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In the last President's message I briefly
mentioned the 3rd World Glaucoma Congress to be held in Boston. I would like to spend a little more time
encouraging you to attend. The meeting will take place at the Hynes Convention Center from July 8th to 11th. Over 70
glaucoma societies from around the world will be represented at what promises to be the biggest glaucoma meeting
ever organized. The Optometric Glaucoma Society is proud to have the status as one of the 14 "regional" societies
of the World Glaucoma Association, the organization responsible for the World Glaucoma Congress. We are well
represented within the WGA and our members are amongst the Congress faculty. The OGS will be hosting a special
symposium on the morning of the 8th July, and has arranged for COPE approval of courses throughout the
congress. Please visit the website http://www.worldglaucoma.org/WGC2009/ and explore the vast array of symposia, basic and clinical courses,
debates and clinical rounds that are planned. The OGS are also planning a social event on the evening of the
8th July following the opening reception. Optometry is a welcomed participant of the World Glaucoma
Congress. It is important that we participate. There are few better cities in North America than Boston
in July. The Gala Evening is being held on Friday, July 10th, at the Boston Public Library. I encourage you
to take this opportunity to experience what promises to be an exceptional meeting, both the education and
the ambience. Early, reduced registration is open until April 30th. I look forward to seeing you at the
World Glaucoma Congress, 2009. It promises to be the highlight of the year for all things glaucoma, make
sure you don't miss out.
John Flanagan PhD, MCOptom, FAAO
President, Optometric Glaucoma Society
Welcome to the
Optometric Glaucoma Society Electronic Journal. This first issue of 2009 focuses on a significant question
that we hope will interest clinicians and scientists alike: what factors may have a role in the cause of
primary open angle glaucoma (POAG)?
As a chronic non-infectious disease, it has long been recognised that (in most patients at least) POAG is
multifactorial. This is readily obvious from the diversity of possible clinical presentations. As such, there
are many theories regarding pathogenesis. This feature issue of the EJ contains review articles that discuss
evidence for three specific questions related to causality. Each review is authored by a research group with
specialist interest in these specific subject areas with the aim of updating you on the latest theories on
the following questions; (1) What causes IOP elevation in glaucoma? (2) What is the role of vascular factors
in the cause of glaucoma? (3) Do the biomechanics of the optic nerve head and sclera increase susceptibility to glaucoma?
Understanding causes of disease is one of the foundations upon which better care in the future may be built. Knowledge
stimulates research and development of new 'tools' that could have a future use in clinical care. Such tools can take
a variety of forms, from new treatments, through to improvements in tests and determination of the most informative
clinical outcome measures. They may also show us how to best assay the effectiveness of treatment, or monitor disease
status. Knowledge of causality may also inform clinical strategies to better identify currently healthy individuals
who are at greatest risk of disease.
Future developments aside, clinicians' improved understanding of causality can
greatly improve patient care. Poll data presented in this issue suggest
that a majority of clinicians already explain the causes of glaucoma to most
of their patients. Because increased involvement in their care is known to improve
patients' adherence to their treatment, up-to-date appreciation of disease processes
will enable us all to continue this active engagement with our patients and
further encourage their participation, maximising the chances of successful
Paul GD Spry, PhD, BSc, MCOptom DipGlauc
VASCULAR FACTORS IN THE PATHOGENESIS OF PRIMARY OPEN ANGLE GLAUCOMA*
There is no direct link between blood flow and glaucoma.
The retina and the ONH autoregulate to a wide range of ocular perfusion pressure.
The vascular endothelium derived vasoconstricting and vasodilating factors affect retinal blood flow.
Over the last few years, retinal vascular reactivity (change in hemodynamic parameters due to
provocative stimuli) has been widely studied using a variety of provocations.
Assessment of the vascular reactivity of the ONH will provide greater
understanding of the pathophysiology of POAG.
Under normal conditions, the retinal and the ONH vessels respond by an increase in diameter,
velocity and blood flow to hypercapnia and a decrease in all the hemodynamic parameters in response to hyperoxia.
A lowering of IOP improves ocular perfusion pressure.
There is no equivocal evidence that any current IOP-lowering topical medications have a
direct vasoactive effect.
Vascular dysregulation may be a factor in the development of POAG.
Untreated POAG and patients with treated progressive disease have been shown to have abnormal
vascular reactivity when compared to normal controls.
Clinically practical tests of ocular vascular reactivity are required.
There are various theories as to the pathogenesis of POAG, including the traditional concepts of biomechanical and
vascular related stress. However, it is generally recognised that glaucoma is typically caused by a combination of
different factors, such that it is the ability to maintain perfusion to an individual optic nerve that determines
the clinical presentation, no matter what the biomechanical and vascular stresses. This brief review will concentrate
on current concepts of vascular factors associated with the onset of POAG.
Over the past three decades, epidemiological and experimental evidence has suggested that impaired ocular blood flow
and/or vascular dysregulation are important risk factors in the pathogenesis of POAG (1-6). Studies suggest that
ischemia-promoting vascular factors may contribute to glaucomatous damage, including vasospasm or inappropriate
vasoconstriction (7), altered ocular perfusion pressure (8,9) and general vascular disorders such as systemic
hypotension, including nocturnal dips in blood pressure, which result in deleterious effects on optic nerve perfusion
(10,11). The role of vasospasm in the pathogenesis of glaucoma has received particular attention (4,12-15).
To understand the potential for a vascular
aetiology in POAG, it is important to be aware of the complex blood supply to the optic
nerve. The retina receives its blood supply through the common carotid artery, internal
carotid artery and ophthalmic artery (OA) with the central retinal artery (CRA) supplying
the inner retina (16) and the posterior ciliary arteries (PCAs) supplying the choroid (17). The
short PCAs (SPCA) supply the posterior choroid and the long PCAs supply the anterior choroid,
ciliary body and iris. The ONH is stratified into 4 layers. At the level of the superficial nerve
fibre layer the ONH is predominantly supplied by the inner retinal circulation and, in part, by
the SPCAs in the temporal region (8,10). The prelaminar region receives its blood supply from
the peripapillary choroid and from the SPCAs. The lamina cribrosa (LC) is supplied exclusively,
and rather surprisingly, by the SPCAs (Figure 1) and the retrolaminar region is nourished by both
the pial vessels and small branches from the CRA (10,18-20). The venous drainage of the ONH is
primarily through the central retinal vein (10,16,21).
