Last Updated: January 2005

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Pathophysiology of open-angle glaucoma

Aqueous dynamics: formation and circulation of the aqueous fluid

The aqueous fluid is an ultrafiltrate of blood. It is clear, watery, and fills both the anterior and posterior chambers. Since both the posterior surface of the cornea (the endothelium) and the lens are avascular, the aqueous fluid is critical in delivering oxygen and nutrients. This means that the lens and the corneal endothelium rely on aqueous fluid as their source of nourishment and conduit for metabolic waste removal.

The flow of aqueous fluid plays an important role in the regulation of intraocular pressure, (IOP). The IOP is determined by the inflow as compared with the outflow of aqueous fluid. The total volume of intraocular aqueous fluid within the anterior segment (which has a fixed size) determines the IOP.

Think of the ciliary processes of the ciliary body as the faucet component of the equation and the trabecular meshwork / canal of Schlemm as the drain. If outflow is equal to inflow, the IOP remains constant. If outflow is less than inflow, the IOP rises. Normal IOP is about 10 to 20 mm Hg.

The aqueous fluid, produced by the ciliary processes, flows:

into the posterior chamber,
across the posterior surface of the iris,
around the border of the pupil,
into the anterior chamber to interact with the surfaces of the lens and corneal endothelium, and,
exits the anterior chamber at the anterior chamber angle primarily via the trabecular meshwork and the canal of Schlemm. The canal is drained by the intra- and episcleral veins. Aqueous fluid mixes with venous blood and is returned to the heart.

The eye continuously forms and reabsorbs the aqueous fluid. The flow of aqueous fluid is less at night compared with during the day. During the day the flow is about 2 microliters/minute, or 120 microliters per hour. For sake of comparison, a drop is about 50 microliters. Thus, aqueous flows into the anterior chamber at the rate of about 2 drops per hour.

The anterior chamber angle is also referred to simply as "the angle". The iris makes up the base of the angle. The trabecular meshwork is found at the apex of the angle. The corneal endothelium makes up the top of the angle. In theory one could place a miniature protractor on the base of the angle and determine the width of the anterior chamber angle in degrees. A 45 degree angle would be considered wide (or "Open"). A 10 degree angle would be considered, "Narrow," or possibly, "Closed".

Most of the aqueous fluid leaves the eye through the trabecular meshwork and flows into the canal of Schlemm. The trabecular meshwork is a sieve-like structure that bridges the anterior chamber angle. Of note, about 10% of the aqueous fluid escapes from the anterior chamber by passing into the ciliary body. It is referred to as uveoscleral outflow. While uveoscleral outflow is not well understood, it appears that topically applied prostaglandins can increase uveoscleral outflow AND lower the IOP.

Intraocular pressure (IOP)

IOP is the pressure that the intraocular fluids (mostly the aqueous fluid) exert against the cornea and sclera. IOP is of particular importance in many types of glaucoma, since damage to the neurons of the optic nerve (also known as retinal ganglion cells) is associated with IOP elevation.

All patients exhibit fluctuation in IOP over the course of a 24-hour period (diurnal fluctuation). The highest IOP levels are usually recorded in the morning hours. Corticosteroids (topical, inhaled or oral) can increase the IOP in susceptible individuals. Steroid sensitivity has recently been shown to have a genetic link. In Caucasians, IOP tends to increase with age. In the Japanese population, IOP tends to decrease with age.

IOP is related to aqueous fluid volume. The anterior chamber volume is fixed. If aqueous fluid production exceeds drainage even by a small amount, the IOP increases until a new equilibrium is reached. Two main factors influence IOP:

aqueous fluid inflow,
resistance to aqueous fluid outflow.

A third factor is pressure within the intra- and episcleral veins. Pressure within these veins directly affects the resistance to aqueous fluid outflow. In the analogy of faucet and drain, increasing the pressure within these small scleral veins is like backing up a drain; IOP will consequently increase.

An important quantitative relationship is provided below:

IOP = F / C + PV

Where, F = aqueous fluid formation rate,
C= outflow rate,
PV = episcleral venous pressure.

