Excerpts
From: The International Glaucoma
Review, Volume 9-3, 2008
(Eleventh in a Series)
The Ocular Surface in Glaucoma
- BAK-containing eyedrops reduce the stability of the tear
film via a detergent effect on the lipid layer that increases
the rate of tear evaporation. These alterations to the function
of the tear film layer are associated with the conjunctival
inflammatory response and an epithelial metaplasia affecting
goblet cells and transmembrane mucins. Ocular surface imprints
from glaucoma patients on long-term treatment thus showed
a reduction of almost 50% in the density of goblet cells
and conjunctival inflammatory changes in patients receiving
treatments with BAK compared to unpreserved beta-blockers.
- Studies both in vitro and in vivo have widely demonstrated
that exposure to preservatives (even at low doses) results
in histological, inflammatory, and toxic changes at the surface
of the eye. Therefore, on the basis of all these experimental
and clinical reports, it is advisable to use benzalkonium-free
solutions whenever these are available on the market.
- Management of glaucoma involves long-term pharmacotherapy
with topical antiglaucoma drugs. Most of the antiglaucoma
eyedrops contain benzalkonium chloride (BAK) as a preservative,
and BAK is known to often induce ocular surface disturbance.
In Japanese glaucoma patients, the prevalence rate of keratoepitheliopathy
due to commercially available latanoprost ophthalmic solution
is reported to be approximately 35%, which may be related
to its relatively high concentrations of BAK. On cultured
human conjunctival epithelial-like cells, latanoprost with
BAK, travoprost with BAK, and BAK alone showed significant
cytotoxic effects, whereas no significant cytotoxic effects
were observed in cells exposed to BAK-free travoprost (travoprost
Z). Observed effects are most likely to be related to BAK.
The data reported are solid, reliable, and impressive; however,
it must be noted that a preservative is a necessary evil
for ophthalmic solutions to avoid contamination by potentially
pathogenic microorganisms. Travoprost Z contains sofZia consisting
of zinc, borate, propylene glycol and sorbitol as its preservative
system instead of BAK. Thus, further investigations are needed
to elucidate potential advantages and disadvantages of this
new preservative system, especially in the clinical setting.
In addition, eyedrop-induced adverse effects are more likely
to be observed in the corneal epithelium rather than the
conjunctival epithelium. It has been suggested that chronic
use of preservative-containing eyedrops may be associated
with the failure of filtering surgery.
M & T Commentary
Given this data, it appears that Travatan Z may be the best
choice for reducing IOP when a prostaglandin is indicated.
Glaucoma Screening and Prevention
- With 90% of glaucoma undiagnosed worldwide, methods to
bring more cases in for care may be considered theoretically
worthwhile. Since patients, siblings, and children of OAG
cases are five to ten times more likely to develop OAG, one
approach is to bring in family members.
- High rates of undiagnosed glaucoma exceeding 50% are reported
from various population studies in developed and developing
countries, while current screening methods outside the clinical
office have been proven to be non-cost effective.
M & T Commentary
We all need to more aggressively reach out to family members
of glaucoma suspects to maximize prevention of glaucomatous
vision compromise.
Exfoliation syndrome (XFG)
- Exfoliation syndrome (AKA pseudoexfoliation syndrome) is
a common ocular syndrome found worldwide. XFG is the most
common secondary form of open-angle glaucoma.
Pressure Spikes and Damage to RGC (retinal ganglion cells)
- In a well-written basic-science paper, Resta et al. Report
that rapid (1-2 minute) IOP spikes of high amplitude (50-90mmHg)
induce irreversible damage in a small but significant number
of RGCs and probably increase the vulnerability of many more
to subsequent pressure insults.
- It is interesting that this deleterious effect on RGCs
seems to be related to the abruptness of the IOP spike rather
than to the pressure level or to the total duration of the
pressure insult. Thus, a slow-offset 7-minute exposure to
90mmHg caused no RGC damage at all in isolated rat retinas,
whereas seven 1-minute abrupt 90mmHg pressure spikes caused
maximal damage with up to 80% of RGCs showing signs of injury
in their somata or dendritic trees. With the exception of
ocular trauma, the experimental conditions created by the
authors do not occur naturally (even acute glaucoma is much
closer to their ‘slow 90mm pulse’ which was harmless.)
M & T Commentary
This last point can be used to counsel and reassure our patients
who have had angle-closure events.
IOP Fluctuation and Progression
A hot topic in glaucoma research recently is whether or not
the variation (or fluctuation) of intraocular pressure (IOP)
is an independent risk factor for glaucoma development and
progression. Results from a present study by Jonas et al.
showed that the IOP itself, not the diurnal IOP variation,
had a significant influence on the rate of glaucoma progression.
