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Glaucoma at ARVO
May 4-10, 2002, Fort Lauderdale, Florida, USA
The Program Committee's Choice
- A unique anatomical entity consisting of cylindrical tubular structures spanning Schlemm's canal was demonstrated.
- Optineurin was identified as the first exclusive gene for POAG.
- Significantly decreased arterial oxygen saturation was shown in glaucomatous eyes.
- Antigens derived from gray matter - and not from white matter - had a neuroprotective effect.
- Mechanic classifiers identified visual field abnormalities four years earlier than traditional methods.
- Antiproliferative gene therapy in monkeys worked for at least 260 days.
- A plasma knife was successfully used for the dissection of ocular tissues.
Four trinities from a minisymposium
I. "Changes in retinal gene expression in response to elevated intraocular pressure and glaucoma":
Rob Nickells
-
Three classes of genes: those that are up-regulated, those that are down-regulated, and those that have unchanged expression patterns.
-
The major contributors to up-regulated genes come from activated Müller and glial cells and from ganglion cells that alternatively exhibit a stress response (e.g., a heat shock response), and then the activation of genes that execute the cell death program.
-
The molecular changes in gene expression in response to ocular hypertension represents a complex response from different cell-types in the retina.
II. "Structural responses to raised IOP: inter-relationship between anatomical structure and IOP-related damage"
Claude Burgoyne
-
IOP is important at all levels of IOP because the ONH is a 'high
stress' environment in which IOP-related stress and strain within the
ONH connective tissues influences blood flow, the astrocyte basement
membrane, and axonal nutrition even at low levels of IOP.
-
IOP-related damage to the axons within the ONH can occur at all levels
of IOP by a variety of mechanisms, and may be astrocyte- and glial-cell-mediated,
regardless of the inciting insult.
-
IOP-related damage to the connective tissues can occur at all levels
of IOP. This is important, not only because it contributes to axonal
damage, but also because it centrally underlies (and explains) the phenomenon
of 'glaucomatous' cupping.
III. "How does the trabecular meshwork regulate IOP?"
Ernst Tamm
-
The major site of aqueous outflow resistance is in the cribriform
or juxtacanalicular region of the TM. Quantity and quality of the extracellular
matrix (EM) in this region appear to modulate TM outflow resistance.
-
There is an increase in fibrillar EM in the cribriform region of
eyes with POAG. The increase of TGF-b in
the aqueous humor of eyes with POAG is likely to contribute to the increase
in trabecular EM.
-
Most of the TGF-b in the aqueous humor
of normal and glaucomatous eyes is in a latent form. Thrombospondin-1
is a very potent endogenous activator of TGF-b.
The TM shows a strong expression of thrombospondin-1 that very likely
activates TGF-b. This local activation may
be critically required to regulate EM turnover in the TM.
IV. "Experimental models of pressure-related optic neuropathy"
Bal Chauhan
-
In a rat model, optic disc cupping and axonal loss are highly correlated
to the level of induced intraocular pressure elevation.
-
There can be loss of axons despite a normal-appearing optic disc
(visualized with modified scanning laser tomography), suggesting that
cupping is a phenomenon with a pressure-related threshold and is not
necessarily due to axonal loss.
-
The above finding is supported by evidence from an ischemia-induced
model of optic nerve damage in which ganglion cells are lost with normal
pressures and no cupping.
TOP-TEN (or less)
Stuart Graham
- Optineurin has been identified as a gene associated with adult-onset
glaucoma, and was linked to a significant number of NTG patients in
the families studied. It may play a neuroprotecting role.
- In the EAE susceptible rat model, a neuroprotoective effect can
be achieved by vaccinating with synthetic copolymer Cop-1 or with uveitogenic
peptides.
- When serial visual fields are assessed by learning machine classifiers
(Sample et al.), defects can be identified several years earlier
than by relying on standard statistical changes.
- Cat 152, a neutralizing anti-TGF2 monoclonal antibody in a phase
II study, shows improved results in phacotrabeculectomy with lower IOPs
and no adverse events. Supplementary 5FU was needed in some cases.
- A modified adenoviral vector (using a Woodchuck hepatitis regulatory
element) can be used to successfully transfect rat retinal ganglion
cells with a single intravitreal injection and deliver BDNF to the cells.
This provided a 38% increased cell survival after four weeks of induced
glaucoma.
- Modifying the corneal compensator in the GDx to be patient-specific
improves its discriminatory ability in glaucoma. It did not affect all
parameters, with the results for ratios or the number remaining unchanged.
- Two new agents that lower IOP by modifying trabecular outflow, ML-7
(Thieme et al.), a myosin light chain kinase blocker, and H-7
(Tian et al.), show potential for the development of drugs that
can increase trabecular outflow facility.
- Viagra has no detectable effect on ocular blood flow or intraocular
pressure.
- Detection of progression of visual fields can vary by several years,
depending on what criteria are adopted. CIGTS, AGIS, GCP analysis or
change based on pointwise linear regression (PLRA) models all vary greatly
in their ability to detect glaucomatous change.
- The presence of small valve-like cylindrical channels crossing from
the trabecular meshwork across Schlemm's canal has been demonstrated
by several different histological methods. Although not lined by endothelial
cells, RBCs could be made to reflux into these tubes.
