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.     

Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma

The pathogenesis of normal (intraocular) pressure glaucoma has remained unclear so far. As hospital‐based studies showed an association of normal‐pressure glaucoma with low systemic blood pressure, particularly at night, and with vasospastic symptoms, it has been hypothesized that a vascular factor may play a primary role in the pathogenesis of normal‐pressure glaucoma. That assumption may, however, be contradicted by the morphology of the optic nerve head. Eyes with normal‐pressure glaucoma and glaucomatous eyes with high‐intraocular pressure can show a strikingly similar appearance of the optic nerve head, including a loss of neuroretinal rim, a deepening of the optic cup, and an enlargement of parapapillary atrophy. These features, however, are not found in any (other) vascular optic neuropathy, with the exception of an enlargement and deepening of the optic cup in arteritic anterior ischaemic optic neuropathy. One may additionally take into account (i) that it is the trans‐lamina cribrosa pressure difference (and not the trans‐corneal pressure difference, i.e. the so‐called intraocular pressure) which is of importance for the physiology and pathophysiology of the optic nerve head; (ii) that studies have shown that the anatomy of the optic nerve head including the intraocular pressure, the anatomy and biomechanics of the lamina cribrosa and peripapillary sclera, retrobulbar orbital cerebrospinal fluid pressure and the retrobulbar optic nerve tissue pressure may be of importance for the pathogenesis of the highly myopic type of chronic open‐angle glaucoma; (iii) that studies have suggested a physiological association between the pressure in all three fluid filled compartments, i.e. the systemic arterial blood pressure, the cerebrospinal fluid pressure and the intraocular pressure; (iv) that an experimental investigation suggested that a low cerebrospinal fluid pressure may play a role in the pathogenesis of normal (intraocular) pressure glaucoma; and (v) that recent clinical studies reported that patients with normal (intraocular) pressure glaucoma had significantly lower cerebrospinal fluid pressure and a higher trans‐lamina cribrosa pressure difference when compared to normal subjects. One may, therefore, postulate that a low cerebrospinal fluid pressure may be associated with normal (intraocular) pressure glaucoma. A low systemic blood pressure, particularly at night, could physiologically be associated with a low cerebrospinal fluid pressure, which leads to an abnormally high trans‐lamina cribrosa pressure difference and as such to a similar situation as if the cerebrospinal fluid pressure is normal and the intraocular pressure is elevated. This model could explain why patients with normal (intraocular) pressure glaucoma tend to have a low systemic blood pressure, and why eyes with normal (intraocular) pressure glaucoma and eyes with high‐pressure glaucoma, in contrast to eyes with a direct vascular optic neuropathy, show profound similarities in the appearance of the optic nerve head.     

Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head.

We studied the degree of axonal transport blockade in various areas of the optic nerve head with acute intraocular pressure (IOP) elevation in 19 squirrel monkey eyes. When IOP was raised to 20 to 50 mm. Hg for 7 hr., mild axonal transport blockade occurred in each area of the disk, most prominently in nerve fiber bundles of the superior pole. With 7 hr. IOP elevations between 50 and 90 mm. Hg, a somewhat greater degree of transport blockade occurred throughout the nerve head, although again the superior and inferior poles were somewhat more affected. The distribution of short-term transport blockade over the entire nerve head corresponds to the diffuse damage of acute glaucoma, but the pattern hints at the preference for damage near the poles of the disk seen in chronic glaucoma. However, before these results can be fully evaluated, further information is needed on axonal pathways through the optic nerve head and on the relationship between transport obstruction and ganglion cell death.     

