Chapter 3 Treatment Principles and Options
3.1 - General Principles of Glaucoma Treatment
The purpose of this chapter is to give a summary overview and it is not meant to be
an all-inclusive text
THE WHOM -TO -TREAT GRAPH The rate of ganglion cell loss and resulting functional
decay is very different among different glaucoma eyes. Quality of life is clearly
reduced when visual field defects become severe, cf. the severe functional impairment.
Line A represents the effect of aging alone. In glaucoma loss of visual function is
often much more rapid. An older patient, diagnosed late in life, with a moderate rate
of progression (B) has a much lower risk of developing severe functional impairment
than a younger patient with the same amount of field loss at diagnosis and rate of
progression (C). A very slow rate of progression may be tolerated by the patient and
treatment left unchanged (D), while a rapid rate of progression (E) needs a considerably
lower target pressure.
It needs to be remembered that it is the extent of binocular visual field or the field
of the better eye that largely determines the patient’s quality of life, while the
rates of progression of each eye separately are needed to determine treatment.
© European Glaucoma Society
To assess the likely Rate of Progression (RoP) is an important part of patient management
and the measured rate is a very important factor that should determine target pressure
and treatment intensity (See Ch. Introduction) [I.D]. Many studies have found that
progression is usually linear1-4, but the goal of intensifying treatment is to decrease
rate of progression.
Please observe that perimetric printouts of progression using the MD or VFI indices
are age-corrected, so that a normal eye would not show any age-related deterioration
The goal of glaucoma treatment is to maintain the patient’s visual function and related
quality of life, at a sustainable cost. The cost of treatment in terms of inconvenience
and side effects as well as financial implications for the individual and society
requires careful evaluation (See Ch. Introduction). Quality of life is closely linked
with visual function and, overall, patients with early to moderate glaucoma damage
have good visual function and modest reduction in quality of life, while quality of
life is considerably reduced if both eyes have advanced visual function loss.
Glaucoma is still a leading cause of blindness in Europe. A considerable percentage
of glaucoma patients become blind in both eyes or encounter serious field loss in
both eyes5-7. Major risk factors for glaucoma blindness are the severity of the disease
at presentation and life expectancy8,9. A 60-year-old patient with bilateral moderate
visual function damage at diagnosis has a greater risk of blindness than an 85-year-old
patient with a similar amount of damage. Similarly a young patient with mild bilateral
damage is at much larger risk of disability in his lifetime than an 80-year-old patient
with moderate unilateral disease Thus, treatment must be individualised to the needs
and rate of progression (RoP) of each patient (See Fig. 1 Ch. Introduction) [I,D].
The risk of ever encountering loss of quality of life from glaucoma should determine
target pressure, intensity of treatment, and frequency of follow-up [I,D].
Thus, patients with severe functional loss or younger patients with manifest disease
should have more aggressive treatment and closer follow-up than patients with little
or no risk, e.g., very old patients with early field loss or unilateral disease [I,D].
Glaucoma suspects, e.g., patients with elevated IOP and otherwise normal findings,
have even smaller risks.
In most patients with advanced glaucoma and reasonable life expectancy, aggressive
IOP lowering treatment might be recommended10,11 [I,D]. Very old patients with mild
loss, relatively low IOP levels and significant health problems, might prefer being
followed without treatment (See also Ch. Introduction) [II,D]. When treatment options
are discussed with a patient, his general health status and personal preferences must
be considered and respected. It is also important to ensure that patients are able
to comply and persist with therapy [I,D].
Disease progression rates (RoP) in POAG, the most common form of glaucoma differ very
much between patients, from rapid to very slow12-16. This makes it necessary to determine
the RoP in patients with manifest glaucoma (See Fig. 1 Ch. Introduction) [I,D]. Many
patients with POAG/NTG show no or only small deterioration despite years of follow-up17,18,
while rapid progression is common in others, e.g. in exfoliation glaucoma18. Glaucoma
patients may continue to show progression despite treatment, even with IOP levels
within the statistically normal range. Relying on tonometry alone for glaucoma follow-up
is, therefore, insufficient regardless of IOP level17,18.
Determining the rate of visual field progression is a new standard in glaucoma care.
The EGS recommends three visual field tests per year for the first two years after
diagnosis to make it possible to identify rapidly progressing patients [II,D]. After
two years of perimetric monitoring without progression being detected the frequency
of tests may be reduced [II,D].
Once the progression rate has been determined the target pressure is re-evaluated
and be based on the measured rate of progression and IOP values measured during the
follow-up time [II,D]. Risk factors are then less important than at diagnosis (See
Individualized glaucoma treatment aims at providing glaucoma management tailored to
the individual needs of the patient; patients with severe functional loss or younger
patients with manifest disease should have more aggressive treatment and closer follow-up
than patients with little or no risk, e.g., patients with ocular hypertension or elderly
patients with mild field loss and low IOP levels19-23 [I,D]. (See FC VI)
In most Western countries approximately half of patients with manifest glaucoma are
undiagnosed24-27, and glaucoma is often diagnosed late8. Improved case finding and
possibly screening of high risk groups are necessary to allow diagnosis at earlier
disease stages. Screening options for high risk groups should be evaluated. To discover
and treat those at risk of losing functionally significant vision is a more important
goal for effective glaucoma management than widespread treatment of patients with
Currently, the only approach proven to be efficient in preserving visual function
is lowering IOP28-31 (See Ch. Introduction and FC VI to XI) [I,A]. Other possible
treatment areas have been investigated, including ocular blood flow and neuroprotection.
There are experimental as well population based studies indicating that perfusion
pressure may be relevant in glaucoma31-37 but very difficult to measure38 a specific
glaucoma phenotype characterised by vascular dysregulation has been described32,33.
An increase of IOP will lead to a reduction of perfusion pressure. Blood pressure
levels may also be important in glaucoma17,36,37. However, there is no conclusive
evidence to support the idea that perfusion pressure can be increased by manipulating
blood pressure or ocular blood flow in glaucoma patients.
Neuroprotection can be defined as a “therapeutic approach” aiming to directly prevent,
hinder and, in some cases, reverse neuronal cell damage. Since glaucoma patients can
continue deteriorating in spite of an apparently well controlled IOP, the need for
effective non-IOP related treatments is widely acknowledged. Several compounds have
been shown to be neuroprotective in animal models of experimental glaucoma39-43.
