The number of people with glaucoma worldwide in 2010 and 2020.

AIM: To estimate the number of people with open angle (OAG) and angle closure glaucoma (ACG) in 2010 and 2020. METHODS: A review of published data with use of prevalence models. Data from population based studies of age specific prevalence of OAG and ACG that satisfied standard definitions were used to construct prevalence models for OAG and ACG by age, sex, and ethnicity, weighting data proportional to sample size of each study. Models were combined with UN world population projections for 2010 and 2020 to derive the estimated number with glaucoma. RESULTS: There will be 60.5 million people with OAG and ACG in 2010, increasing to 79.6 million by 2020, and of these, 74% will have OAG. Women will comprise 55% of OAG, 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 87% of those with ACG. Bilateral blindness will be present in 4.5 million people with OAG and 3.9 million people with ACG in 2010, rising to 5.9 and 5.3 million people in 2020, respectively. CONCLUSIONS: Glaucoma is the second leading cause of blindness worldwide, disproportionately affecting women and Asians.

New paradigms in the mechanisms and management of glaucoma.

During the last 30 years, the definition of glaucoma as been revised to eliminate the inclusion of intraocular pressure. Open angle glaucoma is the second leading cause of blindness in the world, but the proportion of those with the disease who become blind is low. Diagnostic methods for glaucoma need improvement. The pathogenetic steps to loss of neurons in glaucoma are increasingly understood and non-pressure lowering therapies are on the horizon.

Gene therapy for optic nerve disease.

PURPOSE: There has been recent interest in the potential use of gene therapy techniques to treat ocular disease. In this article, we consider the optic nerve diseases that are potentially most amenable to gene therapy. METHODS: We discuss the recent success of gene transfer experiments in animal models of glaucoma, optic neuritis, Leber's hereditary optic neuropathy (LHON), and optic nerve transection, and we assess the possibility of using similar techniques to treat human disease in the future. RESULTS: We have achieved highly efficient transfection of retinal ganglion cells in a rat model of glaucoma following a single intravitreal injection of adeno-associated virus (AAV). In our model, we have found that AAV-mediated gene therapy with brain-derived neurotrophic factor has a significant neuroprotective effect compared to saline or control virus injections. Guy and co-workers have successfully used AAV-mediated gene therapy to replace the defective mitochondrial enzyme subunit in cells derived from human patients with LHON. Gene therapy techniques have also shown promise in animal models of optic neuritis and optic nerve trauma. CONCLUSIONS: Human diseases with single-gene defects such as LHON may soon be treated successfully by gene therapy, assuming that vectors continue to improve and are well tolerated in the human eye. Other optic nerve diseases such as glaucoma that do not have a single-gene defect may also benefit from gene therapy to enhance RGC survival. In all cases, the risks of treatment will need to be balanced against the potential benefits.

Stem cells to replace the optic nerve.

Methods that exist now and that might be developed are suggested to replace retinal ganglion cells and their axons in the optic nerve, ultimately to re-establish functional vision in eyes blind from glaucoma.

The prevalence of glaucoma in a population-based study of Hispanic subjects: Proyecto VER.

OBJECTIVE: To determine the prevalence of glaucoma in a population-based sample of Hispanic adults older than 40 years. METHODS: Using 1990 census data for Arizona, groups of persons living in sections of the city in Nogales and Tucson were randomly selected with a probability proportional to the Hispanic population older than 40 years. We tried to recruit all eligible adults in homes with 1 self-described Hispanic adult. Detailed ocular examinations at a local clinic included visual acuity testing, applanation tonometry, gonioscopy, an optic disc evaluation, and a threshold visual field test. Open-angle glaucoma (OAG) was defined using a proposed international system for prevalence surveys, including threshold visual field defect and optic disc damage. Angle-closure glaucoma was defined as bilateral appositional angle closure, combined with optic nerve damage (judged by field and disc as for OAG). RESULTS: Examinations were conducted in 72% (4774/6658) of eligible persons, with a 1.97% prevalence (95% confidence interval, 1.58%-2.36%) of OAG (94 persons). The age-specific OAG prevalence increased nonlinearly from 0.50% in those aged 41 to 49 years to 12.63% in those 80 years and older. Angle-closure glaucoma was detected in 5 persons (0.10%). Sex, blood pressure, and cigarette smoking were not significant OAG risk factors. Only 36 (38%) of the 94 persons with OAG were aware of their OAG before the study. Screening results with an intraocular pressure higher than 22 mm Hg (in the eye with a higher pressure) would miss 80% of the OAG cases. CONCLUSIONS: The prevalence of OAG in Hispanic persons was intermediate between reported values for white and black persons. The prevalence increased more quickly with increasing age than in other ethnic groups. Glaucoma was the leading cause of bilateral blindness.