Under normal conditions, change in intraocular pressure (IOP) and blood pressure (BP) are autoregulated by the
retinal vessels. Abnormal autoregulation has been proposed in patients with POAG (22-24). Retinal, peripapillary
and ONH capillary blood flow (25-28) have been shown to be decreased in patients with POAG, along with peripapillary
capillary atrophy (29,30). A decrease in blood flow may even play a role in the reduction of axoplasmic flow along
the retinal ganglion cell axons.
Autoregulation is defined as the ability of a tissue to maintain constant blood flow despite changes in perfusion
pressure. The retina lacks autonomic innervation and blood flow is principally regulated by a myogenically driven,
negative feedback mechanism. In most tissues, arterioles are thought to be the major site for regulation of blood
flow to the downstream capillary bed (10,31,32). However, the pericytes in retinal capillaries also regulate flow
to a lesser extent at a local level (31,33-36).
Regulation of blood flow in the ONH and retina is not only achieved through myogenic
mechanisms but also via metabolically-driven mechanisms. Regulation of flow to
metabolic stimuli is determined, for example, by the local concentration of for
example, glucose, O2, CO2 or K+
(10,32,37). The vascular endothelium lines
the lumen of arterioles and is enveloped in vascular smooth muscle cells (16,38).
The endothelium regulates blood flow by producing vasoactive substances termed
Endothelial Derived Constricting Factors (EDCF) and Endothelial Derived Relaxing
Factors (EDRF). Among the various dilating and constricting factors, nitric oxide
(NO, an EDRF) and endothelin-1 (ET-1, an EDCF) are thought to be the major signalling
factors determining vascular tone in the retina. ET-1 is a potent vasoconstrictor.
Plasma levels of ET-1 have been reported to be elevated in POAG, especially NTG,
when compared to normal subjects. NO also plays a pivotal role in maintaining
vascular tone by promoting vasodilation. Vascular tone reflects the balance of
opposing locally produced EDRFs and EDCFs, primarily NO and ET-1, respectively
(39). NO and ET-1 each act via negative feedback mechanisms to limit the action
of the other but this mechanism is thought to be affected in diseases characterized
by endothelial dysfunction. Endothelial dysfunction manifests as an inadequate
vasodilatory response following stimulation of EDRF. Endothelial dysfunction
may reflect impaired NO availability and/or excess ET-1. ET-1 may also contribute
to endothelial dysfunction indirectly through the inhibition of NO bioavailability.
However, it is not possible to assess the level of NO because of its short half
life, although the level of cyclic guanosine monophosphate (cGMP) in the plasma
has been used as an indirect measure of NO expression. It has been reported that
plasma cGMP levels are reduced in patients with POAG compared to age-matched
controls. An overall imbalance in ET-1 and NO production has been proposed in
glaucoma, in particular in POAG, and this disturbance has been suggested
to trigger a series of events that lead to dysregulation of ONH perfusion, and
the apoptotic loss of retinal ganglion cells and glaucomatous optic neuropathy
Figure 1: High definition OCT image
(Spectralis HRA-OCT, Heidelberg Engineering) through a normal optic nerve, showing a
short posterior ciliary artery (SPCA) piercing through the sclera and approaching the
lamina cribrosa. The SPCAs provide the exclusive blood supply to the lamina cribrosa. Note
the surprisingly large vessel diameter in this young, healthy subject.
The change in hemodynamic parameters in response to provocation such
as CO2 (50-53), O2 (47,54-56) or
light flicker (62-66) in the absence of a change in perfusion pressure is often referred to as vascular
reactivity, particularly in the cerebral blood flow literature. Vascular reactivity is an increasingly
important clinical concept in understanding the pathophysiology of glaucoma. The impact of arterial gas
provocation on aspects of retinal hemodynamics has been investigated in both animals and humans.
CO2 is a potent vasodilator while O2 is
a vasoconstrictor. Hypercapnia is the increase in the partial pressure of CO2
(pCO2) in the arterial blood supply and can be indirectly measured
from the peak concentration of CO2 during expiration, termed end-tidal
CO2 (ETCO2). Hypercapnia also induces
hyperventilation, which leads to an unpredictable change in the arterial partial pressure
of O2. As a result, any measured response to a hypercapnic stimulus
without consideration of end-tidal O2 levels results in a poorly
standardised methodology, due to the inter-individual variability of the hyperventilatory response
and the resulting change in arterial O2. Recent studies have
demonstrated differences of the retinal vascular reactivity response in patients with POAG when compared
to age-matched controls using hypercapnic provocation but many are complicated by the impact of
concomitant hyperventilation and confounding change in the arterial O2.
An increase in blood pressure leads to vasoconstriction of arterioles, and vice versa, and thereby maintains
blood flow and this is termed myogenic autoregulation. It occurs secondarily to the activation of stretch
activated ion channels in vascular smooth muscle cells that, in turn, allow calcium ions to enter the smooth
muscle cell to induce contraction (31,67-72). Hormonal factors also participate in the regulation of blood
flow by the signalling of blood vessel smooth muscle cells, endothelial cells and also pericytes (32,38).
In particular, the rennin-angiotensin system activates angiotensin I (AT-I) to form angiotensin II (AT-II)
by the action of angiotensin converting enzyme (ACE) (73,74). Additional neurogenic factors have been proposed
but are not definitively established in the control of human retinal blood flow (75).
The retina and the ONH autoregulate up to an IOP of 30-40mmHg in normal subjects (76-79) and choroidal
blood vessels autoregulate during an ocular perfusion pressure (OPP) increase of up to 40% (80). There
is increasing evidence that vascular dysregulation, or disturbance in autoregulation, is also an important
factor in the pathogenesis of POAG (12,23,48,81-84).
Several studies of POAG have investigated homeostatic levels
of ocular blood flow and the response of the retinal, choroidal
and ONH vasculature to various myogenic and metabolic provocations.