We don’t expect the debate will be over soon since not enough
is known about IOP variation even with several snapshots
throughout the day. The jury for the debate may need to wait
until the time when a device of continuous IOP monitoring
is available. For now, IOP measurements outside office hours
are still very valuable since these readings may show an
IOP level higher than the office-hour IOP and the peak IOP
may occur frequently outside office hours; these topics are
not under debate.
Gonioscopy
Gonioscopy is the current reference standard for angle assessment
and a key component in the clinical examination of glaucoma
patients. However, gonioscopy is difficult to perform in
a reproducible fashion and angle assessment may be affected
by many variables, such as inadvertent pressure on the cornea,
and by light exposure onto the pupil during the examination.
Previous studies have shown that even experienced examiners
demonstrated only moderate agreement in determining angle
width.
Glaucomatous Disease Progression and CCT
There is strong and consistent evidence that CCT is a reliable
indicator for progression of OHT to glaucoma. In addition,
it has been found that low CCT is frequently associated with
the initial diagnosis of glaucoma when patients already on
treatment are reviewed. In contrast, in screening the significance
of CCT is questionable. Importantly, the authors (Dueker
et al.) found that CCT is not helpful in predicting the risk
of glaucoma progression. These results clearly show the reader
that recording CCT is important, but further research is
needed to clarify the role of CCT in glaucoma screening and
during glaucoma treatment, as well as to understand the relationship
between CCT and corneal compliance or CCT and ageing.
Natural Therapies for Glaucoma
Non-pharmaceutical medicine, a more appropriate term than complimentary
or alternative medicine, has been in existence since pre-human
times. With respect to glaucoma, non-pharmaceutical medicine
does nothing that we know of for intraocular pressure nor
would it be expected to, since the pathophysiology of glaucoma
was not even recognized until the early twentieth century.
The major role of non-pharmaceutical and traditional medical
systems is in modulating the immune system, providing neuroprotection,
and improving cardiovascular function. This is where these
agents will come into play in the treatment of glaucoma.
M & T Commentary
At this time, there is little or no evidence of benefit from
non-pharmaceutical medicine.
The most powerful polyphenolic antioxidant in red wine is
resveratrol, which activates the sirtuin enzyme system. Several
studies have demonstrated that resveratrol is an effective
antioxidant. A single infusion of resveratrol can elicit neuroprotective
effects on cerebral ischemia-induced neuron damage through
free radical scavenging and cerebral blood elevation due to
nitric oxide release. Its antiapoptotic activity has led to
the suggestion that resveratrol may make a useful dietary supplement
for minimizing oxidative injury in immune-perturbed states
and human chronic degenerative diseases. The hot molecule of
2007 is curcumin, a component of turmeric, the yellow spice
in curry and an element in Ayurvedic medicine for 5000 years.
Curcumin has antioxidant, anti-inflammatory, anti-infectious,
and anticancer activity and is potentially applicable to treatment
of malignancies, diabetes, allergies, arthritis, Alzheimer’s
disease (AD), and other chronic diseases. Curcumin has at least
ten known neuroprotective actions and targets multiple AD pathogenic
cascades, making it a strong candidate for use in the prevention
or treatment of major disabling age-related neurodegenerative
diseases like AD, Parkinson’s, and stroke. AD, macular degeneration,
and glaucoma share many characteristics, making curcumin worth
studying further for its potential uses in ophthalmology.
M & T Commentary
Even though theoretical and speculative, we wanted to put this
out for your pondering.
“Top Tips” from the South African Glaucoma Society Annual Meeting
- Risk factors for POAG progression: Age; baseline IOP; PEX;
disc hemorrhage; mean deviation.
- Strategies to enhance compliance: Educate the patient about
the disease and treatment; teach the patient how and when
to apply eyedrops; fit the medications into the patient’s
daily routine; use minimal amount of drops, frequency and
concentration; discuss potential side effects; use aids (literature,
tapes, videos).
- Always make sure the disc and visual field fit when making
the diagnosis of glaucoma.
M & T Commentary:
While obvious to most, this basic concept
needs to be stressed!
- Know your drugs: Indications and contraindications; mechanism
of action - inflow suppressants, outflow enhancement; select
combination drugs carefully; consider variable individual
drug response; evaluate drug compliance versus quality of
life.
Reports on Symposia & Debates of the 2007 World Glaucoma
Congress
Symposium: Glaucoma as a Neurodegenerative Disease
- Neurodegenerative disease: An overview
Glaucoma is a leading cause of irreversible world vision loss
characterized by progressive retinal ganglion cell (RGC) death.
Elevated eye pressure is a major risk factor for glaucoma;
however, despite effective medical and surgical therapies to
reduce intraocular pressure, progressive vision loss among
glaucoma patients is common. These observations suggest that
mechanisms independent of intraocular pressure are also implicated
in glaucomatous degeneration.