Ernst Tamm
- Mutations in optineurin are causative for adult-onset POAG.
- Decreased porosity of the inner wall endothelium of Schlemm's canal
may explain the increase in outflow resistance in POAG.
- The conversion rate of pseudoexfoliation syndrome into pseudoexfoliation
glaucoma was studied in a population-based study. Patients with PEX
have a 64% chance of requiring glaucoma treatment by ten years.
- Feline immunodeficiency virus-based lentiviral vectors are a promising
tool for gene transfer in trabecular meshwork cells.
- The activity of Pax6 is required for the formation of Schlemm's
canal and the trabecular meshwork.
- In contrast to previous studies, no clear-cut difference was found
between vitreous glutamate concentrations in glaucomatous and contralateral
control monkey eyes.
- A model of experimental autoimmune glaucoma was developed in rats
by immunization with heat shock protein.
- In eyes with POAG, the number of intrinsic nerve cells in the choroid
is significantly decreased.
- Ganglion cells in glaucomatous eyes retain their intrinsic electrical
properties, but become less responsive to visual stimulation. This reduction
is most likely due to significant changes in the dendritic morphology.
- The histology after successful laser trabeculoplasty was investigated
in eyes with POAG. Meshworks from lasered eyes had an expanded and loose-appearing
juxtacanalicular region with numerous superimposed giant vacuoles. Downgrowth
of Descemet's membrane was uncommon.
Bal Chauhan
- Experimental models of optic nerve damage in rats and monkeys using
a variety of models show regional susceptibility to damage.
- In rats, over 80% of retinal ganglion cells can be transfected with
a modified adeno-associated virus with a single intravitreal injection
of the vector, raising the possibility of gene therapy in diseases leading
to ganglion cell death.
- Novel labelling and imaging techniques may allow in vivo visualization
of retinal ganglion cells in rats.
- Glaucoma results in a reduction of the number of choroidal ganglion
cells.
- The incidence of disc hemorrhages is higher in eyes with smaller
neuroretinal rims. However, it is independent of disc size and shape.
- Ultra-high resolution optical coherence tomography has been adapted
for clinical use, with potential for glaucoma and retinal disease.
- Machine learning classifiers may identify the development of glaucomatous
visual field damage more than four years before clinical and statistical
analysis.
- Digital three-dimensional reconstruction of optic nerve connective
tissues in experimental pressure-related optic neuropathy in monkeys
allows visualization of changes in the sclera, lamina, and scleral canal
wall.
- Vitreal glutamate levels were transiently elevated in a pressure-related
optic neuropathy in rats, but these findings were not confirmed in a
pressure-related monkey model.
- Mutations in the optineurin gene are found in a sizeable number
of patients with adult-onset open-angle glaucoma. This gene may be involved
in regulating apoptosis and vasoaction.
Linda Zangwill
- In a presentation entitled "Designing vaccination for glaucoma:
a new approach to neuroprotective therapy", investigators from the Weitzman
Institute and Proneuron Biotechnologies suggest that, in a rat model
of chronically elevated IOP, the ability to manifest a protective immune
response is directly related to resistance to autoimmune disease development.
These results provide an insight into the mechanism of retinal damage
in anterior chamber disease, and may contribute to the design of future
therapies for glaucoma.
- In a presentation entitled "Predicting development of abnormal standard
visual field in ocular hypertensive eyes: machine learning classifiers
and Statpac-like analysis", investigators from UC San Diego, Salk Institute,
and Devers Eye Institute suggest that analyzing standard automated perimetry
results using machine classifiers and neural networks can detect glaucomatous
visual field damage on average four years before Statpac-like analyses.
These results suggest that we can improve detection of glaucomatous
visual field damage by the use of sophisticated analysis techniques.
- There were several presentations by investigators at Jules Stein
Eye Institute, Bascolm Palmer Eye Institute, Moorfield Eye Institute,
and UC San Diego, highlighting improvements in detecting glaucomatous
eyes with use of individualized (custom) corneal compensation in the
GDx Nerve Fiber Analyzer.
- Two presentations by investigators from the University of Sydney,
University of Wisconsin, Madison, Johns Hopkins University, and the
National University of Singapore of results from the Blue Mountains
Eye Study and the Beaver Dam Eye Study indicate that generalized retinal
arterioral narrowing predicts cardiovascular and cerebrovascular events
(five-year incidence of cardiovascular or cerebrovascular death, and
incident stroke) in older persons and ten-year cardiovascular mortality,
particularly in younger persons, independently of blood pressure and
other known risk factors such as smoking, age, and diabetes. These data
support the concept that a quantitative assessment of retinal microvascular
changes may provide unique information regarding cardiovascular risk
and mortality.
- Results from the population-based Los Angeles Latino Eye Study presented
by investigators at the Doheny Eye Institute suggest that Latinos have
smaller discs, cups, and neuroretinal rim areas than blacks and whites
in the Baltimore Eye Study. This study provides further evidence of
racial and ethnic differences in optic disc topography
Idiosyncratic ARVO impressions on ARMD and so forth
Martin Wax
Rather than list ARVO's 'Top-10' papers, as I was asked to do by the
Managing Editor, I will share my top ARVO experiences from a different perspective.