Quantification of optic nerve axon loss associated with a relative afferent pupillary defect in the monkey.

OBJECTIVE: To quantify the amount of optic nerve axonal loss associated with the presence of a mild relative afferent pupillary defect (RAPD) in an experimental monkey model. METHODS: The right macula of 5 rhesus monkeys (Macaca mulatta) was treated with concentrically enlarging diode laser burns until an RAPD was detected using a transilluminator light and measured with neutral density filters. Intervals between treatments were 3 to 7 days over a period of 2 months. Pupillary responses to light stimulation were recorded with a monocular infrared television pupillometer. Two months after detection of an RAPD, 5 treated and 4 control monkeys underwent euthanasia and enucleation. Histopathologic analysis and quantification of optic nerve axon counts using an image analysis system were performed. RESULTS: No RAPD was observed despite an estimated ganglion cell loss of up to 26%. A 0.6 log unit RAPD was present in 5 monkeys when the laser scar incorporated the entire macula within the temporal vascular arcades. One eye had progressive vitreomacular traction with worsening of the RAPD to 1.8 log units without further laser treatment. Histopathologic evaluation disclosed complete loss of the normal retinal architecture within the macula. The average fiber loss for the 4 treated eyes with 0.6 log unit RAPDs compared with fellow eyes was 53.3% (95% confidence interval [CI], 45.0%-61.6%). The average difference in axon counts between untreated pairs of optic nerves was 12.8% (95% CI, 10.0%-15.6%). Optic nerve axon loss between pairs of experimental and control eyes was statistically significant (P<.001). CONCLUSION: In rhesus monkeys, an RAPD develops after an approximate unilateral loss between 25% and 50% of retinal ganglion cells. CLINICAL RELEVANCE: Owing to redundancy in the anterior visual pathways, unilateral retinal ganglion cell loss may occur prior to the observation of an RAPD. The presence of an RAPD measuring 0.6 log units implies that significant retinal ganglion cell injury has occurred.

Risk factors for late-onset infection following glaucoma filtration surgery.

OBJECTIVE: To determine the risk factors for late-onset infection following glaucoma filtration surgery. METHODS: We performed a case-control study comparing 131 cases of late-onset infection collected from 27 surgeons at 10 centers with 500 controls matched for date of surgery and surgeon. The criterion for the presence of infection was severe anterior chamber reaction occurring later than 4 weeks after surgery. An opaque bleb and positive culture results were not required for diagnosis. Risk factors were identified by univariate and multivariate logistic regression analyses. RESULTS: Some of the risk factors that were statistically significant in the multivariate model after adjusting for age, race, and sex were (1) performance of a full-thickness rather than a guarded procedure (risk ratio [RR], 13.1; 95% confidence interval [CI], 2.12-80.9), (2) filtration surgery performed without concurrent cataract surgery (RR, 2.25; 95% CI, 1.24-4.08), (3) use of mitomycin (RR, 2.48; 95% CI, 1.06-5.83), (4) intermittent use of antibiotics after surgery (RR, 2.10; 95% CI, 1.09-4.02), and (5) continuous use of antibiotics after surgery (RR, 5.94; 95% CI, 2.09-16.9). CONCLUSIONS: Eyes undergoing full-thickness procedures or filtration surgery without cataract extraction are at increased risk for late infection. Intraoperative mitomycin and episodic or continuous antibiotic use after the postoperative period are associated with an increased risk of infection.