The above factors are those that drive IOP.

In the general population, IOP ranges between 10 and 21 mm Hg with a mean of about 15 or 16 mm Hg (plus or minus 3.5 mm Hg during a 24-hour cycle).

Glaucomatous optic neuropathy and optic nerve physiology

Aqueous dynamics and IOP are the keys to understanding the mechanical forces that are exerted onto the retinal ganglion cells (RGCs), the layers of cells that comprise the interface between the vitreous and photosensitive portion of the retina. The RGCs can be viewed as long connectors between the photosensitive portion of the retina and the lateral geniculate nucleus, a relay station deep within the brain en route to the visual cortex.

Taken as a whole, the RGCs make up the neuronal contribution within the optic nerve. There are about 1 million RGCs in the typical optic nerve. These are arranged into approximately 1,000 fiber bundles. By simple arithmetic, each bundle contains approximately 1,000 RGCs. A bundle can be visualized with an ophthalmoscope as a single striation. An individual RGC cannot be visualized at this time because it is too small.

While the number of RGCs does decrease simply as a function of age alone, having one of the glaucomas is associated with an accelerated rate of loss of RGCs; this rate of loss is over and above the rate of loss attributable to age by itself.

All of the topical products and surgical procedures used in the treatment of glaucoma are used in every case to reduce the patient's IOP. It should be noted that reducing IOP is different from treating the underlying neuropathy. The underlying neuropathy is called "Glaucomatous optic neuropathy," or GON.

This means that glaucoma really is a disease of the optic nerve that is impacted by faulty aqueous dynamics rather than a disease of faulty aqueous dynamics per se. The latter is a subtle but important point. GON is associated with the loss of the fiber bundles and the RGCs that they contain. There are no treatments for GON at the present time.

The patient's visual field is comprised of the all of the overlapping receptive fields from all of the RGCs. As the RGCs die because of GON, the portions of the visual field that they serve are lost. The portions of the visual field that are lost are known as scotomas. As the scotomas expand or deepen, the patient becomes partially blind.

As more RGCs die, the partial blindness expands with consequent visual disability. The real problem with GON is that the visual field loss and consequent visual disability is not obvious to the patient. Rather than affecting visual acuity, (the measurable component of straight-ahead or central vision) the visual field loss affects the peripheral part of the visual field first. This pattern of field loss is vaguely similar to a dark ring that surrounds the point of straight-ahead vision. The dark ring characterizes peripheral visual field loss.

Because patients in the early stage of GON can generally see quite well straight ahead, even after they been diagnosed with GON they often do not believe that they have a chronic visual disability or even that they have an ophthalmological disease. Thus one important task of the health care provider is to convince the patient that there really is a chronic disease that must be medicated on a daily basis, managed surgically, or both.

Unfortunately, GON is not only a progressive disease, it is also a bilateral disease although it is often asymmetric initially. This means that in the beginning of GON, one eye will have visual field loss and the other will have a normal visual field. Even in the mid-stage of the disease when the visual fields of both eye have scotomas, because there is overlap between the two separate visual fields of the two eyes, areas of normal visual field of one eye can and do compensate for scotomas in the other eye.

As the GON progresses, the area of visual field loss continues to expand and can affect straight-ahead (central) vision. Clinically this is detected by a reduction of visual acuity as well as characteristic field change. By the time that central vision in one eye has been affected, the disease has reached the advanced stage in that eye.

Sometimes it is only when a small piece of dirt or dust falls into the better-seeing eye that the patient blinks and discovers that the vision in the contralateral eye has been dramatically reduced. These patients are justifiably frightened and often hastily arrange for an appointment. By this time it is late in the course of the disease since no available treatment will restore the function of those RGCs that have already died.

From a therapeutics perspective, the health care provider strives to lower the IOP in the affected eye(s) to a target range and then monitor the visual fields, the health of the optic nerve hear, or both to gauge the rate of visual field loss. If the IOP can not be sufficiently lowered using topical hypotensive agents, several surgical alternatives are available.