I would first like to mention that the glaucoma mini-symposium on 'IOP:
the forgotten risk factor' organized chiefly by this year's Program Committee
Chairman, Clive Migdal, was particularly impressive. Equally impressive
were the talks in the 'New Ideas' session, in which I found Mansoor Sarfarazi's
work on optineurin mutations in glaucoma patients particularly compelling.
This year, I attended many sessions on macular degeneration and diabetic
retinopathy. After all, the main cell of concern to glaucomatologists, the
retinal ganglion cell, lies in the province of the retina. The comparison
of research presently being done in that field to that done in glaucoma,
was quite revealing.
Despite the wealth of evidence that the retinal changes underlying dry
ARMD appear to be inflammatory and involve the immune system, I was surprised
that a special interest group meeting was held only this year to discuss
the evidence as to whether ARMD is an immune-mediated disease. As many of
you may recall, Michal Schwartz and I co-chaired a glaucoma special interest
meeting at last year's ARVO that addressed similar concerns pertinent to
immune system involvement in glaucoma. Could it be that our field is a more
enlightened one than retina in appreciating the role of the immune system
in disease pathogenesis?
In my efforts to learn more about proliferative macular degeneration,
I discovered that the animal models used mainly rely on laser treatment
to induce breaks in the RPE in order to elicit subretinal angiogenesis,
and are not particularly relevant to the natural history of human wet ARMD.
I found that the same caveats could be applied to models of diabetic retinopathy
and inner retinal neovascularization. In the case of the former, streptozotocin-treated
rats do acquire a re-tinopathy, but this only occurs when the animals are
long-lived, thus this disease model has limited pragmatic utility for investigators.
Simi-larly, inner retinal neovascularization models are primarily obtained
with oxygen supplementation in young rodents in order to achieve retinopathy
of prematurity, which also has limited utility to the natural history of
human proliferative retinal disease in an elderly population. Therefore,
considering the vast number of proliferating animal models we now use to
elicit glaucoma, spanning mice to monkeys, we seem to have a distinct edge
in methodology regarding animal models that will help us answer the questions
that interest us the most. Thus, here too, we seem to have the upper hand
over our retina colleagues.
Finally, I was intrigued that many of the studies currently under way
using anti-proliferative therapies, such as those directed against VEGF,
were approved by the FDA for human trials with what appears to be far less
data than those obtained prior to previous trials for many glaucoma agents.
The FDA is primarily concerned with safety and toxicity. But it would seem
that the appropriate studies to determine efficacy regarding dosage, and
the endpoints used, particularly with regard to those agents designed for
intravitreal injections on a recurring six-week interval now commencing
in humans, were not as stringently determined as those that preceded the
phase III clinical trials for many of our glaucoma agents. Once again, in
comparison to retina, the glaucoma community can be proud that its drugs
are typically developed in a manner that yields more rigorous efficacy data
prior to widespread use in clinical trials.
In summary, this year's ARVO left me with a strong impression that, by
many criteria, the pragmatic utility of the science presently performed
in glaucoma research compares very favorably with, and in many cases exceeds,
the work currently being performed in analogous fields such as retinal research.
Interesting Papers on Glaucoma Surgery and Wound Healing
Peng Khaw
As a child, I had images of the 21st century offering surgery with magic
scalpels and the body being made to heal with modern high technology medicines.
As I wandered through the halls maintained with high technology arctic cooling
temperatures in the middle of tropical Florida, browsing my electronic based
abstract book, I used this template to identify papers in the glaucoma surgery
and wound healing category to give us some perspective as to how far we
have come.
First of all, there are high technology scalpels and devices. There was
an interesting surgical plasma cutter from the Stanford group presented
by a physicist (No. 941, Palanker et al.). Another high technology
surgical tool from the Cologne group was the use of photodynamic therapy
to prevent wound healing, using a subconjunctival injection of sensitizing
agent, followed by blue light targeted to a specific area (No. 3337, Jordan
et al.). There are new materials now available for drainage devices,
but biological reactions to these materials are still apparent, although
they are better in some materials. The biomaterials group from Miami tested
a range of materials in a rabbit model and found that hydrophillic polymers
(hydrogels) resulted in the least reaction (No. 3371, Fernandez et al.).
Another high technology use of modern materials was the slow release
pellet of dexamethasone in phacotrabeculectomy introduced by the Singapore
group (No. 3346, Seah et al.). However, clearly these are still new
technologies and the problems of the healing eye and scarring have not yet
been fully overcome, as failures will and are still occurring. Several new
drainage devices were on show, but as yet, the major problem of healing
following surgery has not been solved.