So far, no compound has reached a sufficient level of evidence to be considered as
a neuroprotectant in humans. A large long-term randomized trial using a neuroprotective
agent, memantine, was analysed several years ago, but with negative results. A more
recent study claiming that topical brimonidine might haven neuro-protective properties
in glaucoma patients, has been questioned in a systematic review on neuroprotection
In most western countries, approximately half of patients with manifest glaucoma are
3.2 - Target Iop and Quality of Life
3.2.1 Target Intraocular Pressure (Target IOP)
Therapy in glaucoma management aims to lower IOP to slow the rate of visual field
Target IOP is the upper limit of the IOP estimated to be compatible with a rate of
progression sufficiently slow to maintain vision-related quality of life in the expected
lifetime of the patient. It should be re-evaluated regularly and, additionally, when
progression of disease is identified or when ocular or systemic comorbidities develop
There is no single Target IOP level that is appropriate for every patient, so the
Target IOP needs to be estimated separately for each eye of every patient (See FC
IX and X) [II,D].
Factors to consider when setting the Target IOP include19,28,46 [II,D]:
Stage of glaucoma
The greater the pre-existing glaucoma damage, the lower the Target IOP should be
IOP level before treatment
The lower the untreated IOP levels, the lower the Target IOP should be
Age and life expectancy
Whilst younger age implies greater life expectancy and, therefore, a lower Target
IOP, older age is a risk factor for more rapid progression
Rate of progression during follow-up
The faster the rate of progression, the lower the Target IOP should be
The presence of other risk factors, e.g., exfoliation syndrome
The side effects and risks of treatment
When taking the IOP reading, it is advisable to consider CCT [I,C].
Several clinical studies have identified that worse initial visual field loss is the
most important predictor of blindness from glaucoma7,47-49. When considering the Target
IOP for one eye, the vision status of the other eye should be taken into account.
In a newly-diagnosed patient, the rate of progression is unknown and Target IOP is
based on risk factors for progression (See Ch. 18.104.22.168). After sufficient follow-up
and with sufficient visual field tests to reliably determine the progression status,
usually 2-3 years, the importance of the risk factors for decision-making decreases
and importance of the measured rate of progression increases; the rate of progression
should be used to adjust the Target IOP, taking into account IOP levels over the observation
period, life expectancy, and current levels of visual function damage (See FC X)22.
22.214.171.124 Setting the Target IOP
There is little evidence base to support any particular algorithm to set the Target
IOP, but data from clinical trials may be used as a guide. As clinical trials have
shown that progression occurs in eyes that have an IOP within the statistically normal
range (<21 mmHg), older recommendations that treated IOP should be simply within the
statistically normal range are no longer regarded as sufficiently ambitious.
In newly diagnosed patients, the Target IOP is initially determined according to stage
of disease and the starting IOP, with the treatment goal being a specific IOP level
or a percentage reduction, whichever is the lower50 [II,D]. For instance, in early
glaucoma, an IOP of <21 mmHg with a reduction of at least 20% may be sufficient. In
moderate glaucoma, an IOP <18 mmHg with a reduction of at least 30% may be required
[II,D]. Lower Target pressures may be needed in more advanced disease [I,D]. The Target
IOP based on stage of disease and IOP then needs to be refined according to the presence
of other risk factors, expected longevity of the patient, the burden of therapy and
the patient preferences (See FC X)46 [II,D].
126.96.36.199 Achieving the Target IOP
Initial therapy may be with topical medication or laser trabeculoplasty [I,A]. The
principles of adjusting therapy to achieve treatment targets are shown in Flow Charts
IX - X - XI. To minimize side effects, the least amount of medication required to
achieve the desired therapeutic response should be given. If a patient fails to attain
the Target IOP during follow-up, and additional therapy is being considered, then
the Target IOP should be reaffirmed to ensure that it is still appropriate [II,D].
188.8.131.52 Re-evaluating Target IOP
If the visual field is worsening at a rate that may threaten Quality of Life during
the patient’s expected lifetime, then the Target IOP, if previously met, should be
lowered; a further 20% reduction has been shown to be effective51. If the Target IOP
had not previously been met, then additional therapy should be considered, in consultation
with the patient, weighing the risks and benefits of the additional intervention (See
FC XI) [I,D].
If there are sufficient visual fields to judge the rate of progression, and this rate
is sufficiently slow not to impact on the patient’s quality of life, then the Target
IOP may be revised upward if the Target IOP has not been met or if the patient is
on excessive therapy or is experiencing side effects [II,D].
If there are insufficient visual fields to judge the rate of progression and the Target
IOP has not been met, then additional therapy should be considered, as above [II,D].
3.3 - Antiglaucoma Drugs
Several prospective randomized multi-centre controlled clinical studies have clearly
established the benefits of IOP reduction in managing POAG at various stages of the
disease whether of the ‘high pressure’ or ‘’normal pressure’ variety as well as reducing
the conversion of OHT to POAG10,18,28,52-56 [I,A].
Most forms of open-angle glaucoma and many types of chronic angle-closure glaucoma
are initially treated with topical and occasionally orally administrated agents that
act either on the reduction of aqueous humour production or enhancement of the aqueous
outflow or on both. An uncommon exception to initiating treatment with medical therapy
is for eyes with a very high level of IOP at presentation causing an immediate threat
to sight. Additionally many forms of childhood glaucoma are managed with early surgery
Although acute angle closure with or without glaucoma needs rapid laser or incisional
surgery, medical treatment usually will be initiated as a first step in most cases.
Laser treatment may be a suitable first option for patients with known intolerance
or allergy to topical agents or suspected poor compliance [I,A].
When initially selecting medical therapy it is important to consider some relevant
patient’s characteristics as well as features related to the drug (See FC XII and
FC XIII - Medical Management - Choosing Therapy
3.3.1. Start with Monotherapy
It is recommended to initiate the treatment with monotherapy (See FC XIII - XIV) [II,D].
Treatment is considered “effective” when the achieved IOP reduction on treatment is
comparable to the published average range for that drug in a similar population. According
to a meta-analysis of randomised controlled trials, the highest reduction of IOP is
obtained with prostaglandins, followed by non-selective b-blockers, alpha- adrenergic
agonists, selective b-blockers and at last topical carbonic anhydrase inhibitors57.