The relationship between IOP control and visual field deterioration

The relationship between intraocular pressure (IOP) and visual field progression in patients with glaucomatous optic neuropathy (GON) has been a topic of intense interest since Von Graefe first suggested it in the middle of the 19th century. Since then there have been many studies conducted. These studies have been designed to evaluate different types and stages of glaucoma and include: advanced glaucoma, ocular hypertension and early glaucoma, normal tension glaucoma and ocular hypertension. Among these studies, sample sizes vary from large to small and follow-up intervals vary from long to modest. Treatment paradigms range from surgical plus medical to no treatment at all. Throughout these various studies, the common theme is the association between IOP and the progressive loss of visual field.

Advanced glaucoma, IOP, and progressive visual field loss

In the Advanced Glaucoma Intervention Study (AGIS) 7 study [AGIS, 2000] evaluated patients with an advanced stage of glaucoma. Eligibility criteria included patients with open angle glaucoma (OAG) that could no longer be controlled using maximum accepted and tolerated medical therapy. Visual fields were measured using the Humphrey Visual Field Analyzer (24-2). The visual field defect was scored using a pre-defined range from 0 points (no defect) to 20 points (end-stage GON). A visual defect score of 20 points indicated that a patient could not count fingers at 30 cm. To be eligible, the minimum visual field defect score was 1 and the maximum score was 16.

Each patient was then randomized to one of two surgical sequences:

Argon laser trabeculoplasty - trabeculectomy - trabeculectomy, or,
trabeculectomy - argon laser trabeculoplasty - trabeculectomy.

Surgery via either method was supplemented with medicinal treatment (unspecified). The overall goal was to reach an IOP of less than 18 mm Hg.

Two categories of analyses were performed, a predictive analysis and an associative analysis. In the predictive analysis, 738 eye were evaluated and each eye was assigned to one of three groups after the initial 18 months of follow-up:

Group 1: less than 14 mm Hg,
Group 2: 14 to 17.5 mm Hg,
Group 3: greater than 17.5 mm Hg.

Follow-up visits occurred at 6-month intervals. The mean change from baseline in the visual field defect score was obtained for each of the 3 groups at each follow-up visit.

Four years later, the greatest worsening in the visual field defect score was identified in Group 3, i.e. patients who initially had an IOP greater than 17.5 mm Hg. After 7 years of follow-up, the statistical model estimated worsening in the visual field defect score in Groups 3 and 1. Patients in Group 3 had a visual defect score of 1.89 points greater than those in Group 1.

In the associative analysis, 586 eyes were evaluated and categorized into Group A, B, C or D based upon the percent of visits during the first 6 years of follow-up in which IOP was less than 18 mm Hg. Patients in Group A achieved an IOP less than 18 mm Hg on 100% of follow-up visits; Group B 75% to 99%; Group C 50% to 74%; Group D 0% to 49%. The mean IOP in each of the groups over the first 6 years of follow-up is provided below:

Group A: 12.3 mm Hg,
Group B: 14.7 mm Hg,
Group C: 16.9 mm Hg,
Group D: 20.2 mm Hg.

The mean change in the visual field defect score over the duration of the follow-up interval for Group A was about zero, i.e. no progression. For Groups B, C, and D, the visual field defect score progressively worsened over time with an average worsening of about 2 to 3 points by year 8.

The authors conclude from both the predictive analysis and the associative analysis that a low post-surgical IOP slowed progression of the visual field defect. Their observations support a protective role for a low IOP with respect to visual field deterioration. Furthermore, the benefit of a low post-surgical IOP became stronger over a longer follow-up interval.

In an accompanying editorial [Kass et al., 2000], the variability of the visual field as an outcome measure in the AGIS 7 study was discussed. They made the point that even though the mean change in the visual field defect score was about 0, about 18% of eyes in Group A had an improvement of 4 or more points and about 14% of eyes experienced a visual field defect worsening of 4 or more points. Thus maintaining a low IOP cannot ensure the preservation of the visual field, a point corroborated by others [Stewart et al., 2000]. ]. Further examination of the AGIS data revealed that for each 1mmHg increase in IOP fluctuation or 5 year increment in age, the odds of VF progression increase by 30%[Nouri-Mahdavi et al., 2004]

In a related study in patients with advanced glaucoma [Odberg, 1987], patients were followed between 5 and 18 years. The author set an arbitrary study threshold of 15 mm Hg and found that 58% of eyes with an IOP less than 15 mm Hg had a Goldmann field that did not progress. By comparison, eyes with an IOP greater than 15 mm Hg had Goldmann fields that did not progress in only 15% of cases, i.e. about a 4-fold difference. The author found a clear correlation between diminishing visual field and increasing IOP.