- Glaucoma from the eye to the brain
90% of RGCs project to the lateral geniculate nucleus (LGN),
the first major vision center located deep within the brain.
The LGN conveys three major visual channels, namely, the magnocellular
(motion), parvocellular (red-green) and koniocellular (blue-green)
pathways. Attention to pathology within the length of the
RGC axon and also its LGN target may shed new light into the
underlying pathology and progressive nature of glaucoma.
- Cortical changes in glaucoma
Although a substantial number of ganglion cells may die before
visual field defects become correlated with the loss of ganglion
cells, the continuity of functions over the full range of defects
suggests that early defects are concurrent at the two levels
and that the LGN and the V1 changes are a reflection of reduced
activity of the afferent connections from retinal ganglion
cells. The results do not support the premise that alternative
perimetry stimuli based on magno-parvo distinctions will improve
the accuracy of clinical perimetry for the early detection
of glaucoma.
M & T Commentary
Indeed, this final sentence is supported in more current literature,
and flies in the face of late twentieth century thought.
Symposium: Glaucoma in Asia
- The reason given for this special regional symposium was:
“We should recognize that related problems are rather unique
and different among the many regions in Asia and that we
need to know glaucomas in every region in order to have a
better grasp of the disease in Asia.”
M & T Commentary
Since many patients of Asian ancestry frequent our practices,
we all need to be cognizant of these unique and distinguishing
features/risks profiles.
- Disease spectrum in China
Primary angle closure and primary angle closure glaucoma are
more prevalent and tend to be asymptomatic. The high prevalence
is attributed to the anterior chamber anatomy. Pupil block
appeared to be the predominant mechanism for angle closure
in Chinese people.
A possible explanation for the enigma of low tension glaucoma
in Japan could be the lamina cribrosa. The connective tissue
of lamina cribrosa in NTG could be weaker. The prevalence of
weak lamina cribrosa in Japanese might be more common.
- Primary angle closure suspect
It was stressed that the management of the primary angle closure
suspect should depend on the natural history. Over five years,
only a minority of PACS progressed to angle closure, and none
progressed to glaucoma. Treating all PACS would mean over treatment
for the majority of patients.
Symposium: Does Myopia Cause Glaucoma?
- A symposium on glaucoma and myopia was held for the first
time to look at current evidence regarding the association
between glaucoma and myopia, explore the anatomical basis,
if any, for glaucoma occurring in myopic eyes and investigate
the structural and functional variations in myopic eyes with
and without glaucoma.
- Marked to high myopia is a risk factor for glaucoma, while
low to moderate myopia may not play a pronounced role for
glaucoma. The higher glaucoma susceptibility in eyes with
marked to high myopia fits with the finding of a thinner
lamina cribrosa in combination with a secondary enlargement
of the optic nerve head in highly myopic eyes, possibly due
to the myopic stretching of the posterior fundus pole, and
it fits with the pathophysiologic role the lamina cribrosa
and the peripapillary sclera may play in the glaucomatous
optic neuropathy.
M & T Commentary
This quantification of the degree of myopia is probably of
significant clinical value, needs to be given due consideration.
Debate: Ocular Blood Flow in Glaucoma
The relevance of blood flow alteration in daily practice, when
it comes to glaucoma treatment, seems to be very limited.
M & T Commentary:
Our emphasis added – take note!
- There are plenty of hints indicating the importance of
ocular blood flow in glaucoma, but for the acquisition of
final evidence, which may have a chance to translate into
daily clinical practice, more time and money must be devoted
to technological development.
M & T Commentary
For the time being, beware of clinician exalting the virtues
of such diagnostic instruments.
Debate: How Early Should We Detect Glaucoma
- This debate started with an introduction mentioning the
formulated treatment goals of the European Glaucoma Society:
‘To prevent loss of quality of life at an affordable cost.’
In the introduction it was realized that it was important
to know something about the natural history of the disease
and the typical rate of progression noted in clinical practice.
Questions were formulated whether it would be better to go
out and screen for undetected manifest glaucoma in the population
rather than to focus on detecting the first signs of glaucoma
in glaucoma suspects who were already taken care of in the
medical system.
- Our task is not really to identify early glaucoma per se,
but to identify those patients who are at greatest risk for
symptomatic vision loss, i.e., those patients with more advanced
disease or higher IOP or younger age. Adaptive referral strategies
are needed to achieve this type of screening. Not taking
this into consideration risks overburdening our clinics with
false positive referrals.
- There was no evidence that FDT or SWAP is better than SAP
(Standard Automated Perimetry) in detecting early glaucomatous
damage.
M & T Commentary
Recall our previous commentary a few paragraphs earlier re:
diagnostic instruments!