It should be noted, however, that treatment effects depend on baseline IOP, with larger
reductions in patients with higher pre-treatment pressure levels. At low IOP values
medical and/or laser therapy have smaller effect on IOP. Therefore, when evaluating
the efficacy of a therapy or a drug it is important to consider the pre-treatment
If this initial therapy reduces IOP to the target and is well tolerated, therapy can
be left unchanged, but the patient needs to be monitored with regular checking of
FC XIV - Therapeutical Algorithm in Glaucoma Topical Therapy
184.108.40.206 Switch to Another Monotherapy
If the initial therapy does not seem effective, with the target pressure not being
reached, or the drug is not tolerated, one should switch to another monotherapy rather
than adding a second drug [II,D]. This applies also to prostaglandin analogues, (PGA)
when used as first choice. As there are non-responders to certain PG analogues the
switch to another PGA or another class of monotherapy might be of benefit [II,D].
Laser therapy may also be a therapeutical option (See FC XIII) [I,A].
220.127.116.11 Add Second Drug / Combination Therapy
If the first choice monotherapy is well tolerated and has effective IOP lowering but
has not succeeded in reaching the target pressure, the addition of a second drug should
be considered [II,D]. While individualizing adjunctive therapy, issues to consider
in selecting an adjunctive agent include additive efficacy, safety, frequency of dosing
and cost. It is recommended to combine agents with different modes of action, one
that affects production of aqueous humour and another that influences outflow [II,D].
In general, treatment with a combination of agents of different classes is associated
with superior IOP lowering efficacy compared to each of the components used alone
[I,A] (see Tables 3.1-3.2). However poly- drug regimens for glaucoma pose several
important clinical challenges: multiple topical treatments may jeopardize adherence59,60,
result in reduced efficacy through wash-out of earlier medications with later medications61,62
and increase exposure to preservatives63,64.
Therefore, fixed combination therapy, when available, should be preferable to two
separate instillations of agents [I, B].
Currently, all fixed combinations available in Europe contain a beta-blocker. However,
beta-blocking agents can be associated with systemic side effects and need to be used
cautiously in patients with serious concomitant cardiopulmonary diseases. It is therefore
mandatory to exclude patients with these contra-indications before prescribing fixed
combinations [I,D]. It is not recommended to combine two bottles of fixed combinations
as both will contain a □-blocker and double the amount of this active drug with the
risk of more systemic side effects [I,D]. On the other hand, fixed combinations containing
timolol may be associated with a better local tolerability in some patients, though
data are limited65.
Fixed combinations usually have clinical equivalence to unfixed combinations; slight
differences in IOP-lowering efficacy may be seen in some cases66,67.
Occasionally IOP-lowering agents are available as fixed combinations in some countries
and are in development in others. A new fixed combination without a □-blocker, containing
a carbonic anhydrase inhibitor (brinzolamide 1.0%) and an alpha 2 adrenergic receptor
agonist (brimonidine tartrate 0.2%) has been recently approved by the FDA and submitted
to EMEA but is not yet widely available. Also, a new fixed combination of tafluprost
0.0015% and timolol 0.5% has been submitted to EMEA. Combination therapy, either as
poly-drug regime or as fixed combination, is not recommended as first-line treatment
[II,D]. However, in selected cases, such as advanced glaucoma and/or very high levels
of IOP, the requested IOP reduction
may exceed the efficacy range that can be expected by a single agent. Therefore, although
the standard treatment algorithm remains unchanged, the time interval between incremental
therapeutic steps may be decreased, combination therapy, fixed or unfixed, can be
adopted more quickly than usual or even immediately [II,D]. If combination therapy
fails to lower IOP sufficiently, one can either substitute the second drug or add
a third medication to the fixed combination. At this stage however laser or incisional
surgery, if possible, should be considered [II,D].
Combined IOP-lowering topical medications
DRUG COMBINATIONS - ADDITIVE EFFECT
3.3.2 The Effect on IOP
The pre-post IOP graph shown below is a useful tool to show the IOP changes induced
by treatment and its use should be encouraged in publications.
The Pre - Post IOP Graph.
A simple graph can be used to show the IOP lowering effect. Different shapes/colours
can be used to show different patient series or different observation times. Vertical
and horizontal lines show respectively Pre and Post Treatment IOP levels of interest,
here placed as examples at 15 and 21 mmHg. Areas of desired effect under the oblique
“no effect” line can thus be defined.
Treatment “A” blue dots: eye n 1 lies on the “no effect” line. Eyes n 2 and n 3 both
show a large effect, with only the former below the 15 mmHg line. Eye n 4 shows a
sizeable decrease of IOP but the absolute level is still >21 mmHg.
Treatment “B” red dots. Eyes n 1 and n 2 show a slight increase and a slight decrease
of IOP, respectively; eye n 3 shows a very large effect, as well as eye n 4, both
remaining below the 15 mmHg line.
Assess each eye individually when deciding the most appropriate therapy.
It is essential to involve patients as informed partners in decisions regarding the
management of their condition.
The least amount of medication (and consequent inconvenience, costs and side effects)
to achieve the therapeutic response should be a consistent goal.
A therapeutic medical trial on one eye first can be useful to determine the IOP lowering
efficacy, although not always logistically feasible or advisable (e.g., very high
IOP or advanced disease).
Usually there is no need to start treatment until all baseline diagnostic data are
collected, unless the IOP is very high and there is severe damage.
After diagnosis it is advisable to measure untreated IOP more than once before initiating
The following pages outline the most frequently used anti-glaucoma medications, and
emphasize their mode of action, dosage and side effects. A complete list of all possible
medications is beyond the scope of the Guidelines.
Antiglaucoma drugs have been available since 1875. The following diagram shows the
chronology of the introduction of topical intraocular pressure-lowering medications
IOP lowering molecules and year of first clinical use. FC: fixed combination. In black:
There are six classes of topical antiglaucoma drugs. The following tables contain
only the most common classes and compounds, their most common side effects and contraindications.
They are listed in order of first and second line drugs.
The seventh category is systemically administered osmotics.
The use of some compounds like epinephrine and dipivefrin has decreased significantly
since drugs with better efficacy and fewer side effects became available.
The text should be considered as a general guide, and cannot be all-inclusive.
Class: PROSTAGLANDIN ANALOGUES
Mode of action
Latanoprost 0.005% Tafluprost 0.0015% Travoprost 0.003% - 0.004%
Increase in uveo-scleral outflow
Contact lenses (unless reinserted 15 minutes following administration of the drugs)
Local: Conjunctival hyperaemia, burning stinging, foreign body sensation, itching,
increased pigmentation of periocular skin, periorbital fat atrophy, eyelash changes.