Primary open angle glaucoma (POAG), IOP and progressive visual field loss

In a retrospective analysis, 40 eyes of 40 patients with POAG were followed for at least 8 years using Goldmann perimetry [Kwon et al., 2001]. All of these patients were Caucasians with their peak IOP greater than 21 mm Hg and glaucomatous cupping with or without a corresponding visual field loss. No patients in this study had normal tension glaucoma. The follow up interval was 14.6 years. The results show that the average loss of Goldmann visual field was -1.5% per year for all eyes in this study. For those eyes that showed significant decline, the rate was -2.1% per year. In this cohort, 68% of eyes showed a significant decline. The authors conclude that a higher IOP upon initial presentation is associated with a faster rate of visual field deterioration.

In another retrospective analysis, 15 patients with early POAG were evaluated [Zeyen et al., 1993]. These patients had visual field loss in one eye only, i.e. they had asymmetric visual field involvement because their POAG was early in the course of the disease. Patients were followed for a mean of about 6 years using Octopus perimetry. Visual field was lost at the rate of 3.6 dB per year in the eye that had the initial field defect, a rate about 10 fold greater than that of the contralateral normal eye.

In a prospective study [Rasker et al., 2000], 68 patients with POAG were followed for a mean interval of about 9 years. Target IOP was 20 mm Hg or less and at least a 20% reduction. For those eyes with deteriorating visual fields, the rate of loss was between -2.3% and -3.2% per year depending on the statistics used. This rate of loss per year is about the same as that identified by Kwon et al. above.

In a retrospective study of patients with POAG followed for at least 5 years, 218 patients were evaluated [Stewart et al., 2000]. Criteria for worsening included increased thinning of the neural rim or worsening of the visual field, measured using the Humphrey perimeter. With an IOP of 12 mm Hg or less, no patient had worsening. With an IOP of 18 mm Hg or greater, 26% of patients experienced worsening. Progression was even more marked with an IOP of 21 mm Hg or higher.

Similar data were obtained from 55 patients with POAG followed between 4 to 11 years [Mao et al., 1991]. Eyes with a mean IOP less than 17 mm Hg remained stable while about half of those eyes with a mean IOP between 17 and 21 mm Hg progressed. Eyes with a mean IOP greater than 21 mm Hg uniformly progressed. The authors also observed that those with stable visual fields were slightly younger compared with patients who had progressive visual field loss.

In a related study, 747 patients with chronic simple glaucoma were followed for about 5 years [Vogel et al., 1990]. A higher pretreatment (i.e. untreated) IOP was correlated to a greater initial visual field loss (p< 0.0001). A higher pretreatment IOP was also associated with greater visual field deterioration at the end of the follow up interval. Patients with a treated IOP greater than 22 mm Hg had an annual rate of visual field deterioration more than double that of patients with a treated IOP of 15 or 16 mm Hg.

Supporting data is derived from a study on the rate of visual field loss in patients with untreated POAG [Jay et al., 1993]. Visual field loss was staged from 1 to 5 with 1 representing early glaucoma and 5 representing absolute scotomas near fixation. IOP data was grouped in bands of: 21 to 25 mm Hg, 26 to 30 mm Hg, and greater than 30 mm Hg. Eyes with a higher IOP progressed more quickly than eyes with a lower IOP. For example, it took an average of 14.4 years to progress from early disease to end stage disease if the IOP was between 21 and 25 mm Hg but only 2.9 years if the IOP was greater than 30 mm Hg.

