Download Glaucoma: Macrocosm to Microcosm The

L
E
C
T
U
R
E
Glaucoma: Macrocosm to Microcosm
The Friedenwald Lecture
Harry A. Quigley
J
onas Stein Friedenwald, the son and grandson of ophthalmologists, was born in Baltimore in 1897. He attended Johns
Hopkins Medical School, graduating in 1920. After medical
internship, he spent 1 year studying ophthalmic pathology
with Fredrich Verhoeff (Harvard), had a 1-year preceptorship
with George de Schweinitz (Philadelphia), and then began
practice without further training. He seemed not to need it.
He was in charge of “Ophthalmic Pathology,. . .and directed
the lion’s share of research activities of the Wilmer Institute”
from 1923 to his death in 1955.1(p24) He excelled at the correlation of clinical and pathologic findings, as continued by A.
Edward Maumenee and W. Richard Green at Wilmer after him.
He was described as a “many faceted genius,” accomplished in
physics, mathematics, chemistry, and ophthalmology. In his
1949 Proctor Lecture,2 he summarized evidence that the formation of aqueous humor was an energy-dependent, enzymedriven process. These ideas led to the development of carbonic
anhydrase inhibitors for glaucoma treatment. He placed the
calibration of the Schiotz tonometer on an experimental, scientific footing and studied “ocular rigidity”—an area engaging
the glaucoma field at present in the interaction between cornea and tonometry.3
He wrote on the relation between art and vision mechanisms and debated legal theory with his friend, Supreme Court
Justice Felix Frankfurter. Norman Ashton wrote of Jonas: “His
intellectual grasp of scientific problems and his remarkable
knowledge of many widely different fields of art and learning
made him a quite exceptional person by any standards.”4(p58)
He was instrumental in the development of Hadassah Hebrew
University Medical Center in Israel, visiting in 1936 and 1945
and lecturing in Hebrew.
Robert Moses, his student and colleague, wrote: “He applied physics in his studies on tonometry, chemistry to his
work on aqueous secretion. . . , and optics in his design of an
advanced ophthalmoscope. . . . If a given problem needed
knowledge he did not possess, he simply got some recent
books on the subject, sat down and studied.”4(p58) Wilmer
Chairperson Alan C. Woods stated: “When the pathogenesis of
chronic glaucoma is finally resolved and understood, I am
confident that the solution will rest largely on the foundations
laid down by Jonas Friedenwald.”1(p26)
From the Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Supported in part by National Eye Institute Grants EY02120 and
EY01765 and by The Leonard Wagner Trust, The Robert Wood Johnson Foundation, The Hoffberger Foundation, The Seidler Family Trust,
Mary and Sidney Foulger, and Jonathan Javitt, MD, MPH.
Disclosure: H.A. Quigley, None
Corresponding author: Harry A. Quigley, Director, Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Institute,
Room 122, Johns Hopkins University School of Medicine, Baltimore,
MD 21287; [email protected].
DOI:10.1167/iovs.04 –1070
Investigative Ophthalmology & Visual Science, August 2005, Vol. 46, No. 8
Copyright © Association for Research in Vision and Ophthalmology
During his 32 years of scientific work, he “devoted himself
tirelessly to a large practice. He was never too busy or too tired
to give his skill, his attention and his time to any needy or ill
patient.”1(p27) Thus, Jonas Friedenwald was the epitome of an
ophthalmic clinician scientist. He is a role model to whom all
of us can aspire. As I walk the halls of Wilmer, caring for
glaucoma patients and chasing the mysteries of this disease, I
have often felt the presence of this gentleman giant whose
portrait gazes at us from the wall of the Friedenwald Library. I
could not hope for a greater honor than to receive an award in
his name.
THE SETTING
I had the good fortune to work as a student in the laboratories
of Nobelist George Wald and past ARVO awardees Jay Enoch
and John Dowling. I was first intrigued by glaucoma in 1973,
challenged by friend and teacher Irvin Pollack and by my
ophthalmic father Ed Maumenee. At that time, angle closure
and open-angle glaucoma (OAG) had been conclusively distinguished by gonioscopy, while optic disc photography and
Goldmann perimetry produced standardized evaluations of
nerve damage, and eye drop therapy was becoming somewhat
more acceptable. Laser iridotomy was in its infancy, and laser
angle treatment was 5 years off. We did the first trabeculectomy at Wilmer that year.
But, OAG was then considered a disease of “elevated” intraocular pressure (IOP). We were puzzled by the occurrence
of high IOP in many persons with no disease, while some OAG
sufferers had normal IOP. Epidemiology had scarcely been
applied to determine the prevalence of OAG (except by Mansour Armaly5 and Fred Hollows (Hollows and Graham6)), nor
were its risk factors clear. Clinical changes observed in the
optic disc were not understood histopathologically. Fields
seemed to remain “normal” while the disc increasingly
“cupped,” then function rapidly worsened, confounding our
understanding of the rate of progression. It was often said that
OAG was a disease that couldn’t be diagnosed properly and for
which treatment wasn’t proven to work.
In this report, I will describe aspects of OAG that we now
understand better, focusing on subjects that I have studied in
collaboration with many colleagues. In each area, the remaining challenges will be highlighted.
THE MACROCOSM
OAG Defined
OAG is now defined as a disease of retinal ganglion cells
(RGCs), characterized by structural change in the optic disc
that is best described as excavation, and by a typical, slowly
progressive loss of function that begins in the midperipheral
field and expands both toward the center and peripherally.
There is considerable variation in the normal appearance of the
optic disc7–9 and in the number of RGCs from one person to
2663
2664
Quigley
another.10,11 These differences challenge our ability to distinguish normal from glaucoma as the RGCs die and their axons at
the disc rim are lost. However, the study of population-based
data allows us to define glaucoma operationally for the purpose
of comparisons across studies by using the combined criteria:
a cup/disc ratio so large that it is found in only 2.5% of a
population and visual field defects on automated perimetry in
characteristic locations and severity.12 This definition has now
been used relatively widely, and its usefulness has been evaluated by several epidemiologic groups.13 The level of IOP is no
longer a defining criterion for OAG, but it is an important risk
factor (discussed later).