Localised retinal nerve fibre layer defects in chronic experimental high pressure glaucoma in rhesus monkeys

AIM: To evaluate prospectively in an experimental model of chronic high pressure glaucoma whether the concept of a mainly diffuse pattern of optic nerve damage holds true for high pressure glaucoma. METHODS: The study comprised nine eyes of nine rhesus monkeys (Macaca mulatta) with a mean age of 17.7 (SD 3.1) years (range 13-23 years). Experimental glaucoma was produced by multiple applications of argon laser to the trabecular meshwork. Applanation tonometry was regularly performed and fundus photographs, which were taken serially, were used for retinal nerve fibre layer (RNFL) assessment and morphometric optic disc analysis. Six monkeys, in which arterial hypertension and atherosclerosis had additionally been induced several years before elevation of intraocular pressure, did not show any sign of diffuse loss or localised defects of the RNFL before initiation of glaucoma. RESULTS: Compared with the same eyes at baseline, localised RNFL defects had developed in eight (89%) eyes. It included all three eyes (100%) of the monkeys without arterial hypertension/arteriosclerosis, and five of the six monkeys (83%) with arterial hypertension/arteriosclerosis. Four eyes had multiple localised RNFL defects. In all eyes, diffuse RNFL loss was additionally present. CONCLUSIONS: Besides diffuse loss of RNFL, localised RNFL defects were present in almost all eyes of monkeys with chronic experimental high pressure glaucoma. Challenging the concept that a mostly diffuse type of optic neuropathy occurs in high pressure glaucoma, the results suggest that, in high pressure glaucoma, at least a mixture of localised and diffuse pattern of optic nerve damage prevails.     

The case for autoimmunity in glaucoma

Although the majority of patients with glaucoma have elevated intraocular pressure as the presumed etiology for their resultant neuropathy, it is well known that approximately 25% of patients with glaucoma have intraocular pressure within the normal range for their race. These patients may have conditions that facilitate non-pressure related stress to the retina and optic nerve that might directly contribute to their glaucomatous neuropathy and include chronic or intermittent ischemia (i.e atherosclerosis, heart disease, vasospasm, migraine, sleep apnea), altered scleral/optic nerve head morphology that predisposes to glaucomatous stress (i.e myopia); genetic mutations that predispose to glaucoma damage at normal IOP (OPA-1,optineurin, myocilin) and evidence of aberrant immunity that suggests that their glaucoma might be a form of an autoimmune neuropathy (i.e. presumed autoimmune glaucoma). This review provides a critical assessment of the potential role for autoimmunity as an initiating or exacerbating etiology in some patients with glaucoma.     

The Effect of Chronically Elevated Intraocular Pressure on the Rat Optic Nerve Head Extracellular Matrix

The extracellular matrix of the optic nerve head is altered in both human glaucoma and in experimental primate models of this disease. However, the relationship of this change to glaucomatous optic nerve degeneration is unknown. This report describes similar matrix alterations in rats with unilateral elevated intraocular pressure.Brown Norway rats received episcleral vein injections of hypertonic saline to produce prolonged elevations of intraocular pressure. After up to 6 months of pressure elevation, optic nerve head sections from the rats were evaluated by light microscopic immunohistochemistry using antibodies to collagens I, III, IV and VI, laminin, elastin and chondroitin and dermatan sulfate proteoglycans. In experimental eyes with 11 days or more of pressure elevation, depositions of collagen IV, collagen VI and laminin were found within regions of the optic nerve head that, in normal eyes, are occupied solely by nerve bundles. Collagen I and III deposition appeared to be more dependent on the level and duration of the pressure rise. Eyes with lower mean intraocular pressures showed deposits of interstitial collagens primarily at the level of the sclera, while eyes with higher mean pressure elevations had depositions in the neck regions as well. Chondroitin and dermatan sulfate proteoglycans were deposited in a pattern similar to that of collagen I. No extracellular matrix deposition was seen in the orbital optic nerve in any experimental eye.     