Diagnostic capabilities of frequency-doubling technology, scanning laser polarimetry, and nerve fiber layer photographs to distinguish glaucomatous damage.

PURPOSE: To investigate the ability of three diagnostic tests: frequency-doubling technology (FDT), scanning laser polarimetry (GDx), and nerve fiber layer (NFL) photographs to distinguish normal from glaucomatous eyes. METHODS: Data were obtained in a cross-sectional, hospital clinic-based study, including one eye from each of 253 persons older than 40 years (68 normal, 94 glaucoma suspects and 91 glaucoma patients). We performed a comprehensive ocular examination, as well as static automated perimetry (Humphrey 24-2), screening FDT, GDx, optic nerve stereoscopic photographs and high-contrast NFL photographs. RESULTS: The following were significantly different for glaucomatous patients compared with suspects and normals: mean values of mean deviation (MD, Humphrey 24-2) and corrected pattern standard deviation (CPSD), 11 GDx indices, mean FDT testing time and missed points, and NFL graded defects (ANOVA, Mantel-Haenszel test; p = 0.0001). Using Humphrey 24-2 test results and clinical assessment as the defining features of glaucoma, we found that the optimal mix of sensitivity and specificity values were 84% and 100% for FDT (presence of any defect); 62% and 96% for GDx (The Number, cut-off value of 27); and, 95% and 82% for NFL photographs (presence of any abnormality). FDT testing took the least time to be administered. CONCLUSIONS: The FDT had the best diagnostic performance. Neural network analysis of GDx data outperformed other elements of its software.

Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells.

PURPOSE: Interest in neuroprotection for optic neuropathies is, in part, based on the assumption that retinal ganglion cells (RGCs) die, not only as a result of direct (primary) injury, but also indirectly as a result of negative effects from neighboring dying RGCs (secondary degeneration). This experiment was designed to test whether secondary RGC degeneration occurs after orbital optic nerve injury in monkeys. METHODS: The superior one third of the orbital optic nerve on one side was transected in eight cynomolgus monkeys (Macaca fascicularis). Twelve weeks after the partial transection, the number of RGC bodies in the superior and inferior halves of the retina of the experimental and control eyes and the number and diameter of axons in the optic nerve were compared by detailed histomorphometry. Vitreous was obtained for amino acid analysis. A sham operation was performed in three additional monkeys. RESULTS: Transection caused loss of 55% +/- 13% of RGC bodies in the superior retina of experimental compared with fellow control eyes (mean +/- SD, t-test, P < 0.00,001, n = 7). Inferior RGCs, not directly injured by transection, decreased by 22% +/- 10% (P = 0.002). The loss of superior optic nerve axons was 83% +/- 12% (mean +/- SD, t-test, P = 0.0008, n = 5) whereas, the inferior loss was 34% +/- 20% (P = 0.02, n = 5). Intravitreal levels of glutamate and other amino acids in eyes with transected nerves were not different from levels in control eyes 12 weeks after injury. Fundus examination, fluorescein angiography, and histologic evaluation confirmed that there was no vascular compromise to retinal tissues by the transection procedure. CONCLUSIONS: This experiment suggests that primary RGC death due to optic nerve injury is associated with secondary death of surrounding RGCs that are not directly injured.

Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats.