Prevalence
The glaucomas comprise the second leading cause of blindness
worldwide, after cataract, having surpassed trachoma during
the past decade.14,15 Glaucoma affects more than 50 million
persons and bilaterally blinds more than 7 million. More than
two-thirds of those with primary glaucoma have OAG. These
estimates were constructed from a meta-analysis of existing
prevalence data 10 years ago that was based on age- and
gender-specific world population data. To make the numbers
more relevant to OAG, the world was divided into more logical
groupings than simple geographic or national ones (all Africanderived persons, regardless of continent, were placed in one
group, for example). My teenage son, David, made this possible by performing the first download to a private home from
the U.S. Census Bureau population data.
Much of the world’s OAG is undiagnosed, with only 50% of
cases recognized in developed countries. Even within the
Johns Hopkins Health Care system, a sizable minority of those
with OAG are unaware of their disease.16 In studies by colleagues at Wilmer’s Dana Center, it was reported that the
burden of blindness from OAG and other eye diseases falls
more on the elderly and the poor.17–19 Inspired by the epidemiologic approaches suggested by Alfred Sommer, groups led
by Sheila West, Jim Tielsch, Joanne Katz, and Beatriz Muñoz
continue to learn about the complete spectrum of glaucoma in
populations, rather than trying to determine its nature by
analysis of clinic-based chart data. The prevention of OAG
clearly lies in understanding its fundamental nature and its
contributing risk factors.
Incidence and Progression
To analyze how OAG affects populations, I estimated its incidence—the number of new cases per year at each age. While
this might be calculated by serial examinations of large groups
over extended periods, Leske, Ederer, and Podgor20 suggested
that incidence could be inferred from age-specific prevalence
of OAG. This results from two key features of OAG: once
present, it does not go away; and persons with OAG do not die
faster than the general population. Thus, the rate of new cases
per year should be approximately the incremental increase in
prevalence from younger age groups to older ones. Using this
approach, Susan Vitale and I21 estimated OAG incidence for
European- and African-derived persons. Direct estimates by
follow-up examinations have corroborated our measures.22,23
It is now clear that OAG incidence increases with age, so that
there is a more than linear increase in disease with age. Using
incidence data, we showed how many persons among a defined population will develop OAG in their lifetime and how
long the average OAG person has the disease. This “life-table”
analysis, though dependent on several assumptions, showed
that the typical person with OAG lives approximately 15 years
from initial field loss to death.21
The progression rate for OAG with and without therapy has
been studied recently. It was widely believed that many per-
IOVS, August 2005, Vol. 46, No. 8
sons with glaucoma lose useful vision.24 On the contrary,
population studies document that fewer than 10% of those
with OAG become bilaterally blind.21 Some clinic-based data
appeared to show worse outcomes, but those in the care
system typically have more severe disease. To estimate progression rate, we used a similar method to that for estimating
incidence from prevalence—namely, we calculated mean damage in younger compared with older OAG patients.25 The
resultant slow progression estimated by this method was confirmed in clinical trials,26 as well as in our own longitudinal
studies.27 Approximately 4% of those with OAG have progressive field loss each year of treated follow-up. With an average
length of disease of 15 years, only 60% would be expected to
have any progression, and most do not become significantly
impaired.
Some have (wrongly) concluded from this finding that
“OAG isn’t that bad.” OAG blinds a modest proportion of those
with the disease, but since it is a highly prevalent disorder, this
small proportion is a large absolute number. Furthermore, our
estimates are the mean worsening rate—there are some persons who are injured much more quickly than average. Those
who develop OAG early in life are exposed to the risk of
progression for longer times. It is vitally important that we
develop better methods to measure progression so that aggressive treatment can be offered to these individuals at greater
risk, while preventing those with a more benign course from
suffering the side effects of therapy.
It can be estimated that 1.3 million ocular hypertensive
(OH) OAG suspects are receiving topical preventive therapy in
the United States. If the life-table model is applied, it is estimated that the average OH lives 25.5 years from onset to death,
with nearly 50% moving from OH to OAG status in their lives
(2% per year). Treatment is estimated to cut this conversion
rate in half, sparing 325,000 persons (25% of the total) from
OAG. Conservatively, the unilateral blindness rate from treated
OAG is 20%; hence, 65,000 eyes per year are likely to be saved
from blindness by OH treatment. Annual prostaglandin therapy
costs over $800 per year. Thus, with 25 years of therapy in
2004 dollars ($26 billion), the cost is $400,000 per eye saved
from blindness. It is important that we evaluate both the
individual and the public health consequences of our therapies.
Case Identification (Screening)
The identification of OAG cases in a population is more challenging than the screening for cataract. For adequate predictive power, we must combine two methods of examination:
one for disc structure, one for visual function.28 However,
screening is performed in various contexts, each with a different, optimal approach.29 Community screening programs in
the United States have, unfortunately, a low yield at high
cost.30 In the developing world, case identification is even
more challenging and is impractical for most countries, though
it can be accomplished with extraordinary effort for demonstration or research studies.31,32
In medical care offices, screening with expensive technology may be practical,33 but this has not yet been applied in an
effective way. Too often, a promising set of data generated in
one group of patients is not generalizable to other groups.34 It
is hoped that laser-based imaging devices can be tested in
nonophthalmic care delivery offices with a national, central
reading system to sort suspects from the population at risk.
Risk Factors for OAG Prevalence
To improve case identification, as well as to understand the
causes of OAG, it is important to define its risk factors. Diseases
rarely have only one “cause”; rather, they have groups of
IOVS, August 2005, Vol. 46, No. 8
necessary and contributing factors that differ among persons
with identical phenotypes. A necessary factor in one person
(higher than normal IOP) may be merely contributing in another and not at all present in others. Some risk factor analyses
have dramatically changed our ideas about OAG.
OAG prevalence increases with age, with startlingly high
rates of disease in the very elderly found by David Friedman in
the Salisbury Eye Evaluation OAG study (Friedman DF, personal
communication, December 2004). Since RGCs die during aging, OAG can be thought of as accentuated neuronal aging,
associated with a sagging optic nerve head. Rohit Varma35
found that the nerve rim area of the optic disc was related to
IOP level— higher IOP was associated with fewer nerve fibers
among normal persons. Possibly, the level of IOP affects the
age-related loss of RGC. Of course, aging could affect other
potentiators of OAG progression. Furthermore, age is a surrogate for duration of exposure to the other risk factors for OAG.
The most fundamental change in our view of OAG and IOP
came from clinical observations of Stephen Drance36 and epidemiologic analyses by Al Sommer37 in the Baltimore Survey.