The optic nerve head in glaucoma: role of astrocytes in tissue remodeling

Primary open angle glaucoma is a common eye disease characterized by loss of the axons of the retinal ganglion cells leading to progressive loss of vision. The site of damage to the axons is at the level of the lamina cribrosa in the optic nerve head. The mechanism of axonal loss is unknown but elevated intraocular pressure and age are the most common factors associated with the disease. Previous studies in human glaucoma and in experimental glaucoma in monkeys have established a relationship between chronic elevation of intraocular pressure and remodeling of the optic nerve head tissues known clinically as cupping of the optic disc. This review focuses on the astrocytes, the major cell type in the optic nerve head. Astrocytes participate actively in the remodeling of neural tissues during development and in disease. In glaucomatous optic neuropathy, astrocytes play a major role in the remodeling of the extracellular matrix of the optic nerve head, synthesize growth factors and other cellular mediators that may affect directly, or indirectly, the axons of the retinal ganglion cells. Due to the architecture of the lamina cribrosa, formed by the cells and the fibroelastic extracellular matrix, astrocytes may respond to changes in intraocular pressure in glaucoma, leading to some of the detrimental events that underlie axonal loss and retinal ganglion cell degeneration.     

Optic nerve damage in highly myopic eyes with chronic open-angle glaucoma

PURPOSE: To compare the amount of optic nerve damage in relation to intraocular pressure in highly myopic eyes with chronic open-angle glaucoma versus non-highly myopic eyes with chronic open-angle glaucoma. METHODS: The comparative clinical observational study included 1841 eyes of 1100 patients with chronic open-angle glaucoma. The highly myopic study group consisted of 25 eyes with a myopic refractive error equal to or higher than -8 diopters. It was subdivided into eyes with an optic disc size larger than 2.7 mm2 and eyes with an optic disc smaller than 2.7 mm2. The control group included the remaining, non-highly myopic eyes (n=1816). For all patients, a morphometric analysis of color stereo optic disc photographs was performed. Main outcome measures were morphometric optic disc measurements and intraocular pressure. RESULTS: In the highly myopic, large-optic-disc study group compared with the control group, maximal and minimal intraocular pressure readings were significantly (p<0.05) lower and neuroretinal rim area corrected for optic disc size was slightly (p=0.16) smaller. Comparing the total highly myopic study group with a control group adjusted for optic disc area, neuroretinal rim area was significantly (p=0.039) smaller in the study group with no significant difference in intraocular pressure measurements between the groups. CONCLUSIONS: At a given intraocular pressure in chronic open-angle glaucoma, optic nerve damage may be more pronounced in highly myopic eyes with large optic discs than in non-highly myopic eyes. This may suggest a higher susceptibility for glaucomatous optic nerve fiber loss in highly myopic eyes than in non-highly myopic eyes.     

Characteristics of Optic Nerve Damage Induced by Chronic Intraocular Hypertension in Rat

Purpose:To set up the Sharma‘s chronic intraocular hypertension model and investigate the intraocular pressure (IOP) as well as the optic nerve damage of this model in rat.Methods :The operations of the chronic intraocular hypertension model were performed as described by Sharma in 60 male Lewis albino rats. IOP was measured using the TonoPen XL immediately after surgery and then at 5 day, 2 week or 4 week intervals. Cresyl violet staining of whole-mounted retinas was used to label retinal ganglion cells (RGCs),then RGCs were counted. Paraphenylenediamine (PPD) staining was performed in the semi-thin cross sections of optic nerve of rat, in order to know whether the axons of optic nerve were degenerated or not.Results:There were 47 rats with higher IOP after the episcleral veins cauterized in 60 rats. The ratio of elevated IOP was 78.3%. The IOPs were stable in 4 weeks. After cresyl violet staining, the RGCs loss was 11.0% and 11.3% was found in the central and peripheral retina respectively after 2 weeks of increased IOP. After 4 weeks of increased IOP, the loss of RGCs was 17% for the central retina and 24.6% for the peripheral retina. In the retinas without higher IOP, there was no loss of RGCs. PPD staining showed that optic nerve of rat with about 5.3% damage of axons located at the superior temporal region. Region of affected optic nerve 1 mm posterior to the globe by light microscope showed evidence of damaged axons with axonal swelling and myelin debris.Conclusion:Sharma‘s chronic intraocular hypertension model is a reproducible and effective glaucoma model, which mimics human glaucoma with chronically elevation IOP and induced RGCs loss and damage of optic nerve.     

