EVIDENCE THAT STUDYING VASCULAR CONSIDERATIONS CAN BENEFIT PATIENTS
WITH GLAUCOMA
Alon Harris, PhD
The Scope of Glaucoma
Primary open angle glaucoma (POAG) is a prevalent blinding disease
with increasing occurrence in the United States. For persons over
age 65, glaucoma represents the third most frequently reported
principle diagnosis for visits to physicians for all diseases,
and is the most frequent diagnostic code for ophthalmic visits
among persons in the Medicare age group (1). Medicare records
indicate that the case incidence of glaucoma in all beneficiaries
increased by 39.6% from 1991 to 1998, accounting for nearly 10%
of all eye care charges (2). At current office visit rates and
reimbursement schedules, the estimated 8.8 million physician office
visits for glaucoma in the year 2000 cost approximately $440 million
(1). Eye care procedures and service codes associated with glaucoma
revealed trabeculectomy increased at an average annual rate of
3.0% and visual field study at 2.7% (2). In the year 2000, over
2.47 million people in the United States were estimated to have
this eye disease (3). Moreover, among Medicare patients, increasing
OAG prevalence has been demonstrated, rising from 5% to 6.64%
(3).
Intraocular Pressure
Despite its prevalence, glaucoma remains a multi-factorial optic
neuropathy of unknown etiology and inadequate treatment (4). Although
elevated intraocular pressure (IOP) was identified as a risk factor
for the illness over 100 years ago, a meta-analysis showed steady
disease progression with persons, at all levels of IOP, equally
likely to exhibit deterioration (5). The authors concluded that
“factors quite independent of intraocular pressure may be
responsible for [disease] progression in glaucoma” (5).
Nevertheless, despite its clear inadequacy, IOP reduction remains
the only currently available modality of treatment for glaucoma.
Evidence Based Medicine: Ocular Perfusion Pressure
Evidence based medicine is the translation of the results of medical
research into clinical practice. If the results of clinical research
are to be considered as “evidence”, and specifically,
if they are to alter preferred practice patterns in the management
of a disease, that research must endure rigorous evaluations of
the consequences of clinical actions. This magnitude of evaluation
involves controlled clinical trials in hundreds or thousands of
subjects; often utilizing an epidemiological approach.
According to evidence-based medicine, in 1993, the effectiveness
of IOP reduction in glaucoma treatment was still to be determined
(6). This finding motivated the execution of large scale studies
eventually concluding that the reduction of IOP is beneficial
to the glaucoma patient (7-10). Additionally, population based
studies have also found that vascular related factors are also
risk factors in glaucoma. What benefit glaucoma patients may experience
from IOP reduction or vascular improvements remain uncertain.
In 1983, Framingham Eye Study participants with OAG were reported
to have significantly low BP/IOP ratios. In addition, persons
with definite glaucomatous visual field defects had lower ratios
than those with suspect defects or no defects (11). Low perfusion
pressure (PP) was also an OAG risk factor in the Baltimore Eye
Survey, Egna-Neumarkt, Proyecto VER, and most recently, the Barbados
Incidence Study of Eye Diseases (BISED) (12-15). Additionally,
the Baltimore Eye study found diastolic PP (DPP, DPP = diastolic
BP - IOP) of less than 30 mmHg to be strongly associated with
OAG (risk ratio =6), whereas systolic PP (SPP, SPP = systolic
BP - IOP,) and mean PP (MPP, MPP = mean BP – IOP) were only
mildly associated (12). In the Egna-Neumarkt study, OAG prevalence
increased progressively with decreased DPP (13). The Proyecto
VER study found similar results at a low DPP (14). The BISED study
found all three factors (DPP, SPP, and MPP) to be related to OAG
(15). Low DPP, had the strongest correlation, approximately tripling
the risk ratio of developing OAG. (15).
The only vascular parameter that meets the criteria necessary
to be considered clinically, based on evidence based medicine,
is diastolic perfusion pressure. The relationship between perfusion
pressure and glaucoma is not known, however the existence of a
relationship begs the question: Are vascular deficits and ischemia
involved in the pathogenesis and progression of glaucoma?