The IOP levels of those with OAG overlapped with the normal
population distribution, though, on average, OAG cases had a
higher mean IOP. While OAG was more common at higher
IOP, it occurred nearly as often at normal IOP. Since there
were so many more persons in a population with lower IOP,
the prevalence of OAG at lower IOP was substantial. Thus,
there was no reason to differentiate between the mythical
“low-tension” and “high-tension” OAG, except artificially.
Indeed, analyses of OAG that dichotomize using the ancient
“magic number” 21 mm Hg do themselves a disservice. By
looking only at those with IOP lower or higher than an arbitrary criterion value, they reduce study sample size and the
statistical power to assess risk. In addition, they probably miss
associations that occur in the “other” half of the IOP distribution. IOP should be treated as a parameter, not a cutoff criterion, in order better to understand and study OAG. In OAG
treatment, IOP-lowering is now known to work in lower38 and
higher39 IOP ranges, and we individualize the therapeutic
approach by establishing baseline and target pressures for each
patient, as described by Henry Jampel.40
OAG has a familial occurrence,41 but persons are more
likely to report a positive family history if they have been
previously diagnosed. deJong (Wolfs et al.13) examined all
available family members of a population-based OAG cohort,
estimating 10 times greater risk for first-degree family members. I suggest that targeted projects to increase surveillance
among first-degree relatives would be more highly productive
than random screening. The exciting era of specific OAG genes
began with the discovery of myocilin by Stone, Fingert, and
Alward,42 but we must heed the lesson of other disorders in
which mutations in different genes are associated with similar
phenotype, mutations in a single gene that cause different
clinical pictures, and large numbers of persons with normal
alleles have indistinguishable OAG from those with mutations.
We will learn much from glaucoma’s genetic elements, but
they will not solve everything.
High blood pressure (HBP) has been considered an OAG
risk factor, but the Baltimore Survey43 found a more complex
relationship. Younger persons with HBP are less likely to have
OAG than young normotensives, while older persons with HBP
are at greater risk for OAG. We speculated that the vascular
perfusion of the RGC layer was higher in young eyes with HBP
and that their vessels had not yet undergone chronic damage,
leading to a protective effect. The elderly with HBP, on the
other hand, had vessel damage from prolonged disease, and
their RGCs had poorer nutrition as a result. In addition, lower
BP combined with higher IOP (low perfusion) was a much
more serious risk factor than HBP overall. When the difference
The Friedenwald Lecture
2665
between diastolic BP and IOP is below 50 mm Hg, the risk of
OAG goes up by four times or more. We must investigate the
autoregulation of retinal and optic nerve blood flow in vivo to
elucidate this risk area, and prospective studies in this area are
needed.
While diabetes mellitus was traditionally considered to be
an OAG risk factor, Tielsch et al.44 found no such association,
and other population-based surveys have found no consistent
relationship.45– 48 This is intriguing, since diabetics have higher
IOP than nondiabetics in every survey. Could diabetes, at least
before overt retinopathy, have protective effects that counterbalance the higher IOP? This speculation was supported by the
Ocular Hypertension Treatment Study (OHTS)49 and Early Manifest Glaucoma Trial (EMGT) surveys, in which diabetes was
protective against progressive disease in OH and early OAG.
We typically ignore findings that are dissonant with established
dogma, but I suggest that the vascular permeability defects in
early diabetes may provide protective, serum-derived growth
factors to the RGCs.
Optic disc diameter varies widely in normal subjects, leading to OAG misdiagnosis in large discs with large cup-disc
ratios. Two population studies50,51 show a slightly greater OAG
risk in eyes with larger disc diameter. Caprioli (Caprioli and
Miller52) had shown that larger discs have more nerve fibers.
Biomechanically, a bigger hole in the eyewall would more
poorly resist deformation, suggesting that RGC axons might die
faster in a big disc. This detrimental effect would be balanced
by inherently greater reserve in RGC numbers in big disc eyes.
The fact that high refractive error is also associated with
greater OAG risk may relate to features of the eyewall size,
thickness, and configuration. Differences in disc anatomy may
play a role in greater OAG risk among African-derived persons,
since their discs are larger but have fewer RGC axons for the
same size disc as European-derived persons.9 This combination
confers the biomechanical disadvantage of large size without
the compensation of more fibers.
We must begin to differentiate between risk factors for the
occurrence of disease and those that are associated with progression of disease or response to therapy. These categories
may contain different factors, or factors may be opposite in
two areas (e.g., pigment dispersion syndrome is contributory
to OAG, but is more likely to respond favorably to laser angle
treatment).
In some cases, it is important to ponder why some attributes are not risk factors. When a risk factor study finds a
lack of association, we tend to stop thinking about that factor.
Why isn’t cigarette smoking a factor in OAG (as it is for cataract
and macular degeneration)? Does this suggest that its detrimental effects on oxygenation, vascular perfusion, and free radical
generation are not relevant in OAG?
Ethnic Differences in OAG
The Baltimore Survey53 found greater OAG risk for Africanderived than European-derived persons. Since higher OAG
prevalence is also true of African-derived persons in Tanzania54
and Barbados,55 this risk crosses large differences in culture,
economy, diet, and health delivery among these populations.
Yet, no genes have been identified among African-derived
persons—an area demanding investigation. We must be cautious about ascribing a disease association to gene effects when
the result may be socioculturally derived. Even the designations of ethnicity (“race”) are challengeable on scientific
grounds. Ethnic differences in risk may be partly explained by
lack of access to care, differential response to therapy, cultural
attitudes that inhibit compliance, and the many consequences
of lower economic status. Compared to European-derived persons, OAG prevalence is higher in U.S. Hispanics,46 and in
2666
Quigley
Indians,56 but is similar in prevalence among Chinese.57 Paul
Foster and coworkers58 report that tonometric IOP in Asians
may read differently from Europeans. Whether this is a tonometric artifact or an important pathophysiological difference in
ocular biomechanics remains to be investigated.
CLINICAL OAG DAMAGE
Optic Disc
IOVS, August 2005, Vol. 46, No. 8
humans do best. Disc imaging devices can be forced to yield a
cup-disc ratio, but they detect and follow damage much better
by use of parameters like cup shape measure, neural network
analysis, and average change in superpixel zone topography.
What the human eye does well should be complemented by
what machines can uniquely do better.