Simultaneous management of blood flow and IOP in glaucoma.

Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causation may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis reduce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links ischemia to IOP. Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.     

Macular schisis and detachment associated with presumed acquired enlarged optic nerve head cups

PURPOSE: To describe a clinical syndrome of macular schisis and detachment in patients with acquired optic nerve head cupping resulting from glaucoma. DESIGN: Retrospective review of five patients. METHODS: Patients were included if they had optic nerve cupping and macular schisis with or without detachment with no other identifiable cause. The patients had to have no leakage on fluorescein angiography and no vitreous traction on examination or on optic coherence tomography (OCT). These patients were followed up and visual acuity, intraocular pressure, and the findings of serial fundus and OCT examinations were noted. RESULTS: Five patients had schisis with or without detachment of the macula with pronounced optic nerve head cupping. One patient had resolution of the macular fluid after filtering surgery for uncontrolled glaucoma. Two patients underwent a vitrectomy with intraocular gas and had almost total resolution of macular fluid and improved vision. CONCLUSIONS: Macular schisis and detachment can occur in patients with presumed enlarged optic nerve head cups in the absence of obvious congenital anomalies of the disk. The authors believe the cause is leakage of fluid from the vitreous through a tiny hole in the thin tissue of the cup. This is a similar mechanism to that seen in patients with optic pits. A vitrectomy or steps to reduce the intraocular pressure may result in resolution of the fluid and improved vision.     

Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures

PURPOSE: To determine, using anatomic measurements, whether daily oral dosing with memantine is both safe and effective to reduce the injury associated with experimental glaucoma in primates. METHODS: Argon laser treatment of the anterior chamber angle was used to induce chronic ocular hypertension (COHT) in the right eyes of 18 macaque monkeys. Nine animals were daily orally dosed with 4 mg/kg memantine while the other nine animals received vehicle only. Measurements of intraocular pressure (IOP) from both eyes of all animals were made at regular intervals. Appearance of the optic nerve head, retinal vessels, and surrounding retina was documented with stereo fundus photographs obtained at multiple time points throughout the study. Measurements of optic nerve head topography were obtained from confocal laser scans made from animals with the highest IOPs at approximately 3, 5, and 10 months after elevation of IOP. At approximately 16 months after IOP elevation, animals were killed and histologic counts of cells in the retinal ganglion cell (RGC) layer were made. RESULTS: Histologic measurements showed that, for animals with moderate elevation of IOP, memantine treatment was associated with an enhanced survival of RGCs in the inferior retina. Measurements of optic nerve head topography showed less IOP-induced change in memantine-treated animals. This effect was seen in measurements of both the cup and the neuroretinal rim. A comparison of these same histologic and morphologic measurements in normotensive eyes from the two treatment groups showed that memantine treatment was not associated with any significant effects on these eyes. CONCLUSIONS: Histologic measurements of RGC survival as well as tomographic measurements of nerve head topography show that systemic treatment with memantine, a compound which does not lower intraocular pressure, is both safe and effective to reduce changes associated with experimental glaucoma.     

Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ocular hypertension

As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors that may play a protective role in glaucoma. β‐amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans‐lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucoma mainly through a lower trans‐lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure‐independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including β‐amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic β‐amyloid pathway in glaucoma.     