Increased iris pigmentation, (in green-brown, blue/ grey-brown or yellow-brown irides).
Cystoid macular oedema (aphakic/pseudophakic patients) with posterior lens capsule
rupture or in eyes with known risk factors for macular oedema, reactivation of herpes
Bimatoprost 0.03% Bimatoprost 0.01%
Increase in uveo-scleral outflow
Systemic: Dyspnea, chest pain/angina, muscle-back pain, exacerbation of asthma
Class: Beta-RECEPTOR ANTAGONISTS
Mode of action
Timolol 0.1-0.25-0.5% Levobunolol 0.25% Metipranolol 0.1-0.3% Carteolol 0.5-2.0% Befunolol
Decreases aqueous humour production
Asthma, history of COPD, sinus bradycardia (< 60 beats/min), heart block, or cardiac
Local: Conjunctiva hyperaemia, SPK, dry eye, corneal anesthesia, allergic blepharo-
conjunctivitis Systemic: Bradycardia, arrhythmia, heart failure, syncope, bronchospasm,
airways obstruction, distal oedema, hypotension, Hypoglycemia may be masked in Insulin
dependent Diabetes Mellitus (IDDM), nocturnal systemic hypotension, depression, sexual
Decreases aqueous humour production
Asthma, history of COPD, sinus bradycardia (< 60 beats/min), heart block, or cardiac–
Local: Burning, stinging more pronounced than with non-selective compounds Systemic:
Respiratory and cardiac side effects less pronounced than with non-selective compounds,
depression, erectile dysfunction
Combined IOP-lowering topical medications
Mode of action
Brinzolamide 1% Dorzolamide 2%
Decreases aqueous humour production
Patients with low corneal endothelial cell count, due to increased risk of corneal
Local: Burning, stinging, bitter taste, superficial punctate keratitis, blurred vision,
tearing Systemic: Headache, urticaria, angioedema, pruritus, asthenia, dizziness,
paresthesia and transient myopia.
Acetozolamide Methozolamide Dichlorphenamide
Decreases aqueous humour production
Depressed sodium and/or potassium blood levels, cases of kidney and liver disease
or dysfunction, suprarenal gland failure, hyperchloremic acidosis.
Systemic: Paresthesias, hearing dysfunction, tinnitus, loss of appetite, taste alteration
nausea, vomiting, diarrhoea, depression, decreased libido, kidney stones, blood dyscrasias,
metabolic acidosis, electrolyte imbalance
Class: Alpha-2 SELECTIVE ADRENERGIC AGONISTS
Mode of action
Decreases aqueous humour production
Local: Lid retraction, conjunctival blanching, limited mydriasis (apraclonidine),
allergic blepharoconjuntivitis, periocular contact dermatitis, allergy or delayed
hypersensitivity (apraclonidine and clonidine >brimonidine)
Decreases aqueous humour production and increases uveo-scleral out?ow
Clonidine 0.125 -0.5%
Decreases aqueous humour production
Oral monoamine oxidase (MAO) inhibitor users Pediatric age Very low body weight in
Systemic: Dry mouth and nose (apraclonidine). Systemic hypotension, bradycardia (clonidine),
fatigue, sleepiness (brimonidine)
Class: NON SELECTIVE ADRENERGIC AGONISTS
Mode of action
Epinephrine 0.25-2.0% Dipivefrin 0.1%
Decreases aqueous humour production and may increases uveo-scleral outflow
Occludable angles (iridotomy needed) Aphakic patients (macular oedema)
Local: Conjunctival hyperemia, conjunctival pigmentation. Burning, stinging, ocular
pain, blurred vision, macular oedema Systemic: systemic hypertension, headache, anxiety,
confusion, chest pain, shortness of breath, tachycardia, sweating
Class: PARASYMPATHOMIMETICS (CHOLINERGIC DRUGS)
Mode of action
Pilocarpine 0.5-4% Carbachol 0.75-3%
Facilitates aqueous out?ow by contraction of the ciliary muscle, tension on the scleral
spur and traction on the trabecular meshwork
Post-operative inflammation, uveitis neovascular glaucoma. Patient at risk for retinal
detachment, spastic gastrointestinal disturbances, peptic ulcer, pronounced bradycardia,
hypotension, recent myocardial infarction, epilepsy, Parkinsonism
Local: Reduced vision due to miosisand accommodative myopia, conjunctival, hyperaemia,
retinal detachment, lens opacities, precipitation of angle closure, iris cysts Systemic:
Intestinal cramps, bronchospasm, headache
Demecarium bromide 0.125-0.25% Ecothiophate iodide 0.03% Diisopropyl ?uorophosphates
Same as direct acting drugs
Local and systemic: Side effects are similar but more pronounced than with direct
Class: PARASYMPATHOMIMETICS (CHOLINERGIC DRUGS)
Mode of action
Glycerol Isosorbide Alcohol
Dehydration and reduction in vitreous volume Posterior movement of the iris-lens plane
with deepening of the AC
Cardiac or renal failure
Nausea, Vomiting, dehydration (special caution in diabetic patients). Increased diuresis,
hyponatremia when severe may lead to lethargy, obtundation, seizure, coma. Possible
increase of bood glucose. Acute oliguric renal failure. Hypersensitivity reaction
3.3.3 First Line Drugs
3.3.4 Second Line Drugs
18.104.22.168 Prostaglandin Analogues
Since their development in the 1990s, prostaglandin derivatives (latanoprost, travoprost,
bimatoprost and tafluprost) (Table 3.3) have progressively replaced beta-blockers
as first-choice/first line therapy. This is mainly because they are the most effective
IOP- lowering agents54, lack relevant systemic side effects and require just once-daily
administration. Recently, a number of latanoprost generics as well as preservative-free
and BAC-free prostaglandin formulations have entered the glaucoma market.
The primary mechanism of action of prostaglandins is to increase uveoscleral outflow,
reducing IOP by 25%-35%. Reduction of IOP starts approximately 2-4 h after the first
administration, with the peak effect within approximately 8-12 h. Thus, IOP measurements
taken in the morning represent the peak effect of the prostaglandin analogues for
patients administering the drug in the evening. Clinical trials that measured 24-hour
IOP suggested that evening administration is generally preferable because it gave
a better circadian IOP profile68-70 [II, B]. These studies also reported that eyes
treated with PG derivatives have reduced short-term IOP variability as compared to
eyes treated with other classes of drugs71.