Twenty-first century cell and molecular biology featured strongly in
the presentations covering modulation of healing. The use of antimetabolites
has revolutionized filtration surgery, but many problems still occur despite
the use of larger treatment areas and scleral flaps, which has reduced the
bleb-related complications very significantly in our center. More sophisticated
approaches to modulating post-surgical scarring were apparent. The role
of specific growth factors, particularly transforming growth factor
beta, continues to excite interest. The Erlangen group have found that
fibroblasts of patients with pseudoexfoliation, in which there is an excessive
deposition of an abnormal matrix material, seem to respond to lower concentrations
of this growth factor (No. 3367, Kottler et al.). The Wurzberg group
have shown that, in patients with pseudoexfoliation, laser trabeculoplasty
appears to raise the aqueous levels of TGF-beta significantly (No. 3344,
Wimmer et al.). In a randomized masked pilot study, the use of a
human antibody to TGF-beta 2 (CAT-152), created by modern molecular
cloning techniques not even dreamt of a few decades ago, showed that a greater
proportion of patients following phacotrabeculectomy had an intraocular
pressure < 22 mmHg (100% versus 80% controls) at one year of follow-up (No.
3331, Broadway et al.). Given that glaucoma is a lifelong disease,
the long-term control of healing is in some ways even more important. Delayed
postoperative injections of the TGF-beta 2 antibody (CAT 152) prolonged
the long-term survival of the bleb in an experimental model of filtration
surgery compared with 5-FU and control (No. 3332, Mead et al.), which
is potentially very important for the long-term control of intraocular pressure.
Finally, other novel approaches to scarring control were also presented.
The protein p21 inhibits cyclin-dependent kinases, enzymes required for
cell proliferation. The gene for p21 was inserted into an adenovirus
which was then injected subconjunctivally in a monkey model of glaucoma
and filtration surgery. This showed promising effects on bleb function and
the prevention of cupping (No. 1940, Faha et al.). The enzymes known
as matrix metalloproteinases are important in wound healing. The
very active Cologne group showed that these enzymes are present in Tenon's
fibroblasts (No. 3333, Esser et al.). Inhibition of these
enzymes with a drug designed with a high specificity for these enzymes dramatically
reduced scarring, yet resulted in diffuse non-cystic blebs in a masked randomized
study in an aggressive model of filtration surgery (No. 870, Wong et
al.).
Therefore, 21st Century technology was definitely in evidence. We are
not quite there yet (perfect glaucoma surgery with the long-term control
of scarring and intraocular pressure), but given the evidence, there are
good prospects that we may be in the near future.
IOP is important at all levels of IOP because the ONH is a 'high stress' environment in which IOP-related stress and strain within the ONH connective tissues influences blood flow, the astrocyte basement membrane, and axonal nutrition even at low levels of IOP.
IOP-related damage to the axons within the ONH can occur at all levels of IOP by a variety of mechanisms, and may be astrocyte- and glial-cell-mediated, regardless of the inciting insult.
IOP-related damage to the connective tissues can occur at all levels of IOP. This is important, not only because it contributes to axonal damage, but also because it centrally underlies (and explains) the phenomenon of 'glaucomatous' cupping.
-
The major site of aqueous outflow resistance is in the cribriform or juxtacanalicular region of the TM. Quantity and quality of the extracellular matrix (EM) in this region appear to modulate TM outflow resistance.
-
There is an increase in fibrillar EM in the cribriform region of eyes with POAG. The increase of TGF-b in the aqueous humor of eyes with POAG is likely to contribute to the increase in trabecular EM.
-
Most of the TGF-b in the aqueous humor of normal and glaucomatous eyes is in a latent form. Thrombospondin-1 is a very potent endogenous activator of TGF-b. The TM shows a strong expression of thrombospondin-1 that very likely activates TGF-b. This local activation may be critically required to regulate EM turnover in the TM.
IV. "Experimental models of pressure-related optic neuropathy"
Bal Chauhan
-
In a rat model, optic disc cupping and axonal loss are highly correlated
to the level of induced intraocular pressure elevation.
-
There can be loss of axons despite a normal-appearing optic disc
(visualized with modified scanning laser tomography), suggesting that
cupping is a phenomenon with a pressure-related threshold and is not
necessarily due to axonal loss.
-
The above finding is supported by evidence from an ischemia-induced
model of optic nerve damage in which ganglion cells are lost with normal
pressures and no cupping.
TOP-TEN (or less)
Stuart Graham
- Optineurin has been identified as a gene associated with adult-onset
glaucoma, and was linked to a significant number of NTG patients in
the families studied. It may play a neuroprotecting role.
- In the EAE susceptible rat model, a neuroprotoective effect can
be achieved by vaccinating with synthetic copolymer Cop-1 or with uveitogenic
peptides.
- When serial visual fields are assessed by learning machine classifiers
(Sample et al.), defects can be identified several years earlier
than by relying on standard statistical changes.
- Cat 152, a neutralizing anti-TGF2 monoclonal antibody in a phase
II study, shows improved results in phacotrabeculectomy with lower IOPs
and no adverse events. Supplementary 5FU was needed in some cases.
- A modified adenoviral vector (using a Woodchuck hepatitis regulatory
element) can be used to successfully transfect rat retinal ganglion
cells with a single intravitreal injection and deliver BDNF to the cells.
This provided a 38% increased cell survival after four weeks of induced
glaucoma.
- Modifying the corneal compensator in the GDx to be patient-specific
improves its discriminatory ability in glaucoma. It did not affect all
parameters, with the results for ratios or the number remaining unchanged.