Bilateral nonarteritic anterior ischemic neuropathy following acute angle-closure glaucoma in a patient with iridoschisis: case report

A 55-year-old woman was referred to our clinic because of a one-week history of visual loss and raised intraocular pressure in the left eye followed 4 days later by visual loss in the right eye. Slit-lamp examination showed bilateral conjunctival hyperemia, slight diffuse corneal edema, shallow anterior chamber and fixed and dilated pupil in both eyes. Splitting of the anterior layers of the iris with fibrillar degeneration extending for approximately one quadrant inferiorly was presented in each eye. Fundus examination showed optic disc edema with no vascular tortuosity and no cup in both eyes. The condition was treated as bilateral acute angle-closure glaucoma in a patient with irisdoschisis. After medical treatment and improvement of visual acuity, perimetry revealed a significant visual field defect especially in left eye; this case represents a rare concurrence of acute angle-closure glaucoma and bilateral nonarteritic ischemic optic neuropathy. Although most cases of elevated intraocular pressure, including acute angle-closure glaucoma, do not result in optic disc edema and irreversible vision loss, variations in the vascular supply of the nerve optic head along with others ocular systemic risk factors, may predispose certain individuals to nonarteritic ischemic optic neuropathy during periods of elevated intraocular pressure.     

Argumente f��r eine prophylaktische Therapie der okul?ren Hypertension

Increased intraocular pressure is currently the only manipulable risk factor for glaucoma. In ocular hypertension the intraocular pressure is increased but the optic nerve head and visual field are thought to show no damage. Classification into glaucoma by means of the optic nerve head is often possible only over a period of time because there is a large overlap between the already pathological and still normal findings. In the Ocular Hypertension Treatment Study (OHTS) the effectiveness of prophylactic treatment was demonstrated. In the OHTS and the European Glaucoma Prevention Study (EGPS) risk factors have been identified, such as increased intraocular pressure, size of the excavation of the optic nerve head, decreased central corneal thickness, increased pattern standard deviation in the visual field and age. Before treatment of ocular hypertension is initiated these risk factors and the patient's personal situation should be considered. The higher the intraocular pressure, the smaller the central corneal thickness and the larger the excavation of the optic nerve and the younger the patient, the earlier treatment should be started.     

Axonal transport blockage by acute intraocular pressure elevation in monkeys]

The distribution of orthograde rapid axonal transport blockage in the optic nerve head by acute intraocular pressure (IOP) elevation in monkeys was studied by autoradiography. Tritiated leucine was injected intravenously two hours before IOP elevation, and the IOP was elevated for five hours, maintaining a perfusion pressure of 30mmHg. Serial step cross sections from the optic nerve head at the level of the lamina cribrosa were prepared for light microscopic autoradiography, and the accumulation and distribution of grains were quantitatively analyzed using computerized image analysis. The area of focal grain accumulation was expressed as a percent of the defined optic nerve area and each eight sectors, divided by axially intersecting vertical, horizontal, and diagonal lines, respectively. In eyes with IOP elevation, the mean area of focal accumulation of grains in the temporal half of the optic nerve was significantly larger, compared with the nasal half. Within axonal bundles, the focal high accumulation of grains was frequently identified to be in association with trabecular beams of connective tissue in the peripheral portion of the axonal bundle. These results suggest temporal dominant blockage of axonal transport in the optic nerve head, which may be induced by mechanical compression of the axonal bundles during IOP elevation.     

Intraocular pressure-dependent dynamic changes of optic disc cupping in adult glaucoma patients.

The authors performed a study of intraocular pressure-dependent changes in optic disc cupping in 17 adults with chronic open-angle glaucoma. Analyses with the Rodenstock Optic Nerve Head Analyzer were performed at baseline low intraocular pressure during therapy, after elevation of intraocular pressure (from therapeutic failure or noncompliance), and after reduction of intraocular pressure with successful therapy. Optic disc cupping increased significantly upon short-term increase of intraocular pressure from baseline of 20.4 +/- 2.5 mmHg to 31.1 +/- 5.9 mmHg. Optic disc cupping reverted to baseline after persistent intraocular pressure reduction to 19.3 +/- 4.8 mmHg. These data demonstrate intraocular pressure-dependent dynamic changes of optic disc cupping in patients with demonstrable glaucomatous optic nerve damage. They underscore the detrimental effect of elevated intraocular pressure and the beneficial effect of intraocular pressure reduction on optic disc cup changes.     