These studies have provided some basic understanding of the
possible vascular abnormalities associated with POAG including
an association with an imbalance of vasoactive substances such
as ET-1 (85,86). Recent developments in blood flow measurement
techniques have made the absolute quantification of hemodynamic
parameters possible (87). The majority of studies have suggested
a decrease in blood flow and a decrease in ONH perfusion in
patients with POAG, including NTG. The assessment of retinal
and ONH vascular regulation provides additional information
about ocular physiology. Importantly, we now know that vascular
regulation can be abnormal even when homeostatic retinal blood
flow is within normal limits. The ONH blood flow response to
myogenic provocation has been studied using various hemodynamic
measurement techniques. Using laser Doppler flowmetry, the
blood flow in the ONH did not show a significant change in
normal controls or patients with NTG after 3 weeks wash-out
of topical medications, to a 28% increase in perfusion pressure
during exercise 40. However, there was an increase of vascular
resistance to the alteration in OPP in the NTG group, that
likely indicates an autoregulatory disturbance (40). A similar
result was found in a study that measured change in choroidal
pulsation and ONH blood flow in response to a 20mmHg increase
in OPP, in patients with POAG (88). Similarly, altered autoregulation
has been proposed when measured in response to changes in IOP
in patients with POAG (89). A short term increase in IOP has
been shown to cause a reduced regulatory change in retinal
arteriolar and venular diameter (90). Studies on the diurnal
characteristics of untreated POAG have proposed that mean ocular
perfusion pressure is an early and independent risk factor
for the development of POAG (9). It was also shown that there
was dysfunctional autoregulation in sectors of the ONH in response
to diurnal fluctuation in blood pressure and intra-ocular pressure.
In untreated early glaucoma and age matched controls, the mean
optic nerve blood flow was autoregulated in response to diurnal
fluctuation of the ocular perfusion pressure. However, it was
found that the autoregulatory mechanism in the untreated glaucoma
group was not consistent across the entire nerve head as there
were locations, mostly in the temporal sector of the ONH that
demonstrated dysfunctional autoregulation during the day, suggesting
that regional susceptibility of the nerve head may predict
glaucomatous optic nerve damage.
An exciting new development in vascular reactivity research is the development of an automated gas
flow controller (Respiract TM, Thronhill Scientific Inc) that enables the precise and independent
manipulation of end-tidal CO2 and
end-tidal O2 thereby facilitating the production of a standardised
gas provocation, including a normoxic hypercapnic stimulus. Recent research from our own lab has used
this technique and found that arteriolar vascular reactivity to normoxic hypercapnia was reduced
in untreated POAG and also in patients with progressive POAG, when compared to healthy controls. However,
there was no difference in baseline arteriolar hemodynamics across groups. In addition, plasma ET-1 levels
were demonstrated to be lower in untreated POAG, both at baseline and during normoxic hypercapnia.
There is much still to discover on the role of abnormal blood flow as a factor in glaucoma pathogenesis
and many important questions remain unanswered. In particular, there is a need to develop clinically practical
tests for the assessment of vascular reactivity. In addition, the relationship between systemic biochemical
markers of endothelial function and functional markers of retinal and ONH vascular reactivity, assuming one
exists, needs to be defined. However we are optimistic that continued developments in diagnostic imaging
and techniques for controlled physiological provocation, will soon realize such aspirations.
John G Flanagan PhD, MCOptom, FAAO,
Subha T Venkataraman BOptom, FAAO,
Chris Hudson PhD, MCOptom, FAAO,
School of Optometry, University of Waterloo and Department of Ophthalmology and Vision Sciences,
University of Toronto.
*(This review is a precise of an article submitted for publication)
1. The glaucomas. Vol I & II. Eds: Ritch R., Shields M.B., Krupin T. St.Louis:
2. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog.Retin.Eye Res. 2001;20:595-624.
3. Cioffi GA, Granstam E, Alm A. Ocular circulation. P. Kaufman and A. Alm. In Adler's physiology of the eye. Elsevier; 2002. 747-784 pp.
4. Mackenzie PJ, Cioffi GA. Vascular anatomy of the optic nerve head. Can.J.Ophthalmol. 2008;43:308-312.
5. Grieshaber MC, Mozaffarieh M, Flammer J. What is the link between vascular dysregulation and glaucoma? Surv.Ophthalmol. 2007;52:S144-54.
6. Flammer J, Mozaffarieh M. Autoregulation, a balancing act between supply and demand. Can.J.Ophthalmol. 2008;43:317-321.
For a complete reference list to this article, click here.
ETIOLOGY OF IOP ELEVATION IN PRIMARY OPEN ANGLE GLAUCOMA
Ask any clinician or basic scientist who has studied aqueous outflow for many years "What is the etiology of IOP
elevation in POAG?" Each will have their pet theory but each will also tell you that we do not know. This review
is thus a summary of existing clues rather than a direct answer to the question, "Where does aqueous outflow
resistance reside and how is it generated?" We simply do not know. Equally important, we do not know whether
the added resistance that elevates intraocular pressure (IOP) in primary open angle glaucoma (POAG) is due to more
resistance in the same location as that in which the resistance of the normal eye is found, or an additional resistance
that is added downstream in the glaucomatous eye.
In this regard it is important to recall the corollary to Kirchhoff's law that resistances placed
in series are additive.
Only recently has evidence arisen that the added resistance of the POAG eye might lie, at least in part, in a
location other than that which appears to harbor most of the resistance in the normal eye. In this review,
we will consider some of the principal theories of outflow resistance, concluding with recent data implicating
an added resistance in a previously unappreciated location.
OUTFLOW vs RESISTANCE
Knowing where aqueous leaves the eye is quite different from knowing
where the resistance to outflow resides or how it is generated. We
know that aqueous humor leaves the human eye by two principal pathways.
The major outflow pathway is through the trabecular meshwork, into
Schlemm's canal (SC) and external collector channels, ultimately reaching
the venous blood of the episclera. The other pathway is the uveoscleral
pathway, which leads through the interstices of the ciliary muscle
to the supraciliary and suprachoroidal space to leave the eye. Most
current data suggests that uveoscleral outflow contributes little more
than 10% of total outflow in the normal eye, notwithstanding our
ability to enhance outflow via this pathway in glaucoma using prostanoids
(1,2). As such, this review will only consider resistances in the major
outflow pathway, beginning with the trabecular meshwork.
Figure 1a: Scanning
electron micrograph. This sagittal section traverses
the trabecular meshwork (TM), the juxtacanalicular region
(JCT), Schlemm's canal (SC) and one of the external
collector channels (asterisks) that leads from Schlemm's
canal to the episcleral venous system. (From Freddo
T. Chapter 3. Ocular anatomy and physiology related to
aqueous production and outflow. In: Primary Care of
the Glaucomas. Lewis T, Fingeret M, eds, Appleton and
Lange, 1993. With kind permission of The McGraw-Hill
Figure 1b: Scanning electron micrograph shows the uveal
face of the trabecular meshwork. The intersecting trabecular beams are covered by a uniform, thin layer of
endothelial cells, surrounding an avascular core of collagen and elastin. The larger open spaces seen at the
surface get progressively smaller in deeper layers. (From TF Freddo, MM Patterson, DR Scott, and DL Epstein. Influence of mercurial sulfhydryl agents on aqueous outflow pathways in enucleated eyes. Invest Ophthalmol. Vis. Sci.