- Patients with manifest glaucoma are often detected with
considerable functional loss in at least one eye. This is
thought-provoking. It may make us consider whether a more
important clinical problem for glaucoma care is to try to
detect some of those 50% of patients in the general population
who have glaucoma without knowing, rather than to try to
detect the first signs of glaucomatous damage in patient
who are already under care. From that point of view, more
resources should be used in screening and case finding and
possibly less in early detection in glaucoma suspects. Population
screening might be the only possible method to avoid detecting
glaucoma too late.
M & T Commentary
We wholeheartedly agree with this enlightened perspective.
Debate: Normal-pressure Glaucoma
- Question: Are NTG and POAG two different diseases, or are
these two parts of a single spectrum of one disease?
Response: Intraocular pressure is a continuum. Patients can
have glaucoma at pressures of different ranges, for example,
from 15 to 40mmHg. So, how are we supposed to divide this range
by 1mmHg and distinguish between NTG and HTG? There is no magic
cut of 21mmHg where we can have all the NTGs or 22mmHg and
above where we can have all the HTGs!
Conclusion: NTG and POAG are not two different diseases, but
a continuum of one disease with different risk factors.
- Question: How do we evaluate IOP in NTG patients?
Response: We believe a diurnal-IOP-curve should be completed
before diagnosis is made.
M & T Commentary
Consider teaching family members to use the iCare® tonometer
(www.edigonline.com)
to obtain a much broader perspective on IOP than “in-office”
assessment.
Symposium: Pediatric Glaucoma
- During the last few years there has been a huge increase
in the number of medical therapies for glaucoma. Clinicians
have found these medications useful in children with elevated
intraocular pressure. It is cautioned that when using topical
glaucoma medications, children may be at increased risk of
systemic side effects compared to adults, due to reduced
body mass and blood volume for drug distribution. Certain
drugs, such as brimonidine are contraindicated in very young
children because of systemic side effects.
- Primary congenital glaucoma is a surgical disease and surgery
should be performed at as early an age as possible.
- Primary trabeculectomy is not a first line procedure in
congenital glaucoma, in view of a higher incidence of complications
and lower success rate in normalizing IOP.
- This symposium was concluded with the comment that the
responsibility of the surgeon does not end with surgery and
it is important not to be lulled into a false sense of security
by surgical control of IOP. Visual rehabilitation is as important
in the management of the disease as is IOP control. Anisometropia
and amblyopia must be aggressively managed to give the children
the best change for good vision in both eyes.
Debate: Fixed Combination Drugs
- While the studies of fixed combinations have shown similar
IOP lowering when compared with concomitant use of the components,
we still have questions about adjunctive medications. ‘What
is important to us is whether they are clinically significant
or not.’
- There are several clinical situations in which a patient
may require more than one medication; when the first drug
is effective but the target IOP is not reached, when the
patient is progressing, or when the disease is at an advanced
stage at diagnosis. ‘The real question is fixed versus non-fixed
combinations.’ The use of a fixed combination assumes that
both components are appropriate for the patient.
M & T Commentary
This assumption, we contend, is commonly false, and thus burdens
the patient unnecessarily.
- By combining two medications in one bottle there is a reduced
frequency of dropping and less exposure to preservative.
- With fixed combinations there is reduced risk of mixing
up bottles or dosing frequency. And patients will not have
a wash out effect from administering multiple medications
with too short an interval between.
- ‘Friends don’t let friends take two medications when one
is enough.’ Fixed combination is not the same as adjunctive
therapy. ‘A very good agent when used second or third, may
give you very little IOP lowering compared to when you use
it alone.’
- Fixed combination can have the side effects of both components
so if you plan to use a fixed combination you should demonstrate
that both components are contributing to the IOP lowering
effect.
M & T Commentary
This crucial goal is accomplished with monocular trials of
individual medicines in order to make sure an additional
drop is needed.
- The convenience of fixed combination comes at the cost
of some loss of IOP effect.
- The panel came to consensus on several patients:
─ Physicians must remember that fixed combinations contain
two drugs, with the potential for all the associated adverse
effects.
─ Fixed combination therapy offers potential advantages including
convenience, reduced preservative burden (compared with concomitant
use of the components) and less potential for dosing errors
and washout.
─ Fixed combinations should be used only when both components
are contributing to the IOP-lowering effect.
Symposium: Medical versus Laser Treatment
- The efficacy profile of primary SLT is comparable to that
reported for primary ALT. SLT can be effectively repeated
in the individual eyes.
- There are no strong enough evidences supporting the preferential
indications of one treatment modality vs. the other as primary
therapy in open-angle glaucoma or ocular hypertension. Besides,
data on possible detrimental effect of primary SLT on the
efficacy of more modern medications (and vice versa) are
scarce.
M & T Commentary
Other peer-reviewed publications affirm that ALT and SLT are
clinically equivalent. Beware of SLT “enthusiasts” as there
could be a financial encumbrance supporting unmerited exuberance.
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