PURPOSE: To determine whether acute experimental glaucoma in rats obstructs retrograde transport of brain-derived neurotrophic factor (BDNF) to retinal ganglion cells (RGCs). METHODS: Forty rats had unilateral injection of either (125)I-BDNF (20 animals) or a mixture of (125)I-BDNF and 100-fold excess nonradiolabeled BDNF (20 animals). In each group of 20 animals, eyes contralateral to injection had either normal intraocular pressure (IOP; 10 animals) or IOP elevated to 25 mm Hg below the systolic blood pressure of the eye (10 animals). In each group of 20 rats, ipsilateral eyes had IOP set at systolic blood pressure (4 eyes), had optic nerve transection (10 eyes), or had normal IOP (6 eyes). Six hours after injection, animals were killed and tissues were fixed, embedded, and sectioned for autoradiography. Grain counts were performed over retina and optic nerve using automated image analysis. RESULTS: IOP elevation to 25 mm Hg below systolic blood pressure (perfusion pressure [PP] 25) decreased median retinal nerve fiber layer (NFL) grains by 38% compared with controls (P: < 0.001). Competition by cold BDNF reduced NFL grains by 28% (P: = 0.013). Considering only the radioactivity representing specific retrograde transport of BDNF, IOP elevation to PP25 reduced transport by 74%, whereas elevation to PP0 (equaling systolic blood pressure) reduced specific transport by 83%. CONCLUSIONS: BDNF is transported retrogradely from the superior colliculus in adult rats, and this transport is substantially inhibited by acute IOP elevation. Deprivation of BDNF among RGCs may contribute to neuron loss in glaucoma.

Long term results of glaucoma surgery among participants in an east African population survey.

AIM: To evaluate the long term results of glaucoma surgery among people in East Africa. METHODS: Participants in a population based survey of eye disease prevalence were offered glaucoma surgery using standardised criteria. Either surgical iridectomy or trabeculectomy was carried out as indicated by a medical officer or by one of two ophthalmologists. Trabeculectomy methods included releasable sutures and mitomycin C in the majority of eyes. Subjects were examined during the first week and 2 months after surgery. Nearly 3 years later, re-examination was carried out in those who were still resident in the region. RESULTS: Among 46 people who were offered iridectomy, trabeculectomy, or combined cataract extraction/lens implant/trabeculectomy, 21 people underwent surgery (46%). Of the 21, 19 were re-examined at 3 years (90%), including 16/18 eyes after trabeculectomy. Among these, intraocular pressure (IOP) declined from 29.9 (SD 9.4) mm Hg to 14.7 (5.9) mm Hg, with 16 of 18 eyes (89%) achieving a reduction > 25%. Hypotony maculopathy, late bleb leak, and late endophthalmitis were not detected. Visually significant cataract developed in 5/15 re-examined eyes that underwent trabeculectomy alone (33%), possibly associated with pre-existing cataract and diagnosis of angle closure glaucoma, but not with mitomycin C use. CONCLUSIONS: Nearly half of those with glaucoma among residents of rural African villages accepted the offer of surgical therapy. While technical success was achieved at satisfactory levels, the development of cataract must be considered an important issue for application of glaucoma surgical therapy programmes.

Causes of blindness and visual impairment in a population of older Americans: The Salisbury Eye Evaluation Study.

OBJECTIVE: To determine the causes of blindness and visual impairment in a population-based sample of older Americans. METHODS: A random sample of 3821 residents of Salisbury, Md, between the ages of 65 and 84 years was identified from Medicare records. Sixty-six percent (2520 persons) agreed to undergo an eye examination; 26% of the participants were African American. The clinical examination included acuity testing with an Early Treatment Diabetic Retinopathy Study chart and standardized refraction testing for those with a visual acuity worse than 20/30, slitlamp and dilated retinal examination by an ophthalmologist, tonometry, lens and fundus photography, and a suprathreshold visual field test. Visual impairment was defined as a best-corrected acuity in the better-seeing eye worse than 20/40 and better than 20/200, while blindness was acuity in the better-seeing eye of 20/200 or worse. For those with a visual acuity worse than 20/40 in either eye, one or more causes were assigned by an ophthalmologist and a final cause for each eye was confirmed by a panel of 3 subspecialty ophthalmologists (O.D.S., H.A.Q., and S.B.B.) based on all available evidence. RESULTS: Bilateral presenting acuity worse than 20/40 increased from 4% in the 65- to 74-year age group to 16% in the 80- to 84-year age group. One third of those with presenting acuity worse than 20/40 improved to 20/40 or better with refraction. Overall, 4.5% had a best-corrected acuity worse than 20/40. African Americans were more likely to remain visually impaired than were whites despite refraction (odds ratio [95% confidence interval], 1.7 [1.1-2.6]). Whites were most often impaired or blind from age-related macular degeneration (1.2% vs 0.5%; P=.09). African Americans had higher rates of impairment and blindness from cataract or posterior capsular opacification (2.7% vs 1.1%; P=.006), glaucoma (0.9% vs 0.1%; P=.006), and diabetic retinopathy (1.2% vs 0.2%; P=. 004). CONCLUSIONS: More than half of those with visual impairment or blindness had conditions that were either surgically treatable or potentially preventable. African Americans had a disproportionate number of blinding diseases, particularly those amenable to eye care intervention. Targeted interventions for specific populations to increase appropriate eye care use would greatly improve vision and function in older Americans. Arch Ophthalmol. 2000;118:819-825

