mmHg with an average of 2.9 medications. At last postoperative follow-up, the mean IOP decreased to 14.3 mmHg with 0.7 medication. The tube implant successfully controlled glaucoma in 45 eyes (82%) at 3 years. More severe postsurgical complications were associated with greater glaucoma failure. Graft rejection occurred in 17 eyes, and 7 of these progressed to failure. Nonimmunologic graft failure occurred in an additional 17 eyes (31%). The remaining 31 eyes (56%) had a clear graft. The corneal grafts remained clear in 70% and 55% of eyes at 2 and 3 years, respectively. Corneal graft failure was associated with glaucoma and cornea diagnoses groups, type of tube implant, and relative timing of the two surgeries. Complications occurred in 23 eyes (42%), and 10 of these were serious. CONCLUSIONS A drainage tube implant can successfully control glaucoma in a majority (82%) of keratoplasty eyes at 3 years. However, the success of corneal grafts is low (55%) at 3 years. Postsurgical complications are not uncommon and are associated with poor glaucoma outcome. Other clinical factors are associated with poor graft outcome.

Novel drug delivery systems for glaucoma

Reduction of intraocular pressure (IOP) by pharmaceutical or surgical means has long been the standard treatment for glaucoma. A number of excellent drugs are available that are effective in reducing IOP. These drugs are typically applied as eye drops. However, patient adherence can be poor, thus reducing the clinical efficacy of the drugs. Several novel delivery systems designed to address the issue of adherence and to ensure consistent reduction of IOP are currently under development. These delivery systems include contact lenses-releasing glaucoma medications, injectables such as biodegradable micro- and nanoparticles, and surgically implanted systems. These new technologies are aimed at increasing clinical efficacy by offering multiple delivery options and are capable of managing IOP for several months. There is also a desire to have complementary neuroprotective approaches for those who continue to show progression, despite IOP reduction. Many potential neuroprotective agents are not suitable for traditional oral or drop formulations. Their potential is dependent on developing suitable delivery systems that can provide the drugs in a sustained, local manner to the retina and optic nerve. Drug delivery systems have the potential to improve patient adherence, reduce side effects, increase efficacy, and ultimately, preserve sight for glaucoma patients. In this review, we discuss benefits and limitations of the current systems of delivery and application, as well as those on the horizon.

Digital stereo image analyzer for generating automated 3-D measures of optic disc deformation in glaucoma

The major limitations of precise evaluation of retinal structures in present clinical situations are the lack of standardization, the inherent subjectivity involved in the interpretation of retinal images, and intra- as well as interobserver variability. While evaluating optic disc deformation in glaucoma, these limitations could be overcome by using advanced digital image analysis techniques to generate precise metrics; from stereo optic disc image pairs. A digital stereovision system for visualizing the topography of the optic nerve head from stereo optic disc images is presented. We have developed an algorithm, combining power cepstrum and zero-mean-normalized cross correlation techniques, which extracts depth information using coarse-to-fine disparity between corresponding windows in a stereo pair. The gray level encoded sparse disparity matrix is subjected to a cubic B-spline operation to generate smooth representations of the optic cup/disc surfaces and new three-dimensional (3-D) metrics from isodisparity contours. Despite the challenges involved in 3-D surface recovery, the robustness of our algorithm in finding disparities within the constraints used has been validated using stereo pairs with known disparities. In a preliminary longitudinal study of glaucoma patients, a strong correlation is found between the computer-generated quantitative cup/disc volume metrics and manual metrics commonly used in a clinic. The computer generated new metrics, however, eliminate the subjective variability and greatly reduce the time and cost involved in manual metric generation in follow-up studies of glaucoma.

Automated Segmentation of the Cup and Rim from Spectral Domain OCT of the Optic Nerve Head

PURPOSE To evaluate the performance of an automated algorithm for determination of the cup and rim from close-to-isotropic spectral domain (SD) OCT images of the optic nerve head (ONH) and compare to the cup and rim as determined by glaucoma experts from stereo color photographs of the same eye. METHODS Thirty-four consecutive patients with glaucoma were included in the study, and the ONH in the left eye was imaged with SD-OCT and stereo color photography on the same day. The cup and rim were segmented in all ONH OCT volumes by a novel voxel column classification algorithm, and linear cup-to-disc (c/d) ratio was determined. Three fellowship-trained glaucoma specialists performed planimetry on the stereo color photographs, and c/d was also determined. The primary outcome measure was the correlation between algorithm-determined c/d and planimetry-derived c/d. RESULTS The correlation of algorithm c/d to experts 1, 2, and 3 was 0.90, 0.87, and 0.93, respectively. The c/d correlation of expert 1 to 2, 1 to 3, and 2 to 3, were 0.89, 0.93, and 0.88, respectively. CONCLUSIONS In this preliminary study, we have developed a novel algorithm to determine the cup and rim in close-to-isotropic SD-OCT images of the ONH and have shown that its performance for determination of the cup and rim from SD-OCT images is similar to that of planimetry by glaucoma experts. Validation on a larger glaucoma sample as well as normal controls is warranted.

Apparent central nervous system depression in infants after the use of topical brimonidine

PURPOSE To report two cases in which topical brimonidine resulted in apparent central nervous system depression and unresponsiveness in an infant. METHODS Review of two patients. An 11-day-old infant became lethargic and apneic after a single drop of brimonidine. These symptoms were reproduced after a second administration of brimonidine. A 5-month-old infant became lethargic and poorly responsive after receiving 1 drop of brimonidine in each eye. RESULTS The first patient required admission to the hospital for medical stabilization. He recovered without sequelae. The second patient recovered spontaneously approximately 2.5 hours after administration of brimonidine. CONCLUSIONS Topical brimonidine may be associated with central nervous system depression in infants. The use of brimonidine is not recommended in these patients until further data are available.