In the Baltimore Eye Survey, 151 participants with OAG received both Humphrey and Goldmann perimetry [Quigley et al., 1996]. Participants included 112 African Americans and 39 Caucasian Americans. The extent of visual field loss was graded from 0 to 8. Grade 0 was equivalent to only a few defects and Grade 8 was equivalent to blindness. Among African Americans, a higher IOP or older age was significantly associated with more visual field deterioration. African Americans had a progression rate of 0.23 units per year compared with 0.11 units for Caucasian Americans, i.e. African Americans lost visual field at a rate about double that of Caucasian Americans. The authors also conclude that the severity of visual loss among the African Americans was significantly associated with IOP (p<0.0001).

The glaucoma suspect, IOP and progressive visual field loss

One definition of a 'glaucoma suspect' is a patient who has an elevated IOP or a suspicious disc but no visual field damage. In one study that included glaucoma suspects [Chauhan et al., 1992] follow up continued for about 7 years. Treatment included medical and laser only; there was no incisional surgery. Goldmann fields were used to determine the end point of field progression, which was defined as additional scotomas, a horizontal step, a sector defect, or a depression of 3 contiguous locations. In the beginning of the study 31 patients had normal fields. Of these patients, 18 remained stable and 13 (42%) progressed. Those patients who progressed tended to have a higher mean IOP compared with those who remained stable, i.e. about 22 mm Hg for those that progressed vs. about 19 mm Hg for those that remained stable. The authors concluded that glaucoma suspects, even though treated, can develop visual field defects with mean IOPs as low as 14 mm Hg. They further convey that patients with established visual field loss can progress with mean IOPs as low as 12 mm Hg.

In a prospective study [Rasker et al., 2000] 125 patients (250 eyes) with ocular hypertension were longitudinally evaluated for about 9 years. Their target IOP was 20 mm Hg or less and at least a 20% reduction in IOP. The rate of visual field deterioration was -2.3% per year, which represents an annual conversion rate from ocular hypertension to POAG. Only 10 eyes had deteriorating visual fields.

Normal tension glaucoma, IOP and progressive visual field loss

In the collaborative normal tension glaucoma study [Collaborative normal tension study group, 1998] eligibility included visual field defects and optic disc abnormalities characteristic of glaucoma. In addition, the median of 10 separate IOP determinations had to be 20 mm Hg or less with no reading above 24 mm Hg. All patients had 3 good baseline visual fields performed on a static perimeter. A minimum visual field defect consisted of a cluster of 3 adjacent points depressed by 5 dB from normal and one point depressed by at least 10 dB.

Each patient was then randomized to one of two management strategies:

Untreated and followed, or,
IOP reduction of 30% from the pre-randomization measure by medical or surgical intervention. Neither eye was treated with topical beta-blockers or alpha agonists. Systemic carbonic anhydrase inhibitors were allowed.

Visual field progression was the end-point for this trial. Progression was defined as expansion of an existing scotoma, deepening of an existing scotoma, a new or expanded encroachment upon fixation. Of those enrolled, 145 eyes of 145 patients were randomized. Most patients were followed for 5 or more years.

The mean survival time (time to visual field progression) was 2,688 days in the treated group vs 1,695 days in the control group. The authors conclude that lowering IOP by 30% unequivocally slows the rate of visual field loss and that IOP is a component of normal tension glaucoma. They also point out that of those eyes that remained untreated, 65% showed no progression.

OAG and progressive loss of healthy tissue in the optic nerve head (ONH)

Confirmation of an association between IOP and ONH pathology comes from the Beaver Dam Eye Study wherein IOP was significantly associated with enlargement of the vertical cup-to-disc ratio [Klein et al., 1997] over a five-year follow up interval. From the overall data, IOP is associated with both progressive visual field loss and ONH pathology. A more probing issue relates to the pathophysiology within the ONH that causes the retinal ganglion cells to die resulting in visual field loss.

In patients with early POAG and visual field involvement in only one eye [Zeyen et al., 1993], about 50% of patients showed conversion from normal to ONH disease over the 6 year follow up interval. In the eye that was initially normal, healthy tissue was lost from the ONH rim at the rate of -1.7% per year. By comparison, the eye that had an initial visual field defect, healthy tissue was lost from the ONH rim at the rate of -2.1% per year.