1984; 25:278-285. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)
In the absence of a pumping mechanism, the flow of fluid through a
porous tissue such as the trabecular meshwork is driven passively
by gradients in osmotic and/or hydrostatic pressures. Because
there is no osmotic difference between aqueous and the blood
into which it flows (3), we are left with hydrostatic pressure
as the dominant force. So, it is the pressure difference (P)
between the IOP in the anterior chamber and that in the episcleral
veins (P = 5 mmHg) that drives aqueous humor through this system.
The ratio of this pressure difference to that of aqueous flow
(assuming a typical flow rate (Q) of 2µl/min) equals the
flow resistance (R).
The inverse of the outflow resistance is known as the outflow facility (Ctm).
Q/(Pi - Pe)
where Pi equals
IOP and Pe equals
episcleral venous pressure.
WHERE DOES NORMAL OUTFLOW RESISTANCE RESIDE?
Enroute to SC, aqueous humor leaving the anterior chamber enters the trabecular
meshwork, a nonvascularized tissue that is separated on anatomical grounds into
the uveal meshwork, the deeper corneoscleral meshwork and the still deeper juxtacanalicular
connective tissue (JCT). The uveal and corneoscleral meshwork are configured
as intersecting beams of collagen and elastin in their cores, with an enveloping
layer of thin endothelial cells. The open spaces between the beams become progressively
smaller as aqueous moves through these tissues towards SC (Figure 1). By contrast,
the juxtacanalicular tissue (JCT), just internal to SC is an open connective
tissue matrix with fibroblast-like cells in a collagen and elastin matrix (4)
Figure 2: Transmission electron micrograph shows
juxtacanlicular region (JCT) of the trabecular meshwork and inner wall of Schlemm's canal (SC). The JCT
region exhibits an open matrix including collagen (C) and elastin. The fibroblast-like cells of the region
extend slender connections to the endothelial cells lining Schlemm's canal (arrows). (From Freddo T. Chapter 3. Ocular anatomy
and physiology related to aqueous production and outflow. In: Primary Care of the Glaucomas. Lewis T,
Fingeret M, eds, Appleton and Lange, 1993. With kind permission of The McGraw-Hill Companies Inc.)
The Uveal and Corneoscleral Meshwork.
Early studies of Bárány (5) showed that perfusion of enucleated bovine eyes with hyaluronidase
reduced outflow resistance. From these studies the authors concluded that the glycosaminoglycan substrate for
this enzyme, hyaluronan or hyaluronic acid, was the principal resistive material in the outflow pathways and
presumed that it was distributed in the "open-spaces" between the trabecular beams of the uveal and corneoscleral
meshwork. Only four years later, McEwen (6) showed that there is negligible flow resistance in the uveal and
corneoscleral meshwork. Nonetheless, for many years, the notion that glycosaminoglycans (GAGs) were the resistive
material in the outflow pathway persisted. More recently, immunohistochemical studies have demonstrated the absence
of GAGs in the "open-spaces" of
the meshwork (7,8) and intracameral injection of purified testicular
hyaluronidase in living monkey eyes failed to produce either a reduction
in IOP or a change in outflow facility (9). Most glaucoma investigators
now agree that virtually none of the resistance to outflow resides
in the uveal or corneoscleral meshwork of the normal eye.
The Juxtacanalicular Region (JCT).
The tortuous and much smaller "open-spaces" for flow within the JCT have made this region an attractive candidate
as the tissue that generates the bulk of outflow resistance. But, hydrodynamic analyses have failed to support this
view. (10-12). In a particularly innovative approach, Mäepea and Bill (13) passed a micropressure sensor
through the inner wall of SC and into the meshwork, to measure the point at which the pressure drop occurred. They
found that the pressure drop occurred within 14 µm of the inner wall of SC, a position that should correspond
to a point within the JCT. These findings notwithstanding, calculations of hydraulic conductivity in the JCT,
using measurements of "open space" from
electron micrographs, show a JCT that is simply too porous to account
for the outflow resistance of the normal eye. (10-12,14-17). Indeed, even using the
challenging technique of quick-freeze/deep-etch
(QF/DE) to obtain a more fully preserved extracellular matrix in the
JCT, too much open space remained for the JCT to account
for even normal outflow resistance (18).
An important caveat of this work is that even the QF/DE technique results
in collapse of most of the glycosaminoglycans (GAGs). If these
GAGs were not collapsed, the question remains whether measurements
of "open-space" in such images (if
they could be obtained) would finally give us a calculated hydraulic
conductivity that would allow us to attribute most of the outflow
resistance to the JCT.
The inner wall of SC is composed of endothelial cells, joined by tight junctions
that simplify in complexity and tightness as IOP is raised. (19) The endothelium
of the inner wall encounters a direction of flow toward the lumen of the canal,
similar to that seen in post-capillary venules and lymphatics. (20). There are
a couple of specific features that distinguish the behavior of the inner wall
from the behavior of post-capillary venues and lymphatics. When the inner wall
is chemically fixed for microscopic examination while under conditions of flow,
large blebs are seen along the inner wall, which are termed giant vacuoles (4). We know that the size and number of these vacuoles increases with
IOP (21,22). Similar structures are also found in the choroid plexus of the brain
where cerebrospinal fluid is reabsorbed (23).
In addition to giant vacuoles, the inner wall endothelium of SC exhibits
two types of pores. Some occur at the border between adjacent
endothelial cells ("B" pores) and others are found away from the cell borders ("I" intracellular
pores) (24) (Figure 3). The issue of whether one or both of these pores
might be artifactual remains undetermined. One theory is that
B pores might correspond to areas in which intercellular tight
junctions have been focally interrupted, creating a paracellular
pathway for aqueous to enter SC (19,25).
