Excerpts
From: The International Glaucoma
Review, Volume 10-1, 2008
(and it's supplement)
Normal Tension Glaucoma
Stephen Drance, Emeritus Professor of Ophthalmology, University
of British Columbia, has made more than 300 contributions
to the glaucoma literature spanning half a century. Dr. Drance
reported a number of studies showing that there are different
ways in which primary open-angle glaucoma (POAG) develops
and progresses. Principal component analysis found two clusters
of POAG patients: a vasospastic cluster in which the level
of visual field (VF) defects is related to IOP, and a vascular
sclerotic cluster in which the level of VF defect is not
related to IOP. Both clusters had equal numbers of so-called
NTG (normal tension glaucoma) and chronic POAG patients.
In some patients, the glaucomatous neuropathy was therefore
IOP-dependent but, in others, there was no such IOP relationship.
More than one of these mechanisms could be present in a patient
at the same time or at different stages of their life.
The Collaborative Normal-Tension Glaucoma Study (CNTGS) was
the first glaucoma study with randomly selected untreated controls,
and the first study using the early automated perimeters. The
safety of the untreated controls required very sensitive progression
criteria. From the outcomes of this study, Drance calculated
that 65% of glaucoma patients with a low or normal IOP (< 21mmHg)
were IOP-sensitive and 35% were not IOP-dependent. This finding
confirmed that even normal IOP is part of the pathogenesis
of POAG. The CNTGS also showed that an IOP reduction of 30%
of greater favorably influenced the course of the disease in
NTG patients when the impact of cataracts on VF progression
was removed, but over 20% of the treated patients continued
to progress despite a major reduction in IOP.
Untreated control patients in the CNTGS had a variable course
of disease progression: 50% progressed (5% rapidly and 45%
slowly), while 50% seemed not to progress with careful follow-up.
The findings from the Early Manifest Glaucoma Treatment (EMGT)
study confirmed this proportion of 50% of non-progression among
untreated NTG patients. In this study, over 50% of the patient
population had statistically normal IOP. This demonstrates
that NTG is quite common. Because 50% of NTG patients may not
be progressing when first diagnosed, and NTG patients constitute
almost half of all POAG patients in many parts of the world,
newly diagnosed patients should all have their VISUAL FIELD
and optic discs monitored without treatment to determine if
their disease is progressing and to ascertain the rate of progression
in case of confirmed progression. If therapy is started upon
diagnosis of glaucoma, it is difficult to determine if non-progression
is due to treatment or to nature. As with every rule, there
are some exceptions, but only very few. Thus, the 5% of NTG
patients whose progression is steep are easily and quickly
identified and, obviously, require immediate attention.
In untreated patient of the CNTGS, female gender, migraine
and disc hemorrhage were found to be the risk factors for a
faster rate of progression, while Asian ethnicity seemed to
be beneficial. Although IOP-lowering favorably affected the
course of the disease in female patients and in migraineurs,
it was not statistically effective in males, in people with
a history of vascular disease (multivariate) or a disc hemorrhage.
M & T:
The idea of watching some glaucoma patients for a period of
time to ascertain whether the optic neuropathy is progressive
or not, and further, if it is progressing to determine the
RATE of progression prior to initiating therapy is not new,
but certainly merits our keen clinical attention. We need to
have a reasonable idea of both the qualitative (is it glaucoma
or not) and quantitative aspects (i.e., rate of progression)
of optic neuropathy before therapeutic intervention is made.
More on Normal Tension Glaucoma
Available data have shown that around 50% of patients with
glaucoma, as determined by VF and optic nerve abnormalities,
have an IOP of 20mmHg or less. In addition, a recent study
in Japan showed that the IOP distribution of a population of
glaucoma patients was similar to that of a non-glaucoma population.
Differentiating Between Truth and Myth
About Glaucoma (Anders
Heijl)
One must always try to differentiate between truth and myth
and, too often, myth is allowed to stand in the way of truth.
Destroying myth is just as important for our progress as finding
new truth, and glaucoma is full of myths, or misconceptions,
both old and new.
Old myths are concepts previously thought to represent the
absolute truths but, about which, beliefs are no longer held.
Indeed, the most important of these myths in glaucoma was that
elevated IOP is identical to the disease and vice versa. Another
common myth was that optic disc (OD) hemorrhages were very
rare and non-existent in most countries, and that they were
usually rapidly followed by notching and VF worsening. Indeed,
it is currently known that OD hemorrhages occur in most glaucoma
patients and that they do not change disc topography of VF
in a short time.
Modern myths also exist, and one of the most popular ones if
the concept that IOP fluctuations represent a key risk factor,
or perhaps a more important risk factor than IOP itself, for
glaucoma progression. So far, there is no clear evidence to
support this concept.
Another modern myth is that selective perimetric testing (such
as SWAP of FDT) can detect VF loss before standard white-on-white
perimetry.
M & T:
New expert opinion allows us to keep glaucoma visual field
testing very simple. We always use the standard white 24-2
program. Sometimes, we use SITA-Standard, and at other times
SITA-Fast, but we do keep consistent testing consistent for
each individual patient.