Risk factors associated with progressive ONH damage have been evaluated in a 5-year, retrospective study with 186 treated eyes with POAG and 138 eyes with normal tension glaucoma [Tezel et al., 2001]. Eligibility into this study included a controlled IOP. The ONH was evaluated using stereoscopic color disc photographs and morphometric analyses. Progressive ONH damage was defined as at least a 5% decline in healthy rim tissue. After 5 years, about 38% of the patients with POAG and 51% of patients with normal tension glaucoma experienced progressive damage of their ONH. The authors identify the following risk factors for progression of ONH damage:

A small ring of healthy rim tissue around the circumference of the ONH at baseline,
A large area of parapapillary atrophy at baseline,
A diagnosis of normal tension glaucoma, or,
Combined surgical and medical treatment prior to baseline.

As discussed in the last section, progressive changes in the visual fields correlate to changes in the structure of the optic nerve and ONH. Pathological changes in the ONH have been identified with scanning laser instruments to obtain digitized, high-resolution tomographic sections. Reconstructed images of the ONH can be compared with the visual field [Chauhan et al., 2001]. The question remains about what is happening within the ONH that causes the retinal ganglion cells to die with subsequent visual field defects.

What is known is that adequate perfusion of the ONH is required for adequate nutrition and elimination of metabolic waste. What is less clear is the relationship between high or low systemic blood pressure and the adequacy of local perfusion pressure within the ONH.

Role of systemic blood pressure on GON progression

Systolic and diastolic blood pressure were collected in patients with POAG as part of the Baltimore Eye Survey [Tielsch et al., 1995]. Perfusion pressure was defined as (blood pressure - IOP). Among older patients in particular, a lower perfusion pressure was associated with an increased prevalence of POAG, suggesting a relationship between POAG and ocular blood flow. The authors point out that patients with a low diastolic perfusion pressure had a higher prevalence of POAG although a lower systolic perfusion pressure was also associated with POAG.

In Hispanic subjects, diastolic perfusion pressure (which is the diastolic blood pressure - IOP) was plotted against the percentage of subjects with OAG [Quigley et al., 2001]. The prevalence increased four-fold at a lower perfusion pressure. In the Hispanic data set, the percentage of patients with OAG rises steeply as the diastolic perfusion pressure dips below about 60 mm Hg.

Using 24-hour ambulatory blood pressure monitoring techniques, blood pressure was measured during the night as well as during the day in patients with POAG and normal tension glaucoma [Graham et al., 1999]. Systolic and diastolic pressures declined during sleep. If the mean systolic and diastolic blood pressures fell by more than 10%, patients were categorized as "dippers". In the general population, about two-thirds of people were dippers. In this study population, those with dips in the nocturnal systolic blood pressure were found to have progressive visual field loss (p = 0.001). Visual field progression was also identified in those with dips in diastolic or mean arterial blood pressure. The authors point out that dippers had a greater history of disc hemorrhages. Others point out that trials that specifically evaluate ocular blood flow in glaucoma patients with progressive visual field loss who are also nocturnal dippers have not yet been conducted [Chung et al., 1999].

In a study of 24 eyes of 24 patients with POAG, 11 patients had systemic hypertension and 13 did not [Grunwald et al., 1999]. All patients were evaluated using laser Doppler flowmetry in three areas of the ONH:

the center of the cup,
superotemporal rim, and,
inferotemporal rim.

Blood flow, velocity and volume were the main outcome measures. Overall, the average blood flow in the ONH was 29% less in patients compared with controls. The average flow in patients without systemic hypertension was 26% less than those with systemic hypertension. Mean flow and mean blood pressure were correlated. The authors suggest that a higher blood pressure may result in a higher perfusion pressure, a benefit in maintaining blood flow. They recommend that hypertensive patients treated with an antihypertensive medication may need to be monitored to avoid hypotension in general and nocturnal hypotension in particular because their ONHs may be more vulnerable to glaucoma.