- Two new agents that lower IOP by modifying trabecular outflow, ML-7
(Thieme et al.), a myosin light chain kinase blocker, and H-7
(Tian et al.), show potential for the development of drugs that
can increase trabecular outflow facility.
- Viagra has no detectable effect on ocular blood flow or intraocular
pressure.
- Detection of progression of visual fields can vary by several years,
depending on what criteria are adopted. CIGTS, AGIS, GCP analysis or
change based on pointwise linear regression (PLRA) models all vary greatly
in their ability to detect glaucomatous change.
- The presence of small valve-like cylindrical channels crossing from
the trabecular meshwork across Schlemm's canal has been demonstrated
by several different histological methods. Although not lined by endothelial
cells, RBCs could be made to reflux into these tubes.
Ernst Tamm
- Mutations in optineurin are causative for adult-onset POAG.
- Decreased porosity of the inner wall endothelium of Schlemm's canal
may explain the increase in outflow resistance in POAG.
- The conversion rate of pseudoexfoliation syndrome into pseudoexfoliation
glaucoma was studied in a population-based study. Patients with PEX
have a 64% chance of requiring glaucoma treatment by ten years.
- Feline immunodeficiency virus-based lentiviral vectors are a promising
tool for gene transfer in trabecular meshwork cells.
- The activity of Pax6 is required for the formation of Schlemm's
canal and the trabecular meshwork.
- In contrast to previous studies, no clear-cut difference was found
between vitreous glutamate concentrations in glaucomatous and contralateral
control monkey eyes.
- A model of experimental autoimmune glaucoma was developed in rats
by immunization with heat shock protein.
- In eyes with POAG, the number of intrinsic nerve cells in the choroid
is significantly decreased.
- Ganglion cells in glaucomatous eyes retain their intrinsic electrical
properties, but become less responsive to visual stimulation. This reduction
is most likely due to significant changes in the dendritic morphology.
- The histology after successful laser trabeculoplasty was investigated
in eyes with POAG. Meshworks from lasered eyes had an expanded and loose-appearing
juxtacanalicular region with numerous superimposed giant vacuoles. Downgrowth
of Descemet's membrane was uncommon.
Bal Chauhan
- Experimental models of optic nerve damage in rats and monkeys using
a variety of models show regional susceptibility to damage.
- In rats, over 80% of retinal ganglion cells can be transfected with
a modified adeno-associated virus with a single intravitreal injection
of the vector, raising the possibility of gene therapy in diseases leading
to ganglion cell death.
- Novel labelling and imaging techniques may allow in vivo visualization
of retinal ganglion cells in rats.
- Glaucoma results in a reduction of the number of choroidal ganglion
cells.
- The incidence of disc hemorrhages is higher in eyes with smaller
neuroretinal rims. However, it is independent of disc size and shape.
- Ultra-high resolution optical coherence tomography has been adapted
for clinical use, with potential for glaucoma and retinal disease.
- Machine learning classifiers may identify the development of glaucomatous
visual field damage more than four years before clinical and statistical
analysis.
- Digital three-dimensional reconstruction of optic nerve connective
tissues in experimental pressure-related optic neuropathy in monkeys
allows visualization of changes in the sclera, lamina, and scleral canal
wall.
- Vitreal glutamate levels were transiently elevated in a pressure-related
optic neuropathy in rats, but these findings were not confirmed in a
pressure-related monkey model.
- Mutations in the optineurin gene are found in a sizeable number
of patients with adult-onset open-angle glaucoma. This gene may be involved
in regulating apoptosis and vasoaction.
Linda Zangwill
- In a presentation entitled "Designing vaccination for glaucoma:
a new approach to neuroprotective therapy", investigators from the Weitzman
Institute and Proneuron Biotechnologies suggest that, in a rat model
of chronically elevated IOP, the ability to manifest a protective immune
response is directly related to resistance to autoimmune disease development.
These results provide an insight into the mechanism of retinal damage
in anterior chamber disease, and may contribute to the design of future
therapies for glaucoma.
- In a presentation entitled "Predicting development of abnormal standard
visual field in ocular hypertensive eyes: machine learning classifiers
and Statpac-like analysis", investigators from UC San Diego, Salk Institute,
and Devers Eye Institute suggest that analyzing standard automated perimetry
results using machine classifiers and neural networks can detect glaucomatous
visual field damage on average four years before Statpac-like analyses.
These results suggest that we can improve detection of glaucomatous
visual field damage by the use of sophisticated analysis techniques.
- There were several presentations by investigators at Jules Stein
Eye Institute, Bascolm Palmer Eye Institute, Moorfield Eye Institute,
and UC San Diego, highlighting improvements in detecting glaucomatous
eyes with use of individualized (custom) corneal compensation in the
GDx Nerve Fiber Analyzer.
- Two presentations by investigators from the University of Sydney,
University of Wisconsin, Madison, Johns Hopkins University, and the
National University of Singapore of results from the Blue Mountains
Eye Study and the Beaver Dam Eye Study indicate that generalized retinal
arterioral narrowing predicts cardiovascular and cerebrovascular events
(five-year incidence of cardiovascular or cerebrovascular death, and
incident stroke) in older persons and ten-year cardiovascular mortality,
particularly in younger persons, independently of blood pressure and
other known risk factors such as smoking, age, and diabetes. These data
support the concept that a quantitative assessment of retinal microvascular
changes may provide unique information regarding cardiovascular risk
and mortality.