Maximum IOP lowering is often achieved 3-5 weeks from commencement of treatment. Differences
among drugs within this class in the capability of reducing IOP did not exceed 1 mmHg72.
When combined with most of the other antiglaucoma drug classes, prostaglandin agents
provide additive IOP lowering.
Non-responders to prostaglandin analogues (e.g. eyes with IOP reductions of less than
10% or 15% from baseline) are fewer than 10%73,74. Some reports indicate that poor
responders to one prostaglandin agent might respond to another agent within the same
class75,76. Conjunctival hyperemia, generally mild, is a common finding with slight
difference in frequency and level among agents within this drug class. It usually
decreases over time. Other PG side effects are reported in Table 3.3.
Details on the mode of action, IOP lowering effect, contraindications and side effects
of other first line drugs (□-blockers, carbonic anhydrase inhibitors, alpha-2 selective
adrenergic agonists) and second line drugs are listed in Tables 3.5-3.10.
3.3.5 Local Toxicity of Topical IOP - Lowering Treatment. The Role of Preservatives
Long-term topical glaucoma medications may cause and/or exacerbate pre-existing ocular
surface disease (OSD), such as dry eye, meibomian gland dysfunction and chronic allergy77,
which, in glaucoma patients, has a much higher prevalence than in the general population63,64,78.
OSD may follow chronic use of antiglaucoma medication and/or the preservative benzalkalonium
chloride (BAC). BAC, a quaternary ammonium compound is the most frequently used preservative
agent in eye drops and its usage correlates well with the signs and symptoms of OSD63,64,79-82.
Such signs and symptoms can diminish if BAC-preserved drops are substituted with non-preserved
drops63. An unwanted effect of BAC is a reduction in the success rate of filtering
surgery83-85. In vitro studies suggest that alternative preservatives are significantly
less toxic than BAC86-91.
Other therapeutic possibilities are the use of preservative-free or BAC-free medication,
decreasing the number of preserved eyedrops i.e. by using fixed combinations; treating
the ocular surface with unpreserved tear substitutes and performing earlier laser
or surgery. When considering OSD four factors have to be considered: the active compound,
the specific preservative, the ability of the patient to use single-dose preparations
and the patient’s ocular surface.
The European Medicines Agency (EMEA) has suggested that the use of preservatives should
be avoided in “patients who do not tolerate eye drops with preservatives” and in those
on long-term treatment, or to use “concentration at the minimum level consistent with
satisfactory antimicrobial function in each individual preparation”, with a specific
indication to avoid mercury containing preparations92.
Not all patients are sensitive to preservatives and not all the local side effects
observed with topical antiglaucoma medications are induced by preservatives.
Particular attention should be paid to glaucoma patients with pre-existing OSD or
to those developing dry eye or ocular irritation over time. This can be done by careful
assessment of redness of the eyelid margin, positive corneal and conjunctival fluorescein
staining or reduced tear break-up time [I,D].
3.3.6 Generic IOP - Lowering Topical Medications
By definition a generic drug is identical to a brand name drug in dosage, strength,
route of administration, performance characteristics and intended use. For the purposes
of drug approval, the interchangeability of a generic drug and the corresponding brand-name
drug is based on the criterion of “essential similarity”. In ophthalmology this concept
is problematic, because it is difficult to prove “essential similarity” in clinical
studies. With systemic drugs bioequivalence studies are performed using blood samples
to determine whether the plasma concentration within certain limits equals the branded
drug. With topical eye drops such studies obviously cannot be performed.
No clinical studies are usually required for generic approval in ophthalmology, and
a 10% difference between the concentration of the active principle between the generic
and the branded products is considered acceptable. Whereas the active principle is
assumed to be equal, the adjuvants can vary considerably. This is a critical issue
because different adjuvants may alter the viscosity, osmolarity and pH of the eye
drops and therefore have an impact on both tolerability and corneal penetration.
Nevertheless anti-glaucoma generics drugs are currently prescribed at a large scale,
as many drugs are becoming off patent. For latanoprost, the generic share is more
than 65% in most European countries. To which degree these generics are similar in
efficacy and tolerability is not well studied. Only few clinical studies have compared
the effect of generic and brand IOP lowering medications in glaucoma, with variable
results depending on the type of generic drug93,94. Other studies have shown a difference
between the branded and the generic preparations concerning the size and amount of
drops in the bottle, the structure of the bottle and the bottle tips95-98. Safety
issues with corneal epithelial disorders have also been described with generics, due
to an additional stabiliser compound99. When switching patients from branded to generic
drugs, the IOP should be closely monitored [I,D].
3.3.7 Dietary Supplementation and Glaucoma
Although there is no clinical evidence for clinical benefits arising from the use
of dietary supplements in glaucoma, a recent survey has found that 1 in 9 glaucoma
patients were using complementary and alternative medicine (CAM). Most were using
herbal medicines (34.5%), dietary modifications (22.7%) or dietary supplements (18.8%)100.
Based on the fact that some glaucoma patients continue to progress at low IOPs, there
is much room for hypotheses, preclinical experiments, clinical trials and speculation.
Some data from experimental studies suggest that dietary supplementation may reduce
oxidative stress101, or that the omega 3 polyunsaturated fatty acids (PUFAs) decrease
IOP in rats102. At the present time there is no robust interventional dietary supplementation
study demonstrating the positive effect of such a treatment in glaucoma patients.
Observational studies have suggested a reduced risk for glaucoma with higher fruit
and vegetable intake103 or higher omega 3 PUFAs consumption in selected populations104.
Conversely there is evidence that some of these compounds may cause harm, such as
an increased intake of magnesium associated with a higher incidence of glaucoma105.
At the present time there is no robust interventional dietary supplementation study
demonstrating the positive effect of such a treatment in glaucoma patients
3.3.8 Management of Glaucoma During Pregnancy and Breast-feeding
Pregnancy-related changes in ocular physiology can influence IOP as well as the reliability
of its measurements. Changes in hormonal levels, are thought to induce an IOP-lowering
effect that increases throughout pregnancy (but particularly during the 24th-30th
week) and can last for months after delivery106-108.