Figure 3: Scanning electron micrograph showing pores
within the inner wall of Schlemm's canal as viewed from inside the lumen of Schlemm's canal. Left, an
intracellular or I-pore (I) and an artifactual pore with ragged edge (A); right, an intercellular
or B-pore (B) (From Ethier CR, Coloma FM, Sit AJ, Johnson M. Two pore types in the inner-wall endothelium of Schlemm's canal. Invest Ophthalmol Vis Sci. 1998; 39:2041-2048. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)
If pores were the "bottleneck" that creates resistance in the outflow
pathway one might expect to find their numbers to be inversely related
to resistance. In fact, Allingham, et al. (1992) found that the density
of pores in the inner wall was inversely correlated with resistance
under conditions of perfusion at constant pressure and variable flow.
But when these studies were repeated under conditions of constant flow
with variable pressure, no such relationship was found. (24,27,28).
This leaves uncertain whether pores might be a source of resistance
in the normal eye. But importantly, in both studies, regardless of
perfusion conditions, glaucomatous eyes exhibited fewer pores than
normal eyes (28). Could it be that a change in the capacity of the
endothelium to produce pores in response to changes in pressure and
flow could create an added resistance?
THE FUNNELING EFFECT
There is evidence to support the notion that pores and the JCT may
interact in a way that would not be predicted from anatomy alone. Based
upon fluid dynamic modeling, even if pores and vacuoles contribute
minimal resistance themselves, they could force fluid to flow in limited
patterns to reach them. This phenomenon has been referred to as the "funneling effect".
This model predicts that with flow headed for a small population of
pores, only a limited portion of the JCT is realistically available
for flow, thus increasing resistance (29) (Figure 4).
Figure 4: Schematic representation of the flow pattern
predicted by the "funneling" hypothesis as aqueous moves through the JCT region towards the limited
population of pores in the inner wall of Schlemm's canal. (From Overby D, Gong H, Qiu, G., Freddo T.F., Johnson, M. . "The mechanism of increasing outflow facility during washout in the bovine eye." Invest Ophthalmol Vis Sci. 2002; 43: 3455-3464. With kind permission of copyright holder, the Association for Research in Vision and Ophthalmology.)
External Collector Channels.
Because the external collector channels are tens of microns in diameter,
calculations indicate that these vessels should have negligible flow
resistance (30-33). Still, smooth muscle cells have been found within
the walls of these vessels at their point of origin, raising the issue
of whether they can be regulated at these points in a way that could
increase resistance by contracting (34). Moreover, several investigators
have perfused enucleated eyes following 360 degree trabeculotomy, which
should eliminate all resistance internal to the collector channels.
Results consistently show that only 75% of resistance is eliminated
(35). More study in this area is needed because it suggests that total
resistance, even in the normal eye, is the result of more than one
resistance coupled in series.
WHAT CAUSES THE ADDED RESISTANCE IN POAG AND WHERE IS IT?
Speculating on the source of added resistance in POAG is daunting, especially
when one begins with uncertainty as to the source(s) and location(s) of the resistance
in the normal eye. While there is general presumption that the resistance of
the normal eye resides within the JCT and/or inner wall of SC, or some dynamic
combination of both, this does not guarantee that the additional resistance found
in the eye with glaucoma is the result of higher resistance in the same location(s).
As mentioned earlier, resistances in series are additive. Thus it is possible
that a resistance could be created in the glaucomatous eye that does not exist
at all in the normal eye. Based upon the discussion above, a host of candidates
present for consideration, either singly or in combination.
Extracellular Matrix, Sheath-derived plaques and the Cribriform Plexus.
It has long been noted that there is a progressive accumulation of
extracellular matrix in the JCT region with age. Much of this material,
at least in POAG, is associated with the sheaths of the elastic fibers
of the cribriform plexus (36). Notwithstanding this progressive accumulation
of material, available data do not appear to support the notion that
this added material is sufficient in amount to have any hydrodynamic
consequences (16,37). It is important to note here that this conclusion
is based upon the assumption that the microscopically discernable open
space in these specimens truly reflects the open space present in-vivo.
The cribriform plexus mentioned above is the system of tendons from
the smooth muscle cells of the longitudinal bundle of the ciliary
muscle extending into the meshwork and applying tension to
the JCT region and directly to the inner wall (38). We know that as IOP increases, SC collapses (39,40) and
in doing so additional resistance is created (41,42). Preventing collapse
of SC is likely the mechanism whereby muscarinic agents, such
as pilocarpine, act to decrease outflow resistance (14). These
agents cause the longitudinal fibers of the ciliary muscle
to contract, thus pulling on the cribriform plexus and tethering
the wall of SC open in the face of pressure increases. In this
way, the canal remains open and normal resistance is maintained.
(38,43). Could it be that the documented increase
in "sheath-like material" compromises
the ability of the cribriform plexus to contract, and therefore to
hold the canal open in the absence of the stronger pull of
a muscarinic agent such as pilocarpine?
Contractility and Matrix Interactions.
Even if the source and location of the added resistance in POAG remain unknown,
interventions that reduce resistance and therefore reduce intraocular pressure
can provide us with clues.
Y-27632 is a protein kinase inhibitor selective for Rho associated kinase (ROCK)
(44-46). ROCK regulates the phosphorylation of the regulatory myosin light chain
(MLC) to promote actomyosin-driven cell contractility. By inhibiting ROCK with
Y-27632, MLC phosphorylation is decreased (47,48), resulting in cell relaxation
and disassembly of actin stress fibers and focal adhesions in many cell types
(49), Included among these cell types are human trabecular meshwork (TM) and
SC endothelial cells in-vitro (49,50). Relaxation of stress fiber and focal
adhesions would be expected to facilitate aqueous outflow.
H-7, a serine–threonine kinase inhibitor, also induces relaxation of
cells in the trabecular meshwork. It is hypothesized that H-7-induced
cellular relaxation in the TM may be partially related to its ability
to inhibit Rho kinase (51).
Another group of cell/matrix active agents, latrunculins, also alter
outflow resistance. Latrunculins disrupt cellular F-actin filaments
(52,53). The two most common latrunculins, latrunculin (LAT)-A and
-B, cause reversible dose- and incubation time-dependent destruction of actin bundles and
associated proteins in cultured trabecular meshwork cells. (52-57). These agents also increase outflow
facility in live monkeys, presumably by disrupting the actin cytoskeleton in meshwork cells, leading to relaxation
of the meshwork and/or alteration of cell–cell and cell–extracellular
matrix adherens junctions (55,58).