Visual Field
We strengthened the concept that structural alteration in the
disc and NFL precedes functional abnormality by showing in
human OAG eyes that a substantial minority of RGCs die before
manual or automated perimetric defect.81– 83 This should not
necessarily be used as evidence that all OAG suspects should
be treated, rather it may stimulate the search for more sensitive
and reliable signs of early injury. In early or moderate damage,
we found that OAG causes selectively greater loss of largerdiameter RGCs with larger axon diameters projecting to the
magnocellular lateral geniculate body.84,85 The anatomic facts
supporting this finding have been confirmed in other laboratories in rats, cats, and monkeys with experimental glaucoma,
as well as in human OAG.86 If we accept that there is selective
death of larger RGCs, its pathophysiological basis deserves
further investigation.
As stated by Robert Shaffer, OAG patients don’t care what
their eye pressure is, they care if they can see. It has been of
great interest to us to test how visual field damage (the ophthalmologist’s view of OAG injury) affects persons with the
disease. Quality-of-life questionnaires describe how persons
report the effects of OAG on their functionality. Alternatively,
one can test the actual tasks such as reading, face recognition,
mobility,87 and automobile driving. We know little about
whether it is functionally better to have one normal eye and
one severely damaged eye, or, to have two moderately damaged eyes.88 More studies are needed on the functional effects
of OAG.
The most fundamental difference between OAG and other
optic neuropathies is the physical excavation of the disc. Douglas Anderson and Anita Hendrickson59 demonstrated that acute
IOP elevation in monkeys produces axonal transport obstruction at the nerve head, and I had the joy of working for 2 years
in Doug’s laboratory, detailing how this block was localized to
the portion of the nerve head at the level of the sclera, reversed
after short IOP elevations,60 and correlated with RGC death
after chronic blockade.61
In human OAG eyes, clinical–pathologic correlation shows
that the connective tissue of the lamina cribrosa stretches
backward, collapses its successive plates, and rotates outward
on its scleral insertion to give the typical excavated appearance.62 This does not happen in ischemic optic neuropathy,63
in which RGC death follows a similar distribution, nor in
primary atrophy after optic nerve transection.64 The connective tissue alteration underlying excavation can be produced in
monkey eyes that have high IOP,65 as demonstrated by John
Morrison66 or in human OAG, whether IOP is high or not,67,68
implying that biomechanical effects on nerve head tissue underlie the clinical uniqueness of OAG and its pathophysiology.
The fact that excavation occurs in eyes with OAG at normal
IOP suggests that their lamina cribrosa stretches under forces
that do not distort normal nerve heads and that require higher
IOPs to produce in many eyes. Hence, abnormal connective
tissue response is a likely factor in those with OAG at normal
IOP. Connective tissue structural genes would be good candidates for study in persons with OAG at lower IOP.
The regional architecture of normal nerve heads explains,
in part, why RGCs whose axons pass through the upper and
lower disc die first in OAG. The connective tissue in the nerve
head polar regions is quantitatively thinner,69 providing less
resistance to deformation and contributing to RGC death in an
hourglass pattern.70,71 This is the only known feature of ocular
anatomy or physiology that corresponds to the OAG pattern of
RGC loss; the pattern differs in ischemic72 or compressive73
optic neuropathy. It is important to see whether new methods
of blood flow measurement in regions of the nerve head can
detect regional differences prospectively linked either to connective tissue movement or axon loss. Point-in-time studies will
never solve etiological issues in OAG, as we know that blood
vessels and flow decrease simply as an effect of RGC loss.
It was formerly common to see debates pitting simplistic “mechanical” or “vascular” theories of OAG against one another.
With present sophistication, we realize that many factors can
be contributory and that both biomechanics and vascular nutrition are contributing issues in damage. But, newer, basic
knowledge of neuronal death processes has touched OAG
research. While a study of secondary glaucoma offered evidence for photoreceptor loss,89 we found that photoreceptors
and other retinal layers are generally intact in primary human
OAG90 and only RGCs die. What do we know about RGC death
and what is the next step in research?
Nerve Fiber Layer
How Do RGCs Die?
74
Hoyt et al. recognized that nerve fiber layer (NFL) atrophy in
OAG was visible ophthalmoscopically in green light. Neil Miller
(Sommer et al.75) brought the method to Wilmer, where Al
Sommer (Quigley et al.76) led our efforts to show that detectable NFL damage predicted future OAG visual field loss. With
disc rim change and disc hemorrhage, NFL examination remains one of the few prospectively documented predictors of
functional OAG damage. Through clinical–pathologic comparisons in human OAG eyes77,78 and monkeys,79,80 NFL thickness
was shown to be useful in detecting and monitoring OAG
damage, especially when implemented in laser imaging devices. The digital imagers may soon show prospective predictive power. Part of our difficulty in implementing new technology is the tendency to force machines to duplicate what
THE MICROCOSM
Who Dies in OAG Damage?
Clearly, one site of injury is the RGC axon at the level of the
nerve head where orthograde and retrograde axonal transport
are blocked. In 1994, we found that apoptotic RGC death
occurs in experimental monkey91 and human OAG,92 as well
as in other optic neuropathies (a line of research suggested by
Robert Nickells [Quigley et al.91] and Don Zack [Kerrigan et
al.92]). While many disorders have been reported to be somehow associated with apoptosis, in OAG a logical theory that
links known events and apoptotic cell death suggested itself.
RGCs receive protein signals (neurotrophins) from target neurons in the brain that support their survival. In embryologic
life, RGCs that grow an axon to the proper target receive
brain-derived neurotrophic factor (BDNF) and live, while
mistargeted RGCs die by turning on their apoptotic, pro-
The Friedenwald Lecture
IOVS, August 2005, Vol. 46, No. 8
grammed death genetic sequence. This parsimonious system
prunes two of three early RGCs that would represent excess
retinal baggage.
Gene Therapy for RGCs
If BDNF dependence continues during adult life, the blockade
of axonal transport in OAG would cut off the supply coming
from the brain, possibly reactivating the cell death program. In
this scenario, pathology recapitulates ontogeny. Mary Ellen
Pease, who has headed our laboratory efforts so capably,
showed that BDNF is blocked from entry into the eye by
experimental glaucoma (Quigley et al.93), as is the transport
molecule on which it travels.94 To prove this theory directly,
Hani Levkovitch-Verbin95generated a reproducible model of
IOP elevation in the rat, to allow large-scale, therapeutic studies. Keith Martin96 produced an adeno-associated viral vector
that expressed the human BDNF gene in the inner retina.
Replacement of BDNF in the rat glaucoma model salvaged
nearly 40% of RGC that would otherwise have died.
The hypothesis that neurotrophin withdrawal leads to RGC
death suggests that cell death follows by pathways of intracellular alteration that have been delineated in other cell types.