The most sensitive period is the first trimester due to concerns relating teratogenicity,
as the majority of IOP-lowering medications are within class C (See Table 3.10) meaning
that adverse effects have been seen in animals or that there are no human or animal
data (See Table 3.11). Therefore, for a woman with glaucoma who is of child bearing
age, who might wish to conceive, the treatment strategy during pregnancy should be
discussed [I,D]. The patient should be instructed to inform the ophthalmologist when
pregnancy occurs. The potential risks to the fetus (and neonate) of continuing anti-glaucoma
medications must be balanced against the risk of vision loss in the mother [I,D].
As IOP levels generally decrease during pregnancy, temporary treatment discontinuation
can be considered under strict follow-up in some patients. However, if continuation
of treatment is mandated, the lowest effective dosage of medication should be used.
Moreover, systemic absorption should be reduced by punctal occlusion, eyelid closure,
and blotting excess drops away during administration109 [I,D].
Drugs are classified in Classes A to X for use during pregnancy based on a hierarchy
of estimated fetal risk (See Tables 3.10-3.11)110. Although very similar, some countries
(e.g., Sweden, Australia, the Netherlands, Switzerland, and Denmark) have their own
Drug classification for use of drugs during pregnancy
Controlled studies show no risk. Adequate well-controlled studies in pregnant women
have failed to demonstrate risk to the foetus
No evidence of risk in humans. Either animal findings show risk, but human findings
do not or, if no adequate human studies have been done, animal findings are negative
Risk cannot be ruled out. Human studies are lacking, and animal studies are either
positive for foetal risk or lacking as well. However, potential benefits may justify
the potential risk
Positive evidence of risk. Investigational or post-marketing data show risk to the
foetus. Nevertheless, potential benefits may outweigh the potential risk
Contraindicated in pregnancy. Studies in animals or human, or investigational or
(FDA Classification of Drugs for Teratogenic Risk. Teratology society public affairs
committee. Teratology 1994: 49:446-447).
Brimonidine is a Class B medication: however, there are reports of central nervous
system side effects in young children111. The ability of this drug to cross the placenta
and the lack of well controlled human studies during pregnancy do not allow ruling
out possible adverse effects on the fetus. Betaxolol is also in class B and is characterized
by a larger volume of distribution in the fetal circulation, high binding to proteins
and therefore fewer central nervous systemic effects on the fetus. Timolol although
class C, is available in low dosage (0.1%), in slow-release preparations which can
be used once daily. Although these formulations are thought to reduce systemic absorption,
strong evidence to support this is still lacking. Once-a-day timolol 0.1% gel may
be a valid option if a beta-blocker is considered [I,D]. Prostaglandin-analogues should
be considered with caution because of the theoretical risk of increased uterine contractility
in pregnancy. If premature contractions appear PG should be discontinued immediately
There have been no reports on any fetal complications related to the use of topical
carbonic anhydrase inhibitors in humans, but animal studies have shown that high systemic
doses, are associated with low weight offspring (Manufacturer’s Information: Azopt
product monograph. Fort Worth, Texas, Alcon Ophthalmics, 1998 Manufacturer’s Information:
Trusopt product monograph. West Point, Pennsylvania, Merck Inc., 1999). At clinically
used concentrations, BAC has no known impact on the fetus112.
Table 3.11 summarizes known adverse effects of anti-glaucoma drugs during pregnancy
Although results from animal studies are worrisome, the overall level of evidence
for the risk of giving anti-glaucoma drugs to pregnant women is low.
Laser trabeculoplasty is considered to be a safe alternative113 except in patients
with angle dysgenesis. However, IOP lowering success is lower in younger patients,
such as in women of childbearing age114.
Laser cyclodestruction, in spite of having been suggested as a valid option should
be considered with caution because of risk of sight-threatening complications115.
If surgery is planned, there are a number of considerations to be made. A supine position
should be avoided116. For intervention under local anesthesia, topical, subconjuntival
or retrobulbar, lidocaine is considered to be a safe option117. The use of anti-metabolites
is strictly contraindicated, due to the mutagenic related risk. Depending on previous
ocular surgeries and the age of patient, filtering surgery, including tube shunt implantation,
can be considered112 [II,D].
Topical prednisolone and erythromycin have been shown to cross the placenta to a lesser
extent than other medications of their classes, and can therefore be chosen as postoperative
Special attention should be paid also during breast-feeding. Carbonic anhydrase inhibitors
and beta-blockers may be used in nursing mothers as suggested by the American Academy
of Pediatricians119. These are also the first line choices in infants with congenital
glaucoma when medical therapy is being considered.
Fixed combinations are all class C. Prescribing physicians should separately consider
each of the drugs involved [I,D].
Adverse effects of IOP-lowering medications during pregnancy/breast-feeding
Teratogenicity Dysregulation of placental perfusion
Meningism in newborn
Seizures, fever, diaphoresis
Sympathetic agents • brimonidine
No significant effect
Delay in labor/ uterine hypotony
No reported side-effects
CNS depression, hypotension andapnea
High incidence of miscarriage
One case of miscarriage
No reported side-effects
Delayed fetal ossification, fetal resorption
Teratogenicity (1st trimester) Cardiac rhythm changes Respiratory
Arrhythmia and bradycardia Impaired respiratory control in newborns
Controversy overconcentrations inbreast milk. Apnea and bradycardia
Carbonic anhydrase inhibitors • Topical
Decreased weight gain
Vertebral body malformation
Lower fetal weight
No reported side-effects
No reported side-effects • Oral
Onecase of teratoma
No reported side-effects
3.3.8 Neuroprotection and Glaucoma Treatment
Neuroprotection can be defined as a “therapeutic approach” aiming to directly prevent
or significantly hinder neuronal cell damage. Since glaucoma patients can continue
deteriorating in spite of an apparently well controlled IOP, the need for effective
non-IOP related treatments is widely acknowledged. Several compounds have been neuroprotectant
in preclinical studies120. Only two have reached large scale clinical trials: a large
long-term RCT using an NMDA antagonist, memantine, was analysed in 2008 with negative
results. More recently, the results from a multi-center RCT of adults with low-pressure
glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) has been claimed to show that
brimonidine may have neuroprotective properties in comparison to Timolol44. No direct
comparison has been done with other substances such as PG. However, the authors of
the study and a systematic literature review have (both?) suggested that more substantial
evidence is needed121,122.