- Results from the population-based Los Angeles Latino Eye Study presented
by investigators at the Doheny Eye Institute suggest that Latinos have
smaller discs, cups, and neuroretinal rim areas than blacks and whites
in the Baltimore Eye Study. This study provides further evidence of
racial and ethnic differences in optic disc topography
Idiosyncratic ARVO impressions on ARMD and so forth
Martin Wax
Rather than list ARVO's 'Top-10' papers, as I was asked to do by the
Managing Editor, I will share my top ARVO experiences from a different perspective.
I would first like to mention that the glaucoma mini-symposium on 'IOP:
the forgotten risk factor' organized chiefly by this year's Program Committee
Chairman, Clive Migdal, was particularly impressive. Equally impressive
were the talks in the 'New Ideas' session, in which I found Mansoor Sarfarazi's
work on optineurin mutations in glaucoma patients particularly compelling.
This year, I attended many sessions on macular degeneration and diabetic
retinopathy. After all, the main cell of concern to glaucomatologists, the
retinal ganglion cell, lies in the province of the retina. The comparison
of research presently being done in that field to that done in glaucoma,
was quite revealing.
Despite the wealth of evidence that the retinal changes underlying dry
ARMD appear to be inflammatory and involve the immune system, I was surprised
that a special interest group meeting was held only this year to discuss
the evidence as to whether ARMD is an immune-mediated disease. As many of
you may recall, Michal Schwartz and I co-chaired a glaucoma special interest
meeting at last year's ARVO that addressed similar concerns pertinent to
immune system involvement in glaucoma. Could it be that our field is a more
enlightened one than retina in appreciating the role of the immune system
in disease pathogenesis?
In my efforts to learn more about proliferative macular degeneration,
I discovered that the animal models used mainly rely on laser treatment
to induce breaks in the RPE in order to elicit subretinal angiogenesis,
and are not particularly relevant to the natural history of human wet ARMD.
I found that the same caveats could be applied to models of diabetic retinopathy
and inner retinal neovascularization. In the case of the former, streptozotocin-treated
rats do acquire a re-tinopathy, but this only occurs when the animals are
long-lived, thus this disease model has limited pragmatic utility for investigators.
Simi-larly, inner retinal neovascularization models are primarily obtained
with oxygen supplementation in young rodents in order to achieve retinopathy
of prematurity, which also has limited utility to the natural history of
human proliferative retinal disease in an elderly population. Therefore,
considering the vast number of proliferating animal models we now use to
elicit glaucoma, spanning mice to monkeys, we seem to have a distinct edge
in methodology regarding animal models that will help us answer the questions
that interest us the most. Thus, here too, we seem to have the upper hand
over our retina colleagues.
Finally, I was intrigued that many of the studies currently under way
using anti-proliferative therapies, such as those directed against VEGF,
were approved by the FDA for human trials with what appears to be far less
data than those obtained prior to previous trials for many glaucoma agents.
The FDA is primarily concerned with safety and toxicity. But it would seem
that the appropriate studies to determine efficacy regarding dosage, and
the endpoints used, particularly with regard to those agents designed for
intravitreal injections on a recurring six-week interval now commencing
in humans, were not as stringently determined as those that preceded the
phase III clinical trials for many of our glaucoma agents. Once again, in
comparison to retina, the glaucoma community can be proud that its drugs
are typically developed in a manner that yields more rigorous efficacy data
prior to widespread use in clinical trials.
In summary, this year's ARVO left me with a strong impression that, by
many criteria, the pragmatic utility of the science presently performed
in glaucoma research compares very favorably with, and in many cases exceeds,
the work currently being performed in analogous fields such as retinal research.
Interesting Papers on Glaucoma Surgery and Wound Healing
Peng Khaw
As a child, I had images of the 21st century offering surgery with magic
scalpels and the body being made to heal with modern high technology medicines.
As I wandered through the halls maintained with high technology arctic cooling
temperatures in the middle of tropical Florida, browsing my electronic based
abstract book, I used this template to identify papers in the glaucoma surgery
and wound healing category to give us some perspective as to how far we
have come.
First of all, there are high technology scalpels and devices. There was
an interesting surgical plasma cutter from the Stanford group presented
by a physicist (No. 941, Palanker et al.). Another high technology
surgical tool from the Cologne group was the use of photodynamic therapy
to prevent wound healing, using a subconjunctival injection of sensitizing
agent, followed by blue light targeted to a specific area (No. 3337, Jordan
et al.). There are new materials now available for drainage devices,
but biological reactions to these materials are still apparent, although
they are better in some materials. The biomaterials group from Miami tested
a range of materials in a rabbit model and found that hydrophillic polymers
(hydrogels) resulted in the least reaction (No. 3371, Fernandez et al.).