Stuart McKinnon97 found that cysteine proteases were activated in the rat glaucoma model. This pathway leads to cell
death by digestion of nuclear DNA. This idea led to another
successful gene therapy experiment that preserved RGC in rat
glaucoma by blocking the activation of caspase enzymes.98
Upstream Inhibition of Injury
While these experiments suggest new therapeutic avenues for
OAG, we should be asking how the earliest injury to RGC
might be avoided. If we wait until RGCs are in extremis, it is
more difficult to avoid ultimate neuronal death than if we
stopped the process “upstream.” Since change in lamina cribrosa connective tissues is the keystone of clinical glaucoma
detection and since regional laminar architecture is the explanation of typical field loss pattern, we infer that change in
connective tissue is important in OAG injury. The lamina is
heavily invested with elastin that helps it stand up to 85 years
of ocular pulsation without irreversible stretching. In the OAG
nerve head studies, the number of elastin molecules is unchanged (as reported by Erica Quigley), but their appearance
suggests that they are disconnected from the remainder of the
extracellular matrix.99 –102 Burgoyne103 found a loss of elastic
compliance of the nerve head in acute and chronic IOP elevation experiments in monkeys. The elastin gene or those of
associated extracellular fibrils would be fine choices as candidate OAG genes.
How do RGC axons sense that their environment has
changed, leading to blocked axonal transport? There are pressure-sensitive channels in axonal membranes that may respond
to deformation caused by lamina cribrosa strain. These TRAAK
channels are linked to intracellular actin and microtubular
networks. External compression and/or disturbed energy metabolism could block transport by affecting key motor proteins,
kinesin in the direction toward the brain (orthograde for RGCs)
and dynein for transport toward the RGCs (retrograde). We
have found that experimental glaucoma alters dynein, perhaps
affecting neurotrophin transport toward the cell body along
tubulin tracks using ATP power. Protection of this transport
system may represent an important new therapeutic direction
for OAG.
Dynein-mediated transport runs on ATP energy, and so poor
autoregulation of nutritional blood flow may participate in
ultimate RGC death at this site. In our studies of nerve head
blood flow in chronic monkey glaucoma, axons died without
any detectable decrease in flow or loss of capillary struc-
2667
ture.104 –107 This shows that RGCs can be injured in normal
monkeys without altering blood vessels or flow (i.e., other
factors are sufficient). The monkey experiments do not negate
the high likelihood that poor autoregulation of flow may be a
contributing feature of OAG damage in some elderly humans.
Other Factors Implicated in Damage to RGCs
A variety of other mechanisms have been implicated in OAG
damage. How some of these relate to other risk factors for
glaucoma is, as yet, unclear. For example, glutamate neurotoxicity has been proposed as a mechanism in OAG injury. We
detected disequilibrium responses in the number of glutamate
transporters in experimental glaucoma,108 others report possible therapeutic success in blocking glutamate excitotoxicity
experimentally,109 and human clinical trials are now ongoing.
But, it is unclear why excess glutamate would be present to
injure RGCs in OAG. Perhaps it results from the same neurotrophin signal failure and is a midlevel step in damage. If it
results from already ongoing damage or death of RGCs, then it
would be a secondary degeneration event. It may be more
useful to augment glutamate transport (sequestration) than to
block its receptors.
Oxidative free radicals are implicated in many neuronal
disorders, and there are several reports of possible involvement
in OAG. Typically, oxidative damage occurs in the penumbra
of major vascular injury as a secondary feature. Recent study of
gene expression patterns with microarray analysis by Ron
Farkas et al.110 have shown that experimental glaucoma and
human OAG are associated with increased expression of ironregulating genes that are intended to block free radical damage.
Again, this mechanism may play a role in secondary damage,
but how it becomes activated by the early events of OAG is
unknown at this time.
The 2002 Friedenwald awardee Michal Schwartz111 suggested that immune-mediated phenomena may play a role in
causing or preventing optic nerve damage. The beneficial effects of Copaxone immune therapy show promise, but it also
may block only secondary damage events. To study secondary
degeneration in isolation, we devised a model of partial transection of the optic nerve.112,113 Primary injury to upper retinal RGCs is caused by transection, while injury in the inferior
retina occurs only if secondary excitotoxic or immune-mediated events are the basis for RGC death. We hope to use this
model to dissect in greater detail the events of primary compared to secondary RGC injury.
Acknowledgments
The names of many colleagues, teachers, and friends have appeared
here to highlight who truly did the work involved. Two of my coworkers were my children, David and Erica, others are my surrogate children, and all comprise a research family that has hopefully had fun in
the objective enterprise of generating a few new facts about a complex
disease that is rapidly opening its petals to our poking. Thanks to
Cristina for her love and support and to ARVO for this high honor.
References
1. Woods AC. Jonas S. Friedenwald: In Memoriam. Bull Johns Hopkins Hosp. 1956;99:23– 43.
2. Friedenwald JS. The formation of the intraocular fluid. Proctor
Award Lecture of the Association for Research in Ophthalmology.
Am J Ophthalmol. 1949;32:9 –27.
3. Friedenwald JS. Contribution to the theory and practice of tonometry. Am J Ophthalmol. 1937;20:985–1024.
4. Welch RB. The Wilmer Ophthalmological Institute: 1925–2000:
The First Seventy-Five Years. Annapolis, MD: Eastwind Publishing; 2000.
2668
Quigley
5. Armaly MF. On the distribution of applanation pressure. I. Statistical features and the effect of age, sex, and family history of
glaucoma. Arch Ophthalmol. 1965;73:11–18.
6. Hollows FC, Graham PA. Intra-ocular pressure, glaucoma and
glaucoma suspects in a defined population. Br J Ophthalmol.
1966;50:570 –586.
7. Quigley HA, Brown AE, Morrison JC, Drance SM. The size and
shape of the optic disc in normal human eyes. Arch Ophthalmol.
1990;108:51–57.
8. Quigley HA, Coleman AL, Dorman-Pease ME. Larger optic nerve
heads have more nerve fibers in normal monkey eyes. Arch
Ophthalmol. 1991;109:1441–1443.
9. Varma R, Tielsch JM, Quigley HA, et al. Race-, age-, gender-, and
refractive error-related differences in the normal optic disc. Arch
Ophthalmol. 1994;112:1068 –1076.