3.3.9 Practical Considerations Related to Topical Medical Treatment
The majority of topically applied drugs, particularly if lipophilic, penetrate the
eye via the cornea, in a lesser amount via the conjunctiva and thereafter the sclera.
On average, the total tear film volume is around 7 µl and the rate of tear film turnover
is approximately 15% (±1 µl) per minute but can double (washout effect) after the
application of a topical drop with a volume estimated at 30-50 µl123. Although the
cul- de-sac and tear film compartment can expand transiently after instillation of
a drop it still cannot accommodate this whole volume and less than 5% manages to enter
the eye; the rest will run down the cheek or will be drained through the nasolacrimal
duct where an individually variable systemic absorption takes place through the highly
vascularised nasal mucosa124.
Once the medication is instilled into the conjunctival sac, the spontaneous tear flow
will cause complete washout within 5 minutes.
The washout effect depends not only on the increased tear fluid turnover, but also
on the addition of a second drop within a short period. Therefore when poly-drug regimen
is used, a minimum time span between different drops should be respected. When two
drugs are instilled only 30 seconds apart, almost 50% of the first drug will be washed
out. The recommended delay between drops is 5 minutes with a washout effect of less
than 15%61,62 [I,B].
Blinking also may influence washout and allow only 15% of a topically applied drug
to remain in the eye approximately five minutes after instillation.
As drugs absorbed through the highly vascularised nasal mucosa avoid hepatic first-
pass metabolism this might lead to systemic side effects. The instillation of one
drop of timolol 0.5% for example may lead to a serum concentration of timolol that
equals the intake of an oral 10 mg non-selective beta-blocker125.
There is no evidence that nasolacrimal duct obstruction may increase the efficacy
of a topical drug126 however it may reduce systemic side effects particularly from
beta-blockers by minimizing the drainage into the highly vascularised nasopharyngeal
Patients should be advised to shake the bottle before use as micro-suspensions tend
to settle to the bottom of the bottle leaving the vehicle at the surface. Thus, patients
may be simply applying mainly vehicle to the eye, rather than the active drug ingredient
GENERAL RECOMMANDATIONS [L,D]:
Monotherapy is the first choice when initiating therapy
Baseline IOP should be considered when evaluating the efficacy of a therapy Fixed
Combination therapy should be considered when patients fail to achieve their individualized
intraocular pressure (IOP) targets with monotherapy
The prescription of more than two bottles of IOP lowering eye drops for simultaneous
use should be avoided as it can lead to noncompliance
Fixed combination preparations may be preferable to the use of separate instillation
of two agents
However Fixed Combination are not first-line medications and they are only indicated
in patients who need adjunctive therapy, when IOP is not sufficiently controlled by
one single agent
Ocular surface should be evaluated and considered in clinical management of glaucoma
patients. In case of ocular surface disease, preservative-free formulations should
Generic drops can differ from brand drops and it may be necessary to monitor patients
more closely after switching
During pregnancy, the potential risks of continuing anti-glaucoma medications to the
fetus (and neonate) must be balanced against the risk of vision loss in the mother
See FC IX to
3.4 - Adherence, Compliance and Persistence in Glaucoma
Glaucoma is a chronic progressive disease that requires continuous long-term cooperation
of the patient with the glaucoma management proposed by the doctor.
The commonly used term “compliance” has been increasingly replaced in recent times
by the term “adherence”. Both are defined as the ‘cooperation of the patient with
the recommendations given by the doctor’. However, the former is more passive ("I
am taking the medication”), while the latter implies the active part of the patient
in the process (“I am taking the medication exactly as you told me”).
“Persistence” is defined as the length of time during which the patient is taking
the medication as prescribed129.
Finally three terms should be mentioned:
“White coat compliance” means that the patient’s adherence rises a week before the
consultation and drops quickly afterwards130
“Dyscompliance” is used when physical problems of a patient, like arthritis, lead
to difficulties in correctly applying a therapy
“Alliance” is a special form of adherence meaning that the people around the patient
ensure the correct application of the medication131
3.4.2 Measured Adherence
Despite easier medication schemes (for example drugs which require application once-
daily) and more information for the patients about the disease, the rate of non-adherence
has remained almost the same over the last 25 years; between 30%-70%.
It is important to mention that the patients themselves overestimate their adherence
and persistence rate (GAPS)132.
3.4.3 Factors Associated with Non-Adherence
Four groups of factors encountered as common obstacles to glaucoma medication adherence
have been described133:
Situational / environmental (for example a major event in the patients life, unsteady
life-style with many travels)
Medication (for example costs of the drugs, side effects, complicated dosing regimen)
Patients (for example comorbidity, poor understanding of the disease)
Provider (for example lacking communication with the doctor)
Other influencing factors:
Gender (men are more likely to be non adherent)
Stage of the disease (patients with a less advanced disease tend to be less adherent)
3.4.4 Types of Non-Adherence
Every patient is different and there are several types of non-adherence134.
Failure to take the medication as prescribed (including under- and overdosing, inadequate
doses and wrong timing of dosages)
Failure to use the correct medication (including the application of the wrong medication
or the self administration of not prescribed drugs)
Failure to apply the medication correctly (including incorrect self administration
of the medication)
Failure to continue applying the medication (including problems with side-effects,
issue of costs and missed refills)
3.4.5 Improving Adherence
There are different ways for improving the adherence of patients. The most important
measures are informing the patient about his/her disease and finding a therapeutic
regimen which fits into the patient’s life-style135 [I,D].
Other factors which should improve adherence [I,D]:
The therapy should be simple i.e. not more than two bottles and an application not
more than twice a day
The patient should be instructed how to apply the drops correctly. If necessary, hints
reminders should be given like a daily routine which the patient can connect to the
application of the drops. If a patient has physical problems applying the drops as
arthritis of the fingers, the therapy should be adjusted accordingly or switched to
The doctor should inquire at every visit if the patient has side effects of the medication
and switch if necessary. A patient who complains about side effects is usually not
adherent to therapy.
The patient’s cooperation, described as adherence and persistence, with the prescribed
glaucoma management is mandatory to obtain effective IOP lowering and to prevent glaucoma
progression. No drug can work unless it is taken.
3.5 - Laser Surgery
3.5.1 Laser Iridotomy>136-139
Clinically relevant or suspected pupillary block.
Potential prevention of acute and chronic angle closure (See FC X and XI).
