Ординатура / Офтальмология / Английские материалы / Atlas of Glaucoma, Second Edition_Choplin, Lundy_2007

In this study, however, more basic data were not

However, there is likely to be overlap between

given to allow one to re-analyze the rates. Without

these categories, especially in the case of elevated

additional data, understanding the rates of POAG

intraocular pressure, which affects disease incidence

in this population, given the AAO definition of

as well as progression.

POAG, becomes problematic. In the Barbados Eye

Study of Blacks, definite POAG required the pres-

Age, race, and gender

ence of both optic disc and visual field abnormali-

First, the higher the age of the population, the more

ties. Adding ‘suspect OAG’ participants defined as

prevalent open-angle glaucoma was found to be.

those with ‘less complete’ data (and thus potentially

The relationship between age and prevalence of

including those with only one of the two criteria or

POAG from the four major prevalence studies men-

more equivocal findings in both criteria) would

tioned above is summarized in Table 9.1. Second,

increase the rate of POAG in this population by

comparing across the studies, increased skin pig-

55%! Indeed, only the Baltimore Eye Survey, in

mentation is also associated with a higher preva-

contrast, provides a definition based on either optic

lence of glaucoma, as shown in Table 9.1. Less well

nerve head findings or visual field abnormalities,

settled is the third issue of gender disparities in

of varying strengths, consistent with the AAO defi-

prevalence. In the Barbados and Rotterdam studies,

nition. Recent prevalence studies have estimated

men were noted to have a higher prevalence than

that 2.22 million Americans have open-angle glau-

women, as high as an average of 3.6% across all age

coma as defined by some abnormality of visual func-

groups in the Rotterdam study.

tion (generally fields), and that number is expected

to reach 3.36 million by the year 2020. However,

Intraocular pressure

using the AAO definition of glaucoma, many more

Americans could be diagnosed as having glaucoma.

In subsequent analysis of many of these data sets as

Thus, readers and policy-makers should carefully

well as other independent studies, additional risk fac-

assess how POAG is defined to understand the epi-

tors other than age and race (and perhaps gender) were

demiological magnitude of this disease.

identified. A widely acknowledged risk factor for

POAG is the degree of elevation of the intraocular

Risk factors

pressure. Work from the Baltimore Eye Survey has

shown that, even among normals, the higher the

Nevertheless, across each of these studies, certain

intraocular pressure, the less nerve tissue (as meas-

general risk factors were evident, regardless of the

ured by rim area) exists. Certainly, in every population-

definition of glaucoma. These risk factors can be

based study, the higher the intraocular pressure, the

thought of in two major categories: risk factors that

greater the rate of POAG.

affect the development of POAG, and risk factors

The fluctuation of intraocular pressure in both

that hasten its progression once the disease has devel-

the short term (daily) and the long term (over years)

oped. These factors include age, race, and gender of

has been found to be important in the risk of devel-

the patient, family history, central corneal thickness,

oping worsening of glaucoma. This is a potentially

intraocular pressure characteristics, and perhaps

critical insight, because analysis of the Olmsted

myopia and certain systemic medical diseases.

County data showed that over 20 years the risk of

Study

Race

Age (years)

Prevalence rate (%)

Rotterdam

Not specified

55–59

0.2

85–89

3.3

Baltimore Eye Survey

White

40–49

0.9

White

80

2.2

Black

40–49

1.23

Black

80

11.26

Barbados

Black

40–49

1.4

80

23.2

Beaver Dam

White

43–54

0.9

75

4.7

increases with a longer duration of hypertension, one

into potential factors. For example, Schulzer et al.

might expect a change in the relationship between

found that they could classify two distinct groups

perfusion pressure and hypertension due to decreased

of patients with glaucoma on the basis of hemody-

perfusion.

namic and hematological characteristics. One group

Other associations have been found not to be

demonstrated some systemic sensitivity to stimuli

present, including alcohol intake, smoking, and pos-

causing vasospasm, while another group showed

sibly migraine headache. Yet, as with hypertension

indirect indicators of vascular disease, including

in the past, further study may allow us to better under-

abnormal coagulation. Interestingly, the smaller

stand the potential contributions of nutrition and

former group (25% of study patients) demonstrated

environmental conditions to increasing or decreas-

a correlation between peak intraocular pressure

ing the risk of developing POAG. Such interactions

and severity of field defect, while the latter (75% of

are likely to become even more important as we

patients) did not. For reasons to be discussed below,

better understand the mechanisms underlying

peak intraocular pressure may not be the most

glaucoma in various ocular structures.