10. Sanchez RM, Dunkelberger G, Quigley HA. The number and
diameter distribution of axons in the monkey optic nerve. Invest
Ophthalmol Vis Sci. 1986;27:1342–1350.
11. Repka MX, Quigley HA. The effect of age on normal human optic
nerve fiber number and diameter. Ophthalmology. 1989;96:26 –
31.
12. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition
and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86:238 –242.
13. Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de
Jong PT. Genetic risk of primary open-angle glaucoma: population-based familial aggregation study. Arch Ophthalmol. 1998;
116:1640 –1645.
14. Quigley HA. The number of persons with glaucoma worldwide.
Br J Ophthalmol. 1996;80:389 –393.
15. Thylefors B, Negrel AD. The global impact of glaucoma. Bull
World Health Org. 1994;72:323–326.
16. Wang F, Ford D, Tielsch JM, Quigley HA, Whelton PK. Undetected eye disease in a primary care clinic population. Arch Intern
Med. 1994;154:1821–1828.
17. Tielsch JM, Sommer A, Witt K, Katz J, Royall RM, the Baltimore
Eye Survey Research Group. Blindness and visual impairment in
an American urban population: The Baltimore Eye Survey. Arch
Ophthalmol. 1990;108:286 –290.
18. Muñoz B, West SK, Rubin GS, et al. and the SEE Study team.
Causes of blindness and visual impairment in a population of
older Americans: the SEE Study. Arch Ophthalmol. 2000;118:
819 – 825.
19. Rodriguez J, Sanchez R, Muñoz B, et al. Causes of blindness and
visual impairment in a population-based sample of US Hispanics.
Ophthalmology. 2002;109:737–743.
20. Leske MC, Ederer F, Podgor M. Estimating incidence from agespecific prevalence in glaucoma. Am J Epidemiol. 1981;113:606 –
613.
21. Quigley HA, Vitale S. Models of open-angle glaucoma prevalence
and incidence in the United States. Invest Ophthalmol Vis Sci.
1997;38:83–91.
22. Leske MC, Connell AM, Wu SY, et al. Incidence of open-angle
glaucoma: the Barbados Eye Studies. Arch Ophthalmol. 2001;
119:89 –95.
23. Mukesh BN, McCarty CA, Rait JL, Taylor HR. Five-year incidence
of open-angle glaucoma: the visual impairment project. Ophthalmology. 2002;109:1047–1051.
24. Quigley HA, Maumenee AE. Long-term follow-up of treated openangle glaucoma. Am J Ophthalmol. 1979;87:519 –527.
25. Quigley HA, Tielsch JM, Katz J, Sommer A. The rate of progression in open-angle glaucoma. Am J Ophthalmol. 1996;122:355–
363.
26. Lichter PR, Musch DC, Gillespie BW, et al. and the CIGTS Study
Group. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to
medications or surgery. Ophthalmology. 2001;108:1943–1953.
27. Smith SD, Katz J, Quigley HA. Analysis of progressive change in
automated visual fields in glaucoma. Invest Ophthalmol Vis Sci.
1996;37:1419 –1428.
28. Tielsch JM, Katz J, Singh K, et al. A population-based evaluation of
glaucoma screening: The Baltimore Eye Survey. Am J Epidemiol.
1991;134:1102–1110.
IOVS, August 2005, Vol. 46, No. 8
29. Quigley HA. Current and future approaches to glaucoma screening. J Glaucoma. 1998;7:210 –219.
30. Quigley HA, Park CK, Tracey PA, Pollack IP. Community screening for eye disease by lay persons: the Hoffberger program. Am J
Ophthalmol. 2002;133:386 –392.
31. Quigley HA, West SK, Muñoz B, Mmbaga BBO, Glovinsky Y.
Examination methods for glaucoma prevalence surveys. Arch
Ophthalmol. 1993;111:1409 –1415.
32. Congdon NG, Quigley HA, Hung PT, Wang TH, Ho TC. Screening
techniques for angle-closure glaucoma in rural Taiwan. Acta Ophthalmol. 1996;74:113–119.
33. Wang F, Quigley HA, Tielsch JM. Screening for glaucoma in a
medical clinic with photographs of the nerve fiber layer. Arch
Ophthalmol. 1994;112:796 – 800.
34. Vitale S, Smith SD, Quigley HA, et al. Screening performance of
functional and structural measurements of neural damage in
open-angle glaucoma: a population-based case-control study. J
Glaucoma. 2000;9:346 –356.
35. Varma R, Hilton SC, Tielsch JM, Katz J, Quigley HA, Sommer A.
Neural rim area declines with increase in intraocular pressure in
urban Americans. Arch Ophthalmol. 1995;113:1001–1008.
36. Drance SM. Some factors in the production of low tension glaucoma. Br J Ophthalmol. 1972;56:229 –242.
37. Sommer A, Tielsch JM, Quigley HA, Gottsch JD, Javitt J, Singh K.
Relationship between intraocular pressure and primary open
angle glaucoma among white and black Americans: The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090 –1095.
38. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients
with normal-tension glaucoma and patients with therapeutically
reduced intraocular pressures. Am J Ophthalmol. 1998;126:487–
497.
39. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein
M, the EMGT group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.
Arch Ophthalmol. 2002;120:1268 –1279.
40. Jampel HD. Target pressure in glaucoma therapy. J Glaucoma.
1997;6:133–138.
41. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt J. Family history
and risk of primary open angle glaucoma: The Baltimore Eye
Survey. Arch Ophthalmol. 1994;112:69 –73.
42. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene
that causes primary open angle glaucoma. Science. 1997;275:
668 – 670.
43. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC. Hypertension, perfusion pressure and primary open-angle glaucoma: a
population-based assessment. Arch Ophthalmol. 1995;113:216 –
221.
44. Tielsch JM, Katz J, Quigley HA, Javitt JC, Sommer A. Diabetes,
intraocular pressure and primary open-angle glaucoma in The
Baltimore Eye Survey. Ophthalmology. 1995;102:48 –53.
45. Leske MC, Connell AM, Wu SY, Hyman LG, Schachat AP. Risk
factors for open-angle glaucoma. The Barbados Eye Study. Arch
Ophthalmol. 1995;113:918 –924.
46. Quigley HA, West SK, Rodriguez J, Muñoz B, Klein R, Snyder R.
The prevalence of glaucoma in a population-based study of
Hispanics: Proyecto Ver. Arch Ophthalmol. 2001:119;1819 –
1826.