Others drew similar conclusions in their study of 94 patients with POAG whom they studied with a scanning laser Doppler flowmeter and 30-2 static visual fields [Ciancaglini et al., 2001]. Similar to the Grunwald study [Grunwald et al., 1999], glaucoma patients had blood flow data that was significantly lower than age-matched, healthy controls both within the lamina and the rim. By comparison, visual field losses of the glaucoma patients were only correlated with blood flow reductions within the lamina cribrosa and not the rim. The authors suggest that decreased blood flow within the lamina may be secondary to connective tissue changes and vascular remodelling within the ONH. They further suggest that blood flow parameters within the lamina only partially predict visual field loss.

Circulatory defects of the ONH as identified using fluorescein and indocyanin green angiography

Circulatory defects within the ONH have been identified using angiography [Schwartz, 1994]. Small vessels of the disc that show relatively minimal filling. Absolute defects are those in which there is a lack of filling during the arterial and venous phase of the angiogram. Relative defects are those in which there is no filling during the arterial phase but some filling later, i.e. in the venous phase. Another type of defect is dye leakage from disc vessels. ONH filling defects were observed in about 85% of glaucoma patients. With progression of GON, size and number of the defects increase. An increasing area of angiographic defect is associated with a significant increase in visual field loss. The author suggests that the lack of fluorescein filling may be due to a lack of blood vessels.

Getting corroborating data from autopsy would be helpful but is generally not available. In one study, ONH histopathology was compared with pre-morbid visual field defects from chronic glaucoma [Daicker, 1975]. There was no correlation found between visual field defects and atrophy of the radial peripapillary capillaries.

By comparison, in a retrospective study of 75 eyes of 75 patients with OAG, peripapillary atrophy was assessed using sequential stereoscopic ONH photographs and compared with Humphrey 24-2 visual fields with an average follow up interval of 8 years [Uchida et al., 1998]. Progressive ONH damage was observed among 44% of the eyes studied. Of those with progressive disc damage, 64% had progressive peripapillary atrophy. The authors conclude that progressive ONH damage and progressive visual field loss was associated with peripapillary atrophy. Patients who had progressive peripapillary atrophy had an IOP that was significantly higher than those who did not have progressive peripapillary atrophy, i.e. mean IOPs of 20 mm Hg and 16 mm Hg respectively.

Role of local hemodynamics on GON pathogenesis

Tissue perfusion in any tissue depends less on systemic blood pressure and more on the relationship between local perfusion pressure and local resistance to flow. In the ONH, perfusion pressure is the difference between arterial and venous pressure and depends upon the IOP.

The IOP has a diffuse effect throughout the eye. It exerts force on the lamina cribrosa, astroglia, and axons of the retinal ganglion cells. For the maintenance of venous blood flow, venous pressure in the eye must be slightly above the IOP. Perfusion pressure within the eye increases as IOP is reduced.

The optic nerve, similar to the rest of the central nervous system, exhibits autoregulation of blood flow [Anderson, 1999]. Autoregulation is a physiological phenomenon and means that resistance to blood flow will change dynamically so that flow is constant even as IOP and systemic blood pressure change throughout the day. The chemistry behind autoregulation depends on the release of vasoactive substances in response to vascular smooth muscle stretch (in response to flow changes) and sheer stress of the blood against the endothelial surface.

In a normal eye, autoregulation works well. As a function of age, disease, or both, the capacity of autoregulation may be exceeded or the mechanism itself may become defective. If the IOP of a patient's eye is high, the venous pressure would necessarily rise to be just slightly higher than IOP to permit venous drainage. When venous pressure rises, perfusion pressure falls and in theory there is not enough blood to flow through the ONH vascular bed - even if its vessels were maximally dilated via autoregulation. Alternatively, if the mechanism of autoregulation were intrinsically damaged, then blood flow may be inadequate even at a modest IOP. From this perspective, lowering IOP medically or surgically will reduce vascular resistance and increase the vascular perfusion pressure.