It is of interest that the effects of these various agents are to produce
changes in the meshwork that are strikingly similar to those resulting
from a phenomenon called the wash-out effect (59). When eyes of all
species but humans are perfused, the resistance to outflow decreases
with the volume of fluid (60). The structural correlate for this increase
in facility appears to be similar to that reported following intervention
with these various agents. Common features include expansion of the
subendothelial JCT matrix and distention of the inner wall of SC. Such
changes were reported following Y-27632 perfusion in porcine and bovine
eyes (49), H-7 (61) and latrunculin-B (62) in monkeys, and these changes
are morphologically similar to the "matrix-matrix" type of inner wall/JCT separation previously
shown to correlate with increasing outflow facility during "washout" in bovine eyes (59,63).
Combining these results it would appear that inner wall/JCT separation appears to be a critical change
underlying both drug-induced and washout-induced increases in outflow facility (59,63). What is unclear from
these studies is whether these agents are pointing us toward "the" source of resistance or "a" source
of resistance in the normal eye and the eye with POAG.
It is clear that most of the research in the area of trabecular outflow
resistance, at least in the normal eye, is now focused squarely on
the JCT and inner wall of SC, either separately or in combination.
And yet, despite decades of research, we remain at a loss to convincingly
identify morphological differences in the outflow pathway that would
seem to account for the change in intraocular pressure between normal
eyes and those with early or moderate glaucoma, using existing methods.
Logically, there are several possible explanations. One is that we
simply have not yet found the right methods that will give us a "true picture" of
the open-spaces in the meshwork and the extent to which the spaces
open to flow are reduced in glaucoma. But another possibility is that
a site that offers little or no resistance in the normal eye, becomes
an added resistance in glaucoma because resistances in series are additive!
Figure 5: At 7 mmHg, the aqueous plexus (AP) is more
open compared to the tissue perfused at higher pressures. At 15mmHg, there is focal herniation (arrows) of
the inner wall and JCT at the collector channel (CC) ostium. At 30 and 45mmHg more dramatic herniations of
the inner wall and JCT into the collector channel ostia were found. (From Battista, S.A., Lu Z., Hofmann, S., Freddo, T.F., Overby, D.R., Gong, H. "Acute IOP elevation reduces the available area for aqueous humor outflow and induces meshwork herniations into collector channels of bovine eyes". Invest. Ophthalmol. Vis. Sci. 2008, 49:5346-52. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)
A recent line of evidence by Gong, Freddo and Zhang (64), points to the possibility
that the normally low resistance openings from SC into the external collector
channels may become occluded in glaucomatous eyes. They have documented that
as pressure is elevated, areas of the inner wall of SC progressively collapse
and the attached portions of the JCT that face the openings of the external collector
channels herniate into the openings. In normal eyes, as pressure is reduced,
these herniations withdraw from the openings, relieving them of this partial
occlusion (65) (Figure 5). Of particular interest, however, when enucleated eyes
from patients with POAG were examined, seemingly permanent herniations into the
openings of the collector channels were found, even at a pressure of zero. This
line of investigation has opened up the possibility that glaucoma could be the
result of a series of events, affecting resistance at more than one site along
the outflow pathway.
Candidates for the site or sites of outflow resistance in the normal eye are
being narrowed but the mechanisms that regulate outflow facility remain elusive.
The same remains true for the added resistance in glaucoma, but recent studies
suggest that both trabecular and non-trabecular elements of the outflow pathway
deserve consideration as we continue to unravel this elusive mystery.
Thomas F. Freddo, OD, PhD, DSc(hc), FAAO,
School of Optometry, University of Waterloo,
Waterloo, Ontario, Canada
Haiyan Gong, MD, PhD
Boston University School of Medicine,
Supported by: National Glaucoma Research, a program of the American Health Assistance
Foundation, NIH EY-09699, The Massachusetts Lions Eye Research Fund, Inc., The University of Waterloo, School of Optometry.
For a complete reference list to this article click here.
OPTIC NERVE HEAD BIOMECHANICS IS IMPORTANT IN GLAUCOMA, BUT THE SCLERA IS IMPORTANT AS WELL
Lowering intraocular pressure (IOP) remains the only proven method of preventing the onset and
progression of glaucomatous vision loss, yet the role of IOP in the neuropathy remains controversial. This
arises, in part, from the clinical observation that significant numbers of patients with epidemiologically
normal levels of IOP develop glaucoma (e.g. normotensive glaucoma), whereas other individuals with elevated
IOP may show no signs of the disease over extended periods. In this text we present why the study of ocular
biomechanics is relevant in elucidating the role of IOP and individual sensitivity to IOP. We concentrate on
some of the concepts which we believe are central to understanding the role of the sclera on the mechanics of
the lamina cribrosa (LC).
IOP is the load exerted by the intraocular fluids on the tissues that contain them, and is, by definition, a mechanical
entity. Therefore, while glaucoma is most certainly a multifactorial disease, we believe that it is natural to hypothesize
that biomechanics plays a role in the development and progression of the neuropathy. The optic nerve head (ONH) is of
particular interest from a biomechanical perspective, because it is a weak spot within an otherwise strong corneo-scleral
shell. Also, most evidence suggests that damage to the retinal ganglion cell axons within the LC is the principal
pathophysiology underlying glaucomatous vision loss and ONH cupping.
In the biomechanical paradigm of glaucomatous optic neuropathy, the susceptibility of a particular patient's ONH to IOP
insult is a function of both the acute and long-term biomechanical response of the constituent tissues to elevated
IOP and the resulting mechanical, ischemic and cellular events driven by that response. Eyes with a particular combination
of connective tissue geometry, stiffness and blood supply may be more susceptible to damage at normal levels of IOP, whereas
others may have a combination of these factors that can withstand prolonged periods of relatively high levels of IOP. One of
the challenges of ocular biomechanics is identifying the particular combinations that render an eye more or less susceptible
to the effects of elevated IOP.
Before discussing ocular biomechanics further, it is worth mentioning some terms and concepts from mechanics: Strain is
a measure of the local deformation of a material or tissue, and is usually expressed as the percentage change in length of
the original geometry (e.g. a wire that was originally 10 mm long that has been stretched an additional 1 mm,
exhibits 10% strain). Stress is a measure of the load applied to, transmitted through, or carried by a material or
tissue. For example, the action of IOP on the inner eye wall induces forces (stress) that may deform (strain) the sclera. Note
that mechanical stress is not synonymous with the notions of stress typically used in physiologic or metabolic
contexts (e.g. ischemic or oxidative stress).