47. Mitchell P, Smith W, Chey T, Healey PR. Open-angle glaucoma
and diabetes: the Blue Mountains eye study, Australia. Ophthalmology. 1997;104:712–718.
48. McKay R, McCarty CA, Taylor HR. Diabetic retinopathy in Victoria, Australia: the Visual Impairment Project. Br J Ophthalmol.
2000;84:865– 870.
49. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension
Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714 –
720.
50. Quigley HA, Varma R, Tielsch JM, Katz J, Sommer A, Gilbert DL.
The relationship between optic disc area and open-angle
glaucoma: The Baltimore Eye Survey. J Glaucoma. 1999;8:347–
352.
IOVS, August 2005, Vol. 46, No. 8
51. Healey PR, Mitchell P. The relationship between optic disc area
and open-angle glaucoma. J Glaucoma. 2000;9:203–204.
52. Caprioli J, Miller JM. Optic disc rim area is related to disc size in
normal subjects. Arch Ophthalmol. 1987;105:1683–1685.
53. Tielsch JM, Sommer A, Katz J, Royall RM, Quigley HA, Javitt J.
Racial variations in the prevalence of primary open angle
glaucoma: The Baltimore Eye Survey. JAMA. 1991;266:369 –374.
54. Buhrmann RR, Quigley HA, Barron Y, West SK, Oliva MS, Mmbaga
BBO. The prevalence of glaucoma in a rural east African population. Invest Ophthalmol Vis Sci. 2000;41:40 – 48.
55. Leske MC, Connell AM, Schachat AP, Hyman L. The Barbados Eye
Study. Prevalence of open angle glaucoma. Arch Ophthalmol.
1994;112:821– 829.
56. Ramakrishnan R, Nimalan PK, Krishnadas R, et al. Glaucoma in a
rural population of southern India: the Aravind comprehensive
eye survey. Ophthalmology. 2003;110:1484 –1490.
57. Foster PJ, Oen FT, Machin D, et al. The prevalence of glaucoma
in Chinese residents of Singapore: a cross-sectional population
survey of the Tanjong Pagar district. Arch Ophthalmol. 2000;118:
1105–1111.
58. Foster PJ, Wong JS, Wong E, Chen FG, Machin D, Chew PT.
Accuracy of clinical estimates of intraocular pressure in Chinese
eyes. Ophthalmology. 2000;107:1816 –1821.
59. Anderson DR, Hendrickson A. Effect of intraocular pressure on
rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol. 1974;13:771–783.
60. Quigley HA, Anderson DR. The dynamics and location of axonal
transport blockade by acute intraocular pressure elevation in
primate optic nerve. Invest Ophthalmol. 1976;15:606 – 616.
61. Quigley HA, Addicks EM. Chronic experimental glaucoma in
primates. II. Effect of extended intraocular pressure on optic
nerve head and axonal transport. Invest Ophthalmol Vis Sci.
1980;19:137–152.
62. Quigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21
eyes. Ophthalmology. 1979;10:1803–1827.
63. Quigley HA, Anderson DR. Cupping of the optic disc in ischemic
optic neuropathy. Trans Am Acad Ophthalmol Otolaryngol.
1977;83:755–762.
64. Quigley HA, Anderson DR. The histologic basis of optic disk
pallor in experimental optic atrophy. Am J Ophthalmol. 1977;
83:709 –717.
65. Quigley HA, Hohman RM. Laser energy levels for trabecular
meshwork damage in the primate eye. Invest Ophthalmol Vis Sci.
1983;24:1305–1306.
66. Morrison JC, Dorman-Pease ME, Dunkelberger GR, Quigley HA.
Optic nerve head extracellular matrix in primary optic atrophy
and experimental glaucoma. Arch Ophthalmol. 1990;108:1020 –
1024.
67. Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve
damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol. 1981;99:635– 649.
68. Quigley HA, Hohman RM, Addicks EM, Massof RS, Green WR.
Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol. 1983;95:673–
691.
69. Dandona L, Quigley HA, Brown AE, Enger C. Quantitative regional structure of the normal human lamina cribrosa. Arch Ophthalmol. 1990;108:393–398.
70. Quigley HA, Addicks EM. Regional differences in the structure of
the lamina cribrosa and their relation to glaucomatous optic
nerve damage. Arch Ophthalmol. 1981;99:137–143.
71. Radius RL, Gonzales M. Anatomy of the lamina cribrosa in human
eyes. Arch Ophthalmol. 1981;99:2159 –2162.
72. Quigley HA, Miller NR, Green WR. The pattern of optic nerve
fiber loss in anterior ischemic optic neuropathy. Am J Ophthalmol. 1985;100:769 –776.
73. Levin PS, Newman SA, Quigley HA, Miller NR. A clinico-pathologic study of cranial mass lesions with quantification of remaining axons. Am J Ophthalmol. 1983;95:295–306.
74. Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer
defects in glaucoma. Invest Ophthalmol. 1973;12:814 – 829.
The Friedenwald Lecture
2669
75. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve
fiber atrophy precedes the onset of glaucomatous field loss. Arch
Ophthalmol. 1991;109:77– 83.
76. Quigley HA, Katz J, Derick RJ, Gilbert D, Sommer A. An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology.
1992;99:19 –28.
77. Quigley HA, Miller NR, George T. Clinical evaluation of nerve
fiber layer atrophy as an indicator of glaucomatous optic nerve
damage. Arch Ophthalmol. 1980;98:1564 –1571.
78. Quigley HA. Examination of the retinal nerve fiber layer in the
recognition of early glaucoma damage. Trans Am Ophthalmol
Soc. 1986;84:920 –966.
79. Quigley HA, Addicks EM. Quantitative studies of retinal nerve
fiber layer defects. Arch Ophthalmol. 1982;100:807– 814.
80. Weinreb RN, Dreher AW, Coleman A, Quigley HA, Shaw B, Reiter
K. Histopathologic validation of Fourier-ellipsometry measurements of retinal nerve fiber layer thickness. Arch Ophthalmol.
1990;108:557–560.
81. Quigley HA, Addicks EM, Green WR. Optic nerve damage in
human glaucoma. III. Quantitative correlation of nerve fiber loss
and visual field defect in glaucoma, ischemic neuropathy, disc
edema, and toxic neuropathy. Arch Ophthalmol. 1982;100:135–
146.
82. Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell
atrophy correlated with automated perimetry in human eyes with
glaucoma. Am J Ophthalmol. 1989;107:453– 464.