Bleb reduction and bleb repair after trabeculectomy.

OBJECTIVE: To describe methods and outcomes for repair of bleb-related complications of trabeculectomy surgery. DESIGN: Retrospective, consecutive, noncomparative case series. PARTICIPANTS: Thirty-one persons having bleb revision by two surgeons at the Wilmer Institute from 1994 to the present. INTERVENTION: One of two types of revision surgery was performed: bleb reduction to decrease symptoms from large blebs or bleb repair to improve hypotony, using conjunctival rotation flap or free conjunctival autograft. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure (IOP), reported symptoms, complications, and number of glaucoma medications at the final visit. RESULTS: The mean time from trabeculectomy to bleb revision was 4.4 years. Bleb reduction was performed because of symptomatic, high blebs in 11 eyes of 11 persons. Bleb repair was performed to end bleb leakage in 13 eyes of 13 persons and to increase IOP in 8 eyes of 7 persons with hypotony. Median visual acuity improved from 20/50 before revision to 20/30 at most recent follow-up. Mean IOP increased after treatment from 7.7+/-4.9 to 12.4+/-4.0 mmHg (P < 0.001). Symptoms that caused the revision surgery were eliminated in all cases. None of these eyes has lost IOP control, none has required repeat trabeculectomy, and only 2 of the 32 (6%) require topical glaucoma medication. More than one revision procedure was required in 8 of 32 (25%) eyes. CONCLUSIONS: Surgical bleb revisions for complications after trabeculectomy surgery are safe and effective. Bleb reduction for large, symptomatic blebs or bleb repair for leaking blebs and hypotony did not lead to loss of IOP control.

Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons.

PURPOSE: To compare the number of retinal ganglion cells (RGCs) topographically mapped with specific visual field threshold test data in the same eyes among glaucoma patients. METHODS: Seventeen eyes of 13 persons with well-documented glaucoma histories and Humphrey threshold visual field tests (San Leandro, CA) were obtained from eye banks. RGC number was estimated by histologic counts of retinal sections and by counts of remaining axons in the optic nerves. The locations of the retinal samples corresponded to specific test points in the visual field. The data for glaucoma patients were compared with 17 eyes of 17 persons who were group matched for age, had no ocular history, and had normal eyes by histologic examination. RESULTS: The mean RGC loss for the entire retina averaged 10.2%, indicating that many eyes had early glaucoma damage. RGC body loss averaged 35.7% in eyes with corrected pattern SD probability less than 0.5%. When upper to lower retina RGC counts were compared with their corresponding visual field data within each eye, a 5-dB loss in sensitivity was associated with 25% RGC loss. For individual points that were abnormal at a probability less than 0.5%, the mean RGC loss was 29%. In control eyes, the loss of RGCs with age was estimated as 7205 cells per year in persons between 55 and 95 years of age. In optic nerves from glaucoma subjects, smaller axons were significantly more likely to be present than larger axons (R2 = 0.78, P<0.001). CONCLUSIONS: At least 25% to 35% RGC loss is associated with statistical abnormalities in automated visual field testing. In addition, these data corroborate previous findings that RGCs with larger diameter axons preferentially die in glaucoma.

Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma.

PURPOSE: In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys. METHODS: Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus. RESULTS: With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes. CONCLUSIONS: Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.