Another high technology use of modern materials was the slow release
pellet of dexamethasone in phacotrabeculectomy introduced by the Singapore
group (No. 3346, Seah et al.). However, clearly these are still new
technologies and the problems of the healing eye and scarring have not yet
been fully overcome, as failures will and are still occurring. Several new
drainage devices were on show, but as yet, the major problem of healing
following surgery has not been solved.
Twenty-first century cell and molecular biology featured strongly in
the presentations covering modulation of healing. The use of antimetabolites
has revolutionized filtration surgery, but many problems still occur despite
the use of larger treatment areas and scleral flaps, which has reduced the
bleb-related complications very significantly in our center. More sophisticated
approaches to modulating post-surgical scarring were apparent. The role
of specific growth factors, particularly transforming growth factor
beta, continues to excite interest. The Erlangen group have found that
fibroblasts of patients with pseudoexfoliation, in which there is an excessive
deposition of an abnormal matrix material, seem to respond to lower concentrations
of this growth factor (No. 3367, Kottler et al.). The Wurzberg group
have shown that, in patients with pseudoexfoliation, laser trabeculoplasty
appears to raise the aqueous levels of TGF-beta significantly (No. 3344,
Wimmer et al.). In a randomized masked pilot study, the use of a
human antibody to TGF-beta 2 (CAT-152), created by modern molecular
cloning techniques not even dreamt of a few decades ago, showed that a greater
proportion of patients following phacotrabeculectomy had an intraocular
pressure < 22 mmHg (100% versus 80% controls) at one year of follow-up (No.
3331, Broadway et al.). Given that glaucoma is a lifelong disease,
the long-term control of healing is in some ways even more important. Delayed
postoperative injections of the TGF-beta 2 antibody (CAT 152) prolonged
the long-term survival of the bleb in an experimental model of filtration
surgery compared with 5-FU and control (No. 3332, Mead et al.), which
is potentially very important for the long-term control of intraocular pressure.
Finally, other novel approaches to scarring control were also presented.
The protein p21 inhibits cyclin-dependent kinases, enzymes required for
cell proliferation. The gene for p21 was inserted into an adenovirus
which was then injected subconjunctivally in a monkey model of glaucoma
and filtration surgery. This showed promising effects on bleb function and
the prevention of cupping (No. 1940, Faha et al.). The enzymes known
as matrix metalloproteinases are important in wound healing. The
very active Cologne group showed that these enzymes are present in Tenon's
fibroblasts (No. 3333, Esser et al.). Inhibition of these
enzymes with a drug designed with a high specificity for these enzymes dramatically
reduced scarring, yet resulted in diffuse non-cystic blebs in a masked randomized
study in an aggressive model of filtration surgery (No. 870, Wong et
al.).
Therefore, 21st Century technology was definitely in evidence. We are
not quite there yet (perfect glaucoma surgery with the long-term control
of scarring and intraocular pressure), but given the evidence, there are
good prospects that we may be in the near future.
In a rat model, optic disc cupping and axonal loss are highly correlated to the level of induced intraocular pressure elevation.
There can be loss of axons despite a normal-appearing optic disc (visualized with modified scanning laser tomography), suggesting that cupping is a phenomenon with a pressure-related threshold and is not necessarily due to axonal loss.
The above finding is supported by evidence from an ischemia-induced model of optic nerve damage in which ganglion cells are lost with normal pressures and no cupping.
Idiosyncratic ARVO impressions on ARMD and so forth
Martin Wax
Rather than list ARVO's 'Top-10' papers, as I was asked to do by the Managing Editor, I will share my top ARVO experiences from a different perspective. I would first like to mention that the glaucoma mini-symposium on 'IOP: the forgotten risk factor' organized chiefly by this year's Program Committee Chairman, Clive Migdal, was particularly impressive. Equally impressive were the talks in the 'New Ideas' session, in which I found Mansoor Sarfarazi's work on optineurin mutations in glaucoma patients particularly compelling. This year, I attended many sessions on macular degeneration and diabetic retinopathy. After all, the main cell of concern to glaucomatologists, the retinal ganglion cell, lies in the province of the retina. The comparison of research presently being done in that field to that done in glaucoma, was quite revealing.
Despite the wealth of evidence that the retinal changes underlying dry ARMD appear to be inflammatory and involve the immune system, I was surprised that a special interest group meeting was held only this year to discuss the evidence as to whether ARMD is an immune-mediated disease. As many of you may recall, Michal Schwartz and I co-chaired a glaucoma special interest meeting at last year's ARVO that addressed similar concerns pertinent to immune system involvement in glaucoma. Could it be that our field is a more enlightened one than retina in appreciating the role of the immune system in disease pathogenesis?
In my efforts to learn more about proliferative macular degeneration, I discovered that the animal models used mainly rely on laser treatment to induce breaks in the RPE in order to elicit subretinal angiogenesis, and are not particularly relevant to the natural history of human wet ARMD. I found that the same caveats could be applied to models of diabetic retinopathy and inner retinal neovascularization. In the case of the former, streptozotocin-treated rats do acquire a re-tinopathy, but this only occurs when the animals are long-lived, thus this disease model has limited pragmatic utility for investigators. Simi-larly, inner retinal neovascularization models are primarily obtained with oxygen supplementation in young rodents in order to achieve retinopathy of prematurity, which also has limited utility to the natural history of human proliferative retinal disease in an elderly population. Therefore, considering the vast number of proliferating animal models we now use to elicit glaucoma, spanning mice to monkeys, we seem to have a distinct edge in methodology regarding animal models that will help us answer the questions that interest us the most. Thus, here too, we seem to have the upper hand over our retina colleagues.