Stress and strain (i.e. force and deformation) in a material are related to each other through the material's mechanical
properties. These mechanical properties, often called the material properties, can be thought of as the stiffness or
compliance intrinsic to the material. Hence, under load, a stiff tissue might be under high stress, but exhibit low strain,
whereas an equal shape made of compliant tissue might undergo high strains, even at low levels of stress.
The sclera is the stiffest tissue in the posterior pole of the eye, and is therefore the main load bearing component. Other
tissues, such as the retina, choroid and optic nerve, are much more compliant, meaning that under IOP these tissues may undergo
large strains while still not carrying substantial loads. These soft tissues depend on the stiffer sclera for support and
are essentially shielded by the sclera from loads that would otherwise strain them excessively. The LC is likely somewhere
in between the soft tissues and the sclera, because the laminar beams are composed of stiff connective tissues similar to
that of the sclera, yet it is very porous (LC connective tissue volume fraction is approximately one third) (1). The
mechanical response of the LC to elevated IOP is thus expected to be complex from a purely material perspective. Unfortunately
there are further complications.
Figure 1. Example of how the factors governing scleral
mechanics may combine and interact to affect lamina cribrosa biomechanics. The graph shows computed
tensile strains in the prelaminar neural tissues versus scleral shell thickness for two different scleral
mechanical properties, a compliant sclera (upper curve) and a stiff sclera (lower curve). The plot shows
a strong interaction between the two variables. Specifically, when the sclera is compliant, increased shell
thickness leads to reduced strains, whereas when the sclera is stiff, changes in shell thickness have virtually
no effect on the predicted strains. Conversely, the effects of an increase in stiffness (the distance between
the two lines) are larger in eyes with thin scleral shells (left side) than in eyes with thick
shells (right side). Adapted from 2
The mechanical response of tissue also depends on its geometric characteristicsthe amount of material
and its geometry (Figure 1). The same load induces smaller deformations (lower strains) in a thick bar than
in a thin one, assuming both bars are made of the same material. It is useful to define structural stiffness,
which incorporates both the mechanical properties and geometry into a composite measure of a structure's
resistance to deformation.
Mechanically, the posterior pole of the eye responds to IOP elevations as a system whose structural stiffness
depends on the geometry and mechanical properties of the sclera and LC, and to a lesser extent the other
tissues. Hence, two eyes exposed to identical IOPs may exhibit very different strain and stress fields due to
differences in their structural stiffness (Figure 2). From the perspective of the LC its mechanical response
to IOP is linked to that of the peripapillary sclera because the sclera transmits load to the laminar structure
at its insertion into the scleral canal wall. Therefore, the structural stiffness of the peripapillary sclera
has a significant influence on IOP-related laminar deformation.
Figure 2. En-face views of 3D biomechanical models of the
posterior sclera and ONH. The colors represent the magnitude of stresses induced by elevated IOP. The
plot on the left shows the stress in an idealized model with a circular canal in a perfectly spherical
scleral shell of uniform thickness. The plot on the right shows the stress in a model with an elliptical
scleral canal in a scleral shell with a more anatomically realistic shape and thickness. The thickness of
the peripapillary sclera and the size and shape of the scleral canal influence the magnitude and distribution
of the stress. In both cases, the stresses concentrate around the scleral canal, but the more realistic model
on the right shows stress that varies substantially around the canal and that can extend further out into
the sclera. For clarity, only the scleral tissue stress is shown. Adapted from 9
Computational models have been used to study the factors that determine
scleral response to IOP (2,3). Not surprisingly, these models suggest
that the response of the sclera depends on its mechanical properties
and certain aspects of its geometry (mainly thickness and the globe
size). But these studies also suggest that the factors determining
the scleral response interact with one another, meaning that the effects
of one factor depend on the level of another. This means that anticipating
how the factors combine to determine the scleral structural stiffness
is not necessarily trivial.
The models suggest that a structurally compliant sclera allows the
scleral canal to expand during an acute IOP elevation, tautening the
lamina within the canal and "pulling" it anteriorly. In contrast, a stiffer sclera allows minimal
expansion of the canal. IOP acting directly on the anterior laminar surface "pushes" the lamina in
the posterior direction (Figure 3). The resultant deformation of the lamina for a given change in IOP
is therefore governed by its own structural stiffness, by the extent to which the scleral canal expands
and rotates, pulling the lamina taut and bending or twisting itan indirect action of IOP, and by the
extent to which the lamina itself is deformed posteriorlya
direct action of IOP. The net result of the superposition of these
effects is that it is possible for the anterior-to-posterior deformation
of the LC to be negligible, while the LC is subjected to substantial
strain and stress. In the case of a stiff sclera it is also possible
that IOP induces negligible canal expansion but substantial anterior-to-posterior
deformation of the lamina.
Figure 3. Diagram showing how the mechanical response
of the sclera can influence laminar biomechanics. In the case of a compliant sclera (left), IOP induces
large scleral deformations that result in a large scleral canal expansion that pulls the contained
lamina taut, despite the direct posterior force of IOP on the laminar surface. Conversely, a stiff sclera
deforms very little when exposed to IOP (right), with a correspondingly small scleral canal expansion and
little stretching of the contained lamina, thus allowing the lamina to be displaced posteriorly by the
direct action of IOP on its surface. Note that the structural stiffness of the lamina itself will also
play a role in its deformation. Adapted from 9
The question ariseswhat type of laminar deformation, and its associated modes
of stress and strain are "worse" for
axons? Could the manner in which the lamina deforms be an indicator
of individual susceptibility? The answers to these questions are unknown.
Computational modeling is providing insight, but definitive answers
will not be possible until new imaging technologies are developed.
However, it is still likely that the mode of deformation per se will
be less important for maintenance of healthy axons than will be the
particulars of laminar stress and strain.
Classical structural engineering analysis seeks to identify stresses and strains within a structure to
determine possible modes and regions of failure. However, the long-term nature of the development of
glaucoma suggests that this may not be the most adequate approach in ocular biomechanics as it relates
to glaucoma. A biomechanical view of the ONH must also seek to understand how the stress and strain borne
by the sclera and lamina are related to cellular responses and the resulting tissue remodeling. Such relationships
have been observed in other tissues; tendon, cartilage, arteries and bone are known to regulate tissue composition
and structure through cellular activity based on the stress and strain environment in vivo (4-6). Recent studies
suggest that the eye is not an exception. LC astrocytes have been shown to respond to mechanical stimulation that
likely leads to changes in the extracellular matrix (4,6). The lamina and sclera from glaucomatous eyes have
distinctly different tissue composition and mechanical properties than those from normal eyes (7,8). Hence,
while biomechanics likely plays a prominent role in the pathophysiology of glaucoma, much work remains to elucidate
the mechanisms through which it acts, the other factors with which it interacts, and the changes in the ocular
tissues that it engenders.