In an eye with glaucomatous optic neuropathy, it is possible that autoregulation has failed and that the ONH consequently receives repeated vascular insults. The next issue is how repeated vascular insults result in retinal ganglion cell death, a topic well described by Osborne and his coworkers [Osborne et al., 2001]. Astrocytes are abundant in the optic nerve where they communicate with neighboring astrocytes, Muller cells, and other glial cells within the retina. In the case of an ischemic insult, the nutritional supply to a focal area would be interrupted and this event could be communicated to many retinal astrocytes. A ripple effect could cause a phenomenon known as 'spreading depression' with accompanying voltage changes and increased glucose consumption. An end result may be a release of glutamate, prostaglandins, and nitric oxide that would injure both the retinal ganglion cells and the microglia within the lamina.

Vasospasm and its role in the pathogenesis of GON

In patients with normal tension glaucoma (NTG), vasospasm or inappropriate vasoconstriction may cause critical hypoperfusion leading to death of retinal ganglion cells and consequent loss of visual field. A review of the literature reveals that NTG has been associated with migraine, Raynaud's phenomenon, and reduced baseline blood flow within the ophthalmic artery. In a study of 10 patients with NTG compared with controls, those with NTG had significantly higher resistance indexes and lower end diastolic velocities at baseline [Chung et al., 1999]. After these subjects were challenged with an increased pCO₂, a known vasodilator, the end diastolic velocities increased only in the NTG patients. These data suggest that in the ophthalmic artery of patients with NTG, vascular resistance may be abnormally high and that the increased vascular resistance may be reversible since it responds to pCO₂.

In ophthalmology there is a diagnosis called the "Ocular vasospastic syndrome" and it is characterized not by a glaucomatous visual field but by diffuse visual field loss [Flammer et al., 2001]. It has been identified in young adults and even children. Ocular tissues affected include the conjunctiva, cornea, retinal arteries and veins, choroid, and optic nerve. If the ocular vasospastic syndrome has been diagnosed, it becomes a risk factor for developing glaucoma. It may be associated with a dysfunction of the autonomic nervous system since there is evidence of heart rate variability in patients with normal-tension glaucoma. Endothelin-1, a potent vasoconstrictor, is elevated in the plasma and aqueous fluid of patients with normal tension glaucoma [Kaiser et al., 1995].

Flammer specifically points out that vasospastic disorders should not be automatically equated with Raynaud's phenomenon, Raynaud's disease, or migraine [Flammer et al., 2001]. He goes on to say that although migraineurs have a vasospastic syndrome more frequently than do normals, not all migraineurs have a vasospastic syndrome and not all patients with vasospastic syndrome have migraine.

Pathophysiology of primary-angle closure glaucoma

Similar to open-angle glaucoma, angle closure glaucoma is not a single disease but rather different diseases with a final common pathway [Kim et al., 1997]. The underlying disease process can be characterized as: acute, subacute, intermittent, or chronic. White Europeans and Caucasian Americans usually have pupillary block as the mechanism underlying angle closure. Other mechanisms include plateau iris, lens block, and combined mechanisms. The existence of combined mechanisms can be expected since increased anteroposterior thickness of the lens can increase pupillary block.

There are racial differences in the structure of the anterior chamber. In Asians, the iris joins the sclera more anteriorly; in Caucasians the iris joins the sclera more posteriorly. In Asians, primary-angle closure glaucoma tends to be chronic compared with Caucasians in whom it tends to be acute. In Asia and South Africa, gradual, chronic, asymptomatic angle closure with a consequent rise in IOP and progressive ONH damage is often diagnosed in the late stage of the disease [Kim et al., 1997]. Chronic angle closure glaucoma is diagnosed in the presence of: a closed angle, an IOP greater than 21 mm Hg, ONH changes consistent with GON, and, visual field defects consistent with GON.

In Asians, intermittent or subacute angle closure glaucoma is an important diagnosis to make. The elevated IOP is due to angle closure. The subtly in this disease state is that unlike acute angle closure, the entire angle does not close so the IOP elevation is not as severe. As the disease progresses, more of the angle becomes permanently closed by an adhesive-like substance that accumulates between the iris and the lens.

References

AGIS Investigators, The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000;130:429-440.

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