accurate measure of the effect of intraocular pressure

on the eye, yet this study suggests that studies that

PATHOPHYSIOLOGY OF GLAUCOMA

do not distinguish between these two possible (and

perhaps more) subgroups in hemodynamic studies

may be ‘washing out’ a true effect through cross-

Several mechanisms are likely to underlie the final

contamination of study populations. Indeed, an

common pathway of optic nerve dysfunction and

independent study from Japan found that 17–25% of

ganglion cell death. Indeed, ‘open-angle glaucoma’

patients with POAG also had a vasospastic response,

may be more accurately thought of as a syndrome

a rate similar to the Schulzer study. However, even

rather than one single disease, with subsets of

though 12 control patients had a similar 25% rate

patients with different mechanisms exerting the

of vasospastic response, these patients were 4–8

primary influence on damage to intraocular

years younger than the POAG subjects.

structures.

Other authors have also found deficits in the

Evidence from the epidemiology of the disease

velocity of blood flow in various elements of the

provides key insights for investigation. Possibilities

intraocular circulation, including the retinal, central

include: (1) direct damage to the optic nerve due to

retinal artery, and optic nerve head circulation. In

pressure effects on the connective tissue or the nerve

the optic nerve head circulation study, the authors

fibers; (2) indirect effects of pressure in compromising

demonstrated increased red blood cell aggregability

vascular flow to the optic nerve; (3) susceptibility

due to decreased deformability, a finding similar to

of the affected cells and connective tissue to damage;

those of Schulzer et al. in the majority of their

(4) direct vascular flow compromise; and (5) inter-

patients.

actions between susceptibility, intraocular pressure,

The structural characteristics of the vascular

perfusion pressure and vascular supply (or on vas-

system have also been implicated in the development

cular supply itself) as ameliorated by the perfusion

or worsening of POAG damage. In one review of optic

pressure relative to the intraocular pressure.

disc photographs of 34 eyes with advanced field

However, these findings may not apply to many

loss, the presence of a temporal cilioretinal artery was

or most patients with POAG as defined today. Thus,

found to be protective of preserving central field

there is a need for continued investigation and

and acuity. In other work, Schwartz postulated that

analysis in this area. An interesting implication of

areas of defect in the microcirculation of the disc

this finding is the potential role that it highlights

are associated with both ocular hypertension and

for systemic conditions such as hypothyroidism and

POAG and with worsening of POAG status.

diabetes mellitus which have been associated with

A fourth area of analysis has centered on

a greater risk of glaucoma. Decreased cardiac output

understanding pulsatile ocular blood flow through

or reduced arterial pressure may make individuals

a variety of means. Since the vast majority of pul-

more susceptible to perfusion-deficit damage, while

satile flow travels through the choroidal (and thus

microvascular damage to capillaries and small blood

ophthalmic artery) circulation (from which the optic

vessels may act directly to heighten the likelihood

nerve head circulation derives), measurements of

of ischemia.

flow are only rough measures of choroidal and

ophthalmic artery flow. Nevertheless, while some

Blood flow and hemodynamics

studies have found deficits in flow in POAG

patients as well as differential effects on flow with

When additional issues related to vascular perfu-

different therapies, other studies have not found

sion are examined, several other interesting studies

such differences in flow. Yet what is clear across

add to our understanding. While many of these

studies is that a wide variation exists among indi-

findings are controversial or have been at odds with

viduals in the ability to autoregulate pulsatile ocu-

other published studies, they offer interesting insights

lar blood flow, especially at night. Decreased blood

Primary open-angle glaucoma 121

flow nocturnally or while supine (possibly due to

(affected by the statin class of drugs) may act

increased intraocular pressure related to increased

through these or related mechanisms to alter fluid

episcleral venous pressure in this position) may

transport in those with glaucoma. Second, greater

suggest particular susceptibility in certain patients

attention has been paid to uveoscleral outflow as a

or at certain times.