J. Crawford Downs
Ocular Biomechanics Laboratory, Devers Eye Institute,
Legacy Health System, Portland, OR
Ocular Biomechanics Laboratory, Devers Eye Institute,
Legacy Health System, Portland, OR
Department of Biomedical Engineering, Tulane University, New Orleans, LA
Support: NIH-BRIN/INBRE Grant P20 RR16456 from NCRR
1. Roberts MD, Grau V, Grimm J, Reynaud J, Bellezza A, Burgoyne CF, Downs JC. Remodeling of
the Connective Tissue Microarchitecture of the Lamina Cribrosa Occurs Early in Experimental Glaucoma
in the Monkey Eye. Invest Ophthalmol Vis Sci 2008.
2. Sigal IA. Interactions between geometry and mechanical properties on the optic nerve head.
Invest Ophthalmol Vis Sci In Press.
3. Sigal IA, Flanagan JG, Ethier CR. Factors influencing optic nerve head biomechanics. Invest
Ophthalmol Vis Sci 2005;46(11):4189-99.
4. Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog
Retin Eye Res 2000;19(3):297-321.
5. Kirwan RP, Fenerty CH, Crean J, Wordinger RJ, Clark AF, O'Brien CJ. Influence of cyclical mechanical
strain on extracellular matrix gene expression in human lamina cribrosa cells in vitro. Mol Vis 2005;11:798-810.
6. Pena JD, Agapova O, Gabelt BT, Levin LA, Lucarelli MJ, Kaufman PL, Hernandez MR. Increased elastin
expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. Invest
Ophthalmol Vis Sci 2001;42(10):2303-14.
7. Downs JC, Suh JK, Thomas KA, Bellezza AJ, Hart RT, Burgoyne CF. Viscoelastic material properties
of the peripapillary sclera in normal and early-glaucoma monkey eyes. Invest Ophthalmol Vis Sci 2005;46(2):540-6.
8. Quigley HA, Dorman-Pease ME, Brown AE. Quantitative study of collagen and elastin of the optic nerve
head and sclera in human and experimental monkey glaucoma. Curr Eye Res 1991;10(9):877-88.
9. Sigal IA, Roberts MD, Girard M, Burgoyne CF, Downs J. Biomechanical changes of the optic
disc. In: Levin LA, Albert DM, eds. Ocular disease: mechanisms and management. New York: Elsevier, In Press 2009.
Recognition of World Glaucoma Day on Capitol Hill
To recognize the second annual World Glaucoma Day (WGD) on March 12, the Association for Eye and Vision Research (AEVR)
sponsored a March 10 Capitol Hill briefing to educate Members of Congress and their staff. The event was timely, as the
Senate was passing the Fiscal
Year (FY) 2009 Omnibus appropriations bill, which increases National Eye Institute (NEI) funding by $21.4
over FY2008. That annual spending increase, coupled with the $175
million in two-year funding for NEI research from the American Recovery and Reinvestment
Act of 2009, means nearly $200 million more for vision research.
In introducing the briefing, AEVR Executive Director James Jorkasky read from a March 6 statement
issued by the NEI for WGD in which its Director Paul Sieving, M.D., Ph.D., noted that NEI
currently spends $65 million in support of 168 glaucoma studies, including the newly initiated NEI Glaucoma
Human genetics collaBORation, known as NEIGHBOR, through which seven U.S. research teams will lead genetic
studies of the disease.
The featured speakers included Murray Fingeret, O.D., F.A.A.O., (Brooklyn/St. Albans Campus, Department of
Veterans Administration New York Harbor Health Care System, Exec VP, OGS), who spoke about the incidence and burden
of the disease, and Rohit Varma, M.D., M.P.H., (Doheny Eye Institute, University of Southern California), who spoke
about research and treatments. Both speakers had participated in a March13-14, 2008, joint NEI/Food and Drug Administration
(FDA) Glaucoma Endpoints meeting at which researchers acknowledged that glaucoma is a complex, neurodegenerative disease
in which detectable changes within the eye may not progress linearly or in concert with functional changes, that is, vision loss.
Left to right: The speakers, Rohit Varma and Murray Fingeret
are seen with Cong. John Boozman (R-AR).
World Glaucoma Congress 2009
The Optometric Glaucoma Society and the World Glaucoma Association would like
to invite optometrists to attend the 2009 World Glaucoma Congress (WGC), to be
held in Boston, MA from July 8-11th. Clinicians and scientists from around the
world will come together to discuss and learn about glaucoma. The world's experts
will be present in a forum only seen every other year. This is the first time
the WGC is being held in North America, and should provide a great learning environment
for all ODs. Click here for information
about the meeting.
POLL RESULTS FROM PREVIOUS ISSUE
The results of our most recent Live Poll are finalized and presented. It is encouraging to note that 82% of respondents always explain to newly diagnosed glaucoma patients the cause of their condition. Clinicians and scientists will recognize that our current best understanding of the cause of glaucoma will continue to evolve.
The responses to the question of the largest contributor to the cause of primary open angle glaucoma (POAG) were much more varied. Forty percent believe the principle causative factor to be either deficiency of the vascular supply to the optic nerve (11%) or specifically the susceptibility of the optic nerve to damage (29%). Fifty-one percent of respondents believe the main contributing factor of POAG varied between individuals. This diversity of responses is not surprising given the complicated processes that are involved. This information is encapsulated in this edition by our review articles.
This is a promising time for patients with glaucoma and better understanding of pathogenesis means that this is an exciting time for clinicians and scientists. Stay tuned!
John McSoley, OD
Paul Spry PhD MCOptom
Brad Fortune, OD,
Shaban Demirel, BScOptom,
Algis Vingrys BScOptom,
Douglas Anderson MD
Paul Artes PhD MCOptom
Dick Bennett OD
Murray Fingeret, OD
Ron Harwerth, PhD
Chris Johnson, PhD
Tony Litwak, OD
John McSoley, OD
Ron Melton, OD
Bruce Onofrey, OD, RPh
Leo Semes, OD
Randall Thomas, OD
Thom Zimmerman, MD, PhD
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