A very popular modern myth is that glaucoma leads to blindness
if left untreated. The concept that all glaucoma patients should
become blind if left untreated is indeed not true because,
then, people would have to live forever. Although glaucoma
progresses, at least half of glaucoma patients die undiagnosed
and seeing. Of course, this does not mean that glaucoma patients
should be left undetected or untreated, but it is important
that clinicians not be induced into overtreating their patients
indiscriminately as this has a price in inconvenience, side-effects
and stress.
What Causes Elevated IOP in Glaucoma?
It is believed that elevated IOP in glaucoma is due to a buildup
of extracellular matrix (ECM) material in the trabecular
meshwork, which blocks the outflow system.
Diabetes and Glaucoma
There is no clear evidence to support a relationship between
diabetes and glaucoma. IOP level is usually slightly higher
in diabetic patients; however, this slight increase is currently
thought to be caused by a higher central corneal thickness
(CCT) in these patients. As reported in the OHTS, central
corneal thickness (CCT) was higher in diabetic compared with
non-diabetic subjects, and this increase in CCT may be responsible
for an overestimation of IOP.
M & T:
We stress again that newer studies do NOT support a direct
relationship between diabetes and glaucoma!
Axial Myopia and Glaucoma
With the current means, it is quite difficult to detect glaucoma
in highly myopic eyes, and quite a high number of these patients
will go undetected. Findings have shown that, below -8 diopters,
the optic disc size increases, probably owing to myopic stretching.
Thus, myopic stretching of the optic disc leading to thinning
of the lamina cribosa may be one of the pathogenic mechanisms
leading to an increased susceptibility to glaucoma in highly
myopic eyes. CCT has been suggested to have a role in the
susceptibility to glaucoma, but current evidence does not
strongly support its correlation with the three morphological
factors most probably implicated in the pathogenesis of glaucoma:
lamina cribosa thickness, peripapillary scleral thickness
and distance between intraocular space and CSF (cerebral
spinal fluid) space.
Important Points in Glaucoma Management
Glaucoma management is aimed at preventing progression or,
more precisely, at preventing important or serious progression.
In practice, clinicians initially (after diagnosis) must
perform this by guessing, and the best guess that we all
perform is that of setting target pressure at baseline.
It must be remembered that, in manifest glaucoma, rate of progression
is more important than progression itself, because most patients
progress at some point during their lifetime.
The relationship of structural and functional measurements
of disease progression has been the subject of many studies.
The findings showed a rather poor agreement between the two
types of measurement, indicating that structural damage does
not preceded functional damage as commonly believed. As to
whether structural or functional measurement is more clinically
important, some feel that functional testing has the clear
advantage of showing clinicians where the patient’s vision
is. Another question is how much change is needed for the clinician
to document progression. It is commonly and erroneously believed
that structure is constant unless progression occurs. However,
this is incorrect because there is variability in images of
optic disc caused by diurnal changes, parallax and measurement
errors. In the EMGT (Early Manifest Glaucoma Trial) a very
small perimetric progression (-1.83 dB) was needed to define
definite progression, which was specific and highly sustainable.
This finding suggests that progression may be detected up to
15 times from normal to blindness using standard perimetry.
Available data indicate that about the same number of tests
are needed for functional and structural measurements to document
and quantify progression. Imaging techniques are in their early
phase of development and will certainly improve in the future.
While today functional testing is clearly preferable in follow-up
of glaucoma patients, translation of structural measurements
into functional ones may make imaging techniques much more
clinically important in the future.
Finally, it is important to stress that it may be time to reallocate
healthcare resources. Too much emphasis has been given to early
diagnosis and patients with well-established disease are often
forgotten. For these patients, there is a need for more follow-ups
for the determination of rate of progression, instead of detection
of progression. Today, a patient’s rate of progression is the
most important parameter in long-term follow-up. Instead of
focusing on maximum treatment of all patients, it is more relevant
to clinical management that a clinician understands the importance
of the level of the functional damage, the rate of progression,
and the patient’s age and life expectancy. Clinical progress
in glaucoma will require a change of focus from diagnosis to
progression and progression rate.
Normal RGC Loss
There are approximately 1 million RGCs (retinal ganglion cells)
at birth, about half of which are lost after 100 years of
life; that is, about 5,000 RGCs per year. This corresponds
to a rate of about 0.5% of RGCs lost per year, or about 15
RGCs per day.
Sleep Apnea Syndrome and Circadian IOP
Obstructive sleep apnea (OSA) is more prevalent in subjects
with primary open-angle glaucoma (POAG) than in the general
public and POAG is more prevalent in subjects with OSA than
in the general public. OSA is often treated by nocturnal
administration of continuous positive airway pressure (CPAP).
CPAP is known to raise intraocular pressure (IOP).
In a study to determine the impact of CPAP on circadian IOP,
it was noted that IOP dropped significantly within 30 minutes
of stopping CPAP in the morning. By raising intra-thoracic
pressure, thus venous pressure, thus episcleral venous pressure,
CPAP likely raises IOP by reducing aqueous outflow. CPAP-induced
IOP elevation may explain the increased prevalence of POAG
in subjects with OSA, and these subjects may warrant ongoing
glaucoma screening. When established glaucoma patients require
CPAP therapy, the clinician should be aware that the resulting
IOP changes may not be detectable during office hours, and
that these patients may be at risk for disease progression
despite apparently well-controlled IOP as measured in the diurnal
period.
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