potentially underrecognized pathway of fluid egress

Finally, recent work has pointed towards reti-

from within the eye. If outflow is similar in humans

nal vessel diameter as a marker for associated glau-

to the 35–50% seen in primate models, then we can

comatous damage. While causation is unclear, other

anticipate much greater attention in the future to

work suggesting that lower end-arteriolar pressure

this pathway. Third, the family of matrix metallo-

predicts the progression from ocular hypertension

proteinases and other factors associated with tissue

to glaucoma, based on the pressure attenuation

injury and stress offer important insights into chronic

index.

damage mechanisms in the trabecular meshwork

While partially clarifying the role played by

(and potentially elsewhere).

vascular factors in the pathogenesis of glaucoma-

The next effect of these mechanisms is that out-

tous optic neuropathy, the above studies have also

flow from the eye is impaired, resulting in pressure

pointed out its complexity. It is now more apparent

dysfunction. Evidence is mounting that the most

that understanding ocular perfusion requires a

important characteristic of intraocular pressure for

consideration of not only ocular blood flow para-

the development and progression of glaucoma may

meters and their autoregulation (or lack thereof),

not be the peak or average intraocular pressure;

but also an appreciation of systemic vascular fac-

rather, it is the variation in intraocular pressure that

tors, systemic diseases, and the potential role played

may be most crucial. For example, David et al. and

by ocular and systemic medications. Vascular fac-

Asrani et al. found that the diurnal variation in intraoc-

tors are only part of the equation in understanding

ular pressure was higher in ocular hypertensives and

ocular perfusion, however. While such factors may

those with glaucoma than in normal patients, confirm-

be especially important in the nearly half of

ing the findings of a series of studies by Drance,

patients with glaucoma who will have an intraocu-

Katavisto, and Kitazawa. Indeed, Oliver et al.

lar pressure reading in the normal range on any one

found that patients in Olmsted County, MN, who

pressure examination, it is clear that intraocular

went blind from glaucoma did not differ appreciably

pressure is also critical, since it generates much of

from those who maintained vision in terms of their

the resistance to flow and perfusion.

mean intraocular pressure over 20 years.

Studies of progression after intervention also

Intraocular pressure

found an important role for the variation of pressure.

For example, Elsas et al. found that the variation in

Intraocular pressure retains a critical role in the

intraocular pressure was significantly greater in eyes

pathogenesis of glaucoma, since it is one part of

prior to laser trabeculoplasty than it was after trabecu-

the equation that determines the relative health of

loplasty, with variation decreasing from 33% of the

the optic nerve. Traditional work regarding the tra-

average intraocular pressure to less than 10%. In

becular meshwork remains critical, since impaired

another study, Saiz et al. found that those patients

outflow leading to elevated intraocular pressure

who underwent successful trabeculectomy had

may result in the optic nerve damage that charac-

not only lower peak intraocular pressures but also

terizes glaucoma, either structurally from direct

significantly lower amplitudes of diurnal variation

pressure effects or indirectly through compromised

in intraocular pressure than before surgery. The

perfusion. The mechanisms of decreases in outflow

Advanced Glaucoma Intervention Study investiga-

facility underlying the pressure elevation have

tors showed that over the long term patients who

become better understood over the past few years.

consistently had intraocular pressures of 18 or less

Several important avenues of investigation offer

were far less likely to have visual field progression

the potential for not only a better understanding of

than those whose pressures fluctuated more widely.

trabecular meshwork function (and dysfunction) but

From a biophysical standpoint, it is reasonable

also potential new avenues for treatments. First,

that variation in intraocular pressure may be respon-

cytoskeletal changes mediated by key changes in

sible for mechanical effects in the optic nerve head

actin and myosin pathways have been shown to be

leading to glaucomatous optic atrophy. The human

instrumental in altering the ability of trabecular

body adapts amazingly well to static pressure loads,

meshwork cells to modulate fluid transport across

but it is the repeated loading and unloading of

the meshwork. Tan and others have shown that

stress that causes breakdowns in structural properties

disruptions of the cytoskeletal structure of inter-

(as in metal fatigue in airliners subject to repeated

ference with the actin–myosin interactions can

takeoffs, landings, and pressurizations). Such variation

significantly increase outflow through the trabecular

may be important in leading to repeated episodes of

meshwork. Aquaporin mechanisms as well as

relative ischemia that may over time cause injury

other intermediate pathways such as rho kinase

to the optic nerve fibers, ultimately resulting in