Central corneal thickness in low-tension glaucoma

BACKGROUND: It is possible that the intraocular pressure (IOP) is underestimated in eyes whose central cornea is thinner than normal. The objective of this study was to determine and establish the significance of central corneal thickness in patients with low-tension (normal-tension) glaucoma compared with those with chronic open-angle glaucoma (COAG) or ocular hypertension and healthy eyes. METHODS: The study was carried out from February 1998 to May 1999. Central corneal thickness was measured by ultrasonic pachymetry and IOP was measured by Goldmann applanation tonometry in 25 patients with low-tension glaucoma (untreated IOP less than 21 mm Hg with evidence of optic nerve head damage and corresponding visual field loss on automated perimetry), 80 patients with COAG (untreated IOP 21 mm Hg or greater with evidence of optic nerve head damage and corresponding visual field loss on automated perimetry), 16 patients with ocular hypertension (untreated IOP 21 mm Hg or greater, with normal optic nerve head and no history of glaucoma or elevated IOP, and normal visual field on automated perimetry) and 50 control subjects (untreated IOP less than 21 mm Hg with normal optic nerve head and no history of glaucoma or elevated IOP). Analysis with Pearson's product-moment correlation was performed to determine the correlation of IOP and central corneal thickness, and one-way analysis of variance was used to compare corneal thickness between groups. RESULTS: The central cornea was significantly thinner in the low-tension glaucoma group (mean 513.2 mu [standard deviation (SD) 26.1 mu]) than in the COAG group (mean 548.2 mu [SD 35.0 mu]) and the control group (mean 556.7 mu [SD 35.9 mu]) (p < 0.001). No significant difference in corneal thickness was found between the COAG and control groups. The ocular hypertension group had significantly thicker corneas (mean 597.5 mu [SD 23.6 mu]) than the three other groups (p < 0.001). INTERPRETATION: Patients with low-tension glaucoma may have thinner corneas than patients with COAG and healthy subjects. This results in underestimation of their IOP. Corneal thickness should be taken into account when managing these patients to avoid undertreatment.     

Predictive factors for progressive optic nerve damage in various types of chronic open-angle glaucoma

PURPOSE: To evaluate whether various types of chronic open-angle glaucoma differ in predictive factors for progression of glaucomatous optic nerve damage. DESIGN: Observational cohort study. METHODS: SETTING: Prospective observational clinical study. PATIENTS: 517 eyes of 300 Caucasian patients with chronic open-angle glaucoma with elevated intraocular pressure (primary open-angle glaucoma, n = 289; secondary open-angle glaucoma, n = 50) and with normal intraocular pressure (n = 178). OBSERVATION PROCEDURE: During follow-up (median: 49 months, 6 months-130 months), all patients underwent repeated evaluation of color stereo optic disk photographs and white-on-white visual field examination. MAIN OUTCOME MEASURES: Progression of glaucoma was defined as neuroretinal rim loss during the study period. RESULTS: For patients with elevated intraocular pressure, significantly predictive factors for eventual progression were older age, advanced perimetric damage, smaller neuroretinal rim, and larger area of beta zone of parapapillary atrophy. In contrast, in the normal intraocular pressure group, a significant predictive factor was presence of disk hemorrhages at baseline. Within the patients with elevated intraocular pressure, the primary open-angle glaucoma group and the secondary open-angle glaucoma group did not differ in predictive factors for progression of glaucoma. CONCLUSIONS: Open-angle glaucoma patients with normal intraocular pressure and open-angle glaucoma patients with elevated intraocular pressure differ in predictive factors for eventual progression of glaucomatous optic nerve damage. It may have clinical importance and may be helpful in the discussion of the pathogenesis of the glaucomas.