To reduce iris thickness and facilitate perforation instil 1 drop of Pilocarpine 2%-4%
[I,D]. If the cornea is edematous, like acute angle closure, use topical glycerin
10% if available, systemic acetazolamide, intravenous mannitol or oral hyperosmotic
agents (See FC XI). For prevention of IOP spikes use topical alpha 2 agonist 1 hour
prior to the procedure and immediately afterwards [I,B].
After instillation of topical anesthetic a contact lens with contact lens fluid is
placed onto the cornea. The lens keeps the eyelids open, stabilizes the eye, provides
additional magnification, focuses the laser beam and acts as a heat sink.
Lenses used are: Abraham (+66 diopters), Wise (+103 diopters) or CGI©LASAG CH lens.
Iridotomy site [II,D] is usually chosen in the superior quadrants of the iris well
covered by the upper eyelid (to reduce visual symptoms), in a thin looking area or
an iris crypt. Whole thickness perforation of the iris is assumed when pigment, mixed
with aqueous, flows from the posterior into the anterior chamber. Once a full thickness
hole has been made, it should be enlarged horizontally to achieve an adequate size.
Iridotomy size [II,D] should be sufficient for patency inspite of iris oedema, pigment
epithelial proliferation and pupil dilation. Transillumination through the iridotomy
is not a reliable indicator of success [II,D].
Lasers parameters for Nd:YAG laser iridotomy
50-70 μm (constant for each laser model)
Pulses per burst
Set defocus to zero Focus the beam within the iris stroma rather than on the surface
of the iris* Avoid any apparent iris vessels Use the least amount of energy that is
effective139 Lens capsule damage is possible above 2 mJ energy With most Lasers less
than 5 mJ per pulse is required
Lasers parameters for Nd:YAG laser iridotomy
In case of thick dark irides, to reduce total Nd:YAG energy, pretreatment with argon
laser in 2 stages may be considered141 [II,B]. In the first stage a low power argon
of 90-250 mW, duration 0.05 sec, spot size 50mm is applied, followed by the high power
argon of 700 mW, duration 0.1 sec, spot size 50 mm to create a punched-out crater
appearance. Laser iridotomy is completed with Nd:YAG laser.
Laser parameters for continuous-wave Argon laser iridotomy
When no Nd:YAG laser is available, Argon laser may be used [II,D].
Laser parameters should be individualized to each patient and adjusted appropriately
during the procedure.
The following parameters are suggested [II,D]:
Medium brown irides
Preparatory stretch burns
Penetration burns [II,D]
700-1500 mW (average 1000 mW)
Pale blue or hazel irides
1st step: to obtain a gas bubble
Up to 1500 mW
2nd step: penetration through the gas bubble
Thick, dark brown irides (chipping technique)
Bleeding from the iridotomy site; this can usually be stopped by gentle pressure applied
to the eye with the contact lens. With the argon laser corneal epithelial and/ or
endothelial burns may develop.
Visual disturbances occur in 6-12% (glare, blurring, ghost images, halo, crescent)
are less likely to occur when the iridotomy is completely covered by the eyelid142,143.
Transient elevation of the IOP is the most common complication in the early period.
Elevation of IOP at 1 hour after iridotomy occurs in approximately 10% of primary
angle closure suspect eyes144. Acute and (chronic) rise in IOP is more likely to occur
in eyes with peripheral anterior synechiae in whom the small amount of trabecular
meshwork not closed is likely to have compromised outflow function (and is secondarily
closed by the iris pigment and tissue generated by the iridotomy).
Postoperative inflammation is transient and mild, rarely resulting in posterior synechiae.
Closure of the iridotomy may occur during the first few weeks after the procedure,
due to accumulation of debris and pigment granules.
Rare complications include sterile hypopyon, cystoid macular oedema, retinal haemorrhages
and malignant glaucoma145,146.
Check the IOP after 1-3 hours [II,D].
Topical corticosteroids for 4-7 days instilled 3-4 times a day.
Check the angle regularly with gonioscopy, and the patency of peripheral iridotomy.
If the patency is uncertain check with gonioscopy, reconsider the mechanism, perform
ultrasound biomicroscopy (UBM) / anterior segment-optical coherence tomography (AS-OCT)
if available and/or repeat the iridotomy.
Retroillumination alone for judging the patency is insufficient.
3.5.2 Laser Trabeculoplasty (LT)147-154
Lowering of IOP in primary open-angle, exfoliative and pigmentary glaucoma, high risk
ocular hypertension (OH):
When IOP is not satisfactorily controlled with medications (i.e. efficacy, tolerability
As initial treatment (See FC VII)
Preoperative preparation: [I,B]
For prevention of IOP spikes instillation of topical alpha 2 agonist (apraclonidine
1% or brimonidine) 1 hour prior to the procedure and immediately afterwards is optional.
Use topical anesthesia.
Most frequently used lasers are:
Argon continuous-wave laser (green or blue/green) - argon laser trabeculoplasty (ALT)
Q-switched, short pulsed, frequency–doubled Nd:YAG (532 nm) laser - selective laser
Lenses: Goldmann type gonioscopy lens, Ritch trabeculoplasty lens©, CGA©, Meridian,
Latina (SLT), Magnaview.
Identify angle landmarks after inspection of all quadrants and place the laser burns
between the anterior pigmented trabecular meshwork (TM) and the non-pigmented trabecular
meshwork over 180° or 360°.
Laser parameters for laser trabeculoplasty
Laser parameters [I, D]
3 nsec (fixed)
500-1200 mW according to the reaction on the TM; with heavily pigmented TM low power
0.4 to 1.2 mJ according to the desired reaction; in heavily pigmented TM start with
low levels e.g. 0.4 mJ
Transient bleaching or small gas bubble formation
The power is titrated until the appearance of tiny air bubbles, »champagne bubbles«,
at the site of the laser burn, then the power is reduced by increments of 0.1 mJ until
there are no visible bubbles*
Number of spots
50-100 evenly spaced
spots over 180-360° 50-100 non-overlapping spots spaced over 180 -360°
some continue with the power that causes champagne bubble formation
Transient elevation of IOP155,156
Peripheral anterior synechiae (after ALT)
Corneal endothelial damage in corneas with pigment on endothelium (after SLT)157.
Post-operative management: [II,D]
Check IOP in selected patients (e.g. with advanced glaucomatous damage, one- eyed
patients, high pre-laser IOP, exfoliation syndrome, heavily pigmented