83. Kerrigan-Baumrind LA, Quigley HA, Pease ME, Kerrigan DF,
Mitchell RS. The number of ganglion cells in glaucoma eyes
compared to threshold visual field tests in the same persons.
Invest Ophthalmol Vis Sci. 2000;41:741–748.
84. Quigley HA, Sanchez RM, Dunkelberger GR, L’Hernault NL, Baginski TA. Chronic glaucoma selectively damages large optic
nerve fibers. Invest Ophthalmol Vis Sci. 1987;28:913–920.
85. Quigley HA, Dunkelberger GR, Baginski TA, Green WR. Chronic
human glaucoma causes selectively greater loss of large optic
nerve fibers. Ophthalmology. 1988;95:357–363.
86. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res.,
1998;18:39 –57.
87. Turano KA, Rubin GS, Quigley HA. Mobility performance in
glaucoma. Invest Ophthalmol Vis Sci. 1999;40:2803–2809.
88. Jampel HD, Friedman DS, Quigley HA, Miller R. Correlation of the
binocular visual field with patient assessment of vision. Invest
Ophthalmol Vis Sci. 2002;43:1059 –1067.
89. Panda S, Jonas JB. Decreased photoreceptor count in human eyes
with secondary angle-closure glaucoma. Invest Ophthalmol Vis
Sci. 1992;33:2532–2536.
90. Kendell KR, Quigley HA, Kerrigan LA, Pease ME, Quigley EN.
Primary open-angle glaucoma is not associated with photoreceptor loss. Invest Ophthalmol Vis Sci. 1995;36:200 –205.
91. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ,
Zack DJ. Retinal ganglion cell death in experimental glaucoma
and after axotomy occurs by apoptosis. Invest Ophthalmol Vis
Sci. 1995;36:774 –786.
92. Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME. TUNELpositive ganglion cells in human primary open angle glaucoma.
Arch Ophthalmol. 1997;115:1031–1035.
93. Quigley HA, McKinnon SJ, Zack DJ, et al. Retrograde axonal
transport of brain-derived neurotrophic factor in retinal ganglion
cells is blocked by acute intraocular pressure elevation in rats.
Invest Ophthalmol Vis Sci. 2000;41:3460 –3466.
94. Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack
DJ. Obstructed axonal transport of the neurotrophin receptor
TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci. 2000;
41:764 –774.
95. Levkovitch-Verbin H, Quigley HA, Martin KRG, Valenta D, Kerrigan-Baumrind, LA, Pease ME. Translimbal laser photocoagulation
to the trabecular meshwork as a model of glaucoma in rats. Invest
Ophthalmol Vis Sci. 2002;43:402– 410.
96. Martin KRG, Quigley HA, Zack DJ, et al. Gene therapy with
brain-derived neurotrophic factor protects retinal ganglion cells
in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2003;44:
4357– 4365.
2670
Quigley
97. McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA, et al. Caspase
activation and amyloid precursor protein cleavage in rat ocular
hypertension. Invest Ophthalmol Vis Sci. 2002;43:1077–1087.
98. McKinnon SJ, Lehman DM, Tahzib NG, et al. Baculoviral IAP
repeat-containing-4 protects optic nerve axons in a rat glaucoma
model. Mol Ther. 2002;5:780 –787.
99. 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;10:877–
888.
100. Quigley HA, Brown A, Dorman-Pease ME. Alterations in elastin of
the optic nerve head in human and experimental glaucoma. Br J
Ophthalmol. 1991;75:552–557.
101. Quigley HA, Pease ME, Thibault D. Change in the appearance of
elastin in the lamina cribrosa of glaucomatous optic nerve heads.
Graefes Arch Clin Exp Ophthalmol. 1994;232:257–261.
102. Quigley EN, Quigley HA, Pease ME, Kerrigan LA. Quantitative
studies of elastin in the optic nerve heads of persons with openangle glaucoma. Ophthalmology. 1996;103:1680 –1685.
103. Burgoyne CF, Quigley HA, Thompson HW, Vitale S, Varma R.
Early changes in optic disc compliance and surface position in
experimental glaucoma. Ophthalmology. 1996;102:1800 –1809.
104. Quigley HA, Flower RW, Addicks EM, McLeod DS. The mechanism of optic nerve damage in experimental acute intraocular
pressure elevation. Invest Ophthalmol Vis Sci. 1980;19:505–517.
105. Quigley HA, Hohman RM, Addicks EM. Quantitative study of
optic nerve head capillaries in experimental optic disk pallor.
Am J Ophthalmol. 1982;93:689 – 699.
106. Quigley HA, Hohman RM, Addicks EM, Green WR. Blood vessels
IOVS, August 2005, Vol. 46, No. 8
107.
108.
109.
110.
111.
112.
113.
of the optic disk in chronic glaucoma. Invest Ophthalmol Vis Sci.
1984;25:918 –931.
Quigley HA, Hohman RM, Sanchez RM, Addicks EM. Optic nerve
head blood flow in chronic experimental glaucoma. Arch Ophthalmol. 1985;103:956 –962.
Martin KRG, Levkovitch-Verbin H, Valenta D, Baumrind, L, Pease
ME, Quigley HA. Retinal glutamate transporter changes in experimental glaucoma and following optic nerve transection in the
rat. Invest Ophthalmol Vis Sci. 2002;43:2236 –2243.
Neufeld AH, Sawada A, Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal
ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad
Sci USA. 1999;96:9944 –9948.
Farkas RH, Chowers I, Hackam AS, et al. Increased expression of
iron-regulating genes in monkey and human glaucoma. Invest
Ophthalmol Vis Sci. 2004;45:1410 –1417.
Schwartz M. Neurodegeneration and neuroprotection in
glaucoma: development of a therapeutic neuroprotective
vaccine: the Friedenwald lecture. Invest Ophthalmol Vis Sci.
2003;44:1407–1411.
Levkovitch-Verbin H, Quigley HA, Kerrigan-Baumrind LA, D’Anna
S, Kerrigan DF, Pease ME. Optic nerve transection in monkeys
may result in secondary degeneration of retinal ganglion cells.
Invest Ophthalmol Vis Sci. 2001;42:975–982.
Levkovitch-Verbin H, Quigley HA, Martin KRG, Zack DJ, Pease
ME, Valenta DF. A model to study differences between primary
and secondary degeneration of retinal ganglion cells in rats by
partial optic nerve transection. Invest Ophthalmol Vis Sci. 2003;
44:3388 –3395.