Finally, I was intrigued that many of the studies currently under way using anti-proliferative therapies, such as those directed against VEGF, were approved by the FDA for human trials with what appears to be far less data than those obtained prior to previous trials for many glaucoma agents. The FDA is primarily concerned with safety and toxicity. But it would seem that the appropriate studies to determine efficacy regarding dosage, and the endpoints used, particularly with regard to those agents designed for intravitreal injections on a recurring six-week interval now commencing in humans, were not as stringently determined as those that preceded the phase III clinical trials for many of our glaucoma agents. Once again, in comparison to retina, the glaucoma community can be proud that its drugs are typically developed in a manner that yields more rigorous efficacy data prior to widespread use in clinical trials.
In summary, this year's ARVO left me with a strong impression that, by many criteria, the pragmatic utility of the science presently performed in glaucoma research compares very favorably with, and in many cases exceeds, the work currently being performed in analogous fields such as retinal research.
Interesting Papers on Glaucoma Surgery and Wound Healing
Peng Khaw
As a child, I had images of the 21st century offering surgery with magic scalpels and the body being made to heal with modern high technology medicines. As I wandered through the halls maintained with high technology arctic cooling temperatures in the middle of tropical Florida, browsing my electronic based abstract book, I used this template to identify papers in the glaucoma surgery and wound healing category to give us some perspective as to how far we have come.
First of all, there are high technology scalpels and devices. There was an interesting surgical plasma cutter from the Stanford group presented by a physicist (No. 941, Palanker et al.). Another high technology surgical tool from the Cologne group was the use of photodynamic therapy to prevent wound healing, using a subconjunctival injection of sensitizing agent, followed by blue light targeted to a specific area (No. 3337, Jordan et al.). There are new materials now available for drainage devices, but biological reactions to these materials are still apparent, although they are better in some materials. The biomaterials group from Miami tested a range of materials in a rabbit model and found that hydrophillic polymers (hydrogels) resulted in the least reaction (No. 3371, Fernandez et al.). Another high technology use of modern materials was the slow release pellet of dexamethasone in phacotrabeculectomy introduced by the Singapore group (No. 3346, Seah et al.). However, clearly these are still new technologies and the problems of the healing eye and scarring have not yet been fully overcome, as failures will and are still occurring. Several new drainage devices were on show, but as yet, the major problem of healing following surgery has not been solved.
Twenty-first century cell and molecular biology featured strongly in the presentations covering modulation of healing. The use of antimetabolites has revolutionized filtration surgery, but many problems still occur despite the use of larger treatment areas and scleral flaps, which has reduced the bleb-related complications very significantly in our center. More sophisticated approaches to modulating post-surgical scarring were apparent. The role of specific growth factors, particularly transforming growth factor beta, continues to excite interest. The Erlangen group have found that fibroblasts of patients with pseudoexfoliation, in which there is an excessive deposition of an abnormal matrix material, seem to respond to lower concentrations of this growth factor (No. 3367, Kottler et al.). The Wurzberg group have shown that, in patients with pseudoexfoliation, laser trabeculoplasty appears to raise the aqueous levels of TGF-beta significantly (No. 3344, Wimmer et al.). In a randomized masked pilot study, the use of a human antibody to TGF-beta 2 (CAT-152), created by modern molecular cloning techniques not even dreamt of a few decades ago, showed that a greater proportion of patients following phacotrabeculectomy had an intraocular pressure < 22 mmHg (100% versus 80% controls) at one year of follow-up (No. 3331, Broadway et al.). Given that glaucoma is a lifelong disease, the long-term control of healing is in some ways even more important. Delayed postoperative injections of the TGF-beta 2 antibody (CAT 152) prolonged the long-term survival of the bleb in an experimental model of filtration surgery compared with 5-FU and control (No. 3332, Mead et al.), which is potentially very important for the long-term control of intraocular pressure.
Finally, other novel approaches to scarring control were also presented. The protein p21 inhibits cyclin-dependent kinases, enzymes required for cell proliferation. The gene for p21 was inserted into an adenovirus which was then injected subconjunctivally in a monkey model of glaucoma and filtration surgery. This showed promising effects on bleb function and the prevention of cupping (No. 1940, Faha et al.). The enzymes known as matrix metalloproteinases are important in wound healing. The very active Cologne group showed that these enzymes are present in Tenon's fibroblasts (No. 3333, Esser et al.). Inhibition of these enzymes with a drug designed with a high specificity for these enzymes dramatically reduced scarring, yet resulted in diffuse non-cystic blebs in a masked randomized study in an aggressive model of filtration surgery (No. 870, Wong et al.).
Therefore, 21st Century technology was definitely in evidence. We are not quite there yet (perfect glaucoma surgery with the long-term control of scarring and intraocular pressure), but given the evidence, there are good prospects that we may be in the near future.