Clinical Evidence of Vascular Deficits: Pilot Data
Clinical studies have detected numerous ocular blood flow deficits
in some primary open angle glaucoma (POAG) patients. Fluorescein
angiography has demonstrated reduced total retinal blood flow,
and dye leakage from optic nerve head capillaries (16), suggesting
peripapillary ischemia in glaucoma (17). Scanning laser Doppler
flowmetry has documented reduced blood flow in the juxtapapillary
retina (18). Further evidence suggests the choroidal circulation
in glaucoma fails to appropriately vasodilate (19), with delays
in choroidal filling associated with a thinning of the entire
choroid (20). In addition, the retrobulbar vessels in both normal
tension glaucoma (NTG) and POAG patients exhibited increased resistance
indices during color Doppler imaging (21, 22). These vascular
abnormalities may be among the earliest manifestations of glaucoma
(23-25). Additionally, magnetic resonance imaging (MRI) studies
document diffuse small-vessel ischemia throughout the brain in
NTG patients (26). Reduced perfusion pressure to the eye (potentially
nocturnal) may cause glaucomatous disease progression, despite
well-controlled IOP (27). Nevertheless, despite accumulating evidence
that glaucoma patients suffer from inadequate ocular blood flow,
current clinical treatment of the illness involves neither documentation
of nor treatment for these deficits (28).
The most recent evidence suggests that glaucoma characteristically
damages the photoreceptors and the horizontal cells, as well as
the retinal ganglion cells (29, 30). The retinal ganglion cells
are nourished by the retinal circulation, while the photoreceptors
receive their blood supply mostly from the underlying choroid.
Therefore, to define how enhanced blood flow may improve visual
function, it is essential to evaluate blood flow to the retina
and to the choroid, for the retinal ganglion cells and photoreceptor
cells, respectively. If visual function deterioration in glaucoma
is indeed caused by specific damage to retinal ganglion cells
(31), improving retinal flow should improve this deficit. If,
instead, photoreceptor deterioration underlies the decline in
visual function, then improving choroidal flow may mitigate this
process. Finally, if loss of both cell types occurs in glaucoma
(27-32), then retinal and choroidal blood flow improvement may
each have a beneficial effect.
The Impact of Ischemia on Retinal Ganglion Cells
In animal models of glaucoma, retinal ganglion cells die via apoptosis
(32, 33), a process in which ischemia has demonstrated a central
role (33). In in vivo and in vitro models of retinal ischemic/reperfusion
injury emphasize the critical impact of loss of nutrient delivery,
especially to the apparently highly sensitive retinal ganglion
cells (34,35). In this context, it is clear that “neuroprotection”
of these cells may immediately be accomplished by improving ocular
blood flow. Consequently, it is logical to consider relief of
ischemia and increase in delivered oxygen and “nutrition”
as a prime and heretofore unexplored route to immediate neuroprotection
in glaucoma.
Visual function has been linked to hemodynamics in clinical studies
of glaucoma and diabetes. Hyperoxia acutely improved the contrast
sensitivity of diabetic patients with substantial initial defect
(36). Acute enhancement of ocular perfusion may improve visual
function in some patients with NTG (37-41). In another series
of experiments, CO2 breathing reduced resistance indices in the
ophthalmic artery to normal levels in NTG patients, suggesting
the existence of reversible ocular vasospasm (42). Findings similar
to these short-term results with CO2 breathing have been obtained
both acutely and over six months in NTG patients treated with
Ca++ channel blockers (38-40, 43, 44). These studies suggest that
improving ocular perfusion in glaucoma may simultaneously and
immediately enhance visual function but the mechanism for this
action has not been defined.
Today, the role of vascular factors in the management of glaucoma
is in the same condition as IOP was ten years ago. There is currently
no evidence supporting its role in the clinical management of
the disease, in spite of numerous small clinical findings supporting
the role of vascular deficits and ischemia in glaucoma. Existing
clinical research supports the funding of a large scale prospective
ocular hemodynamic study which will reveal what benefit, if any,
glaucoma patients may experience from improved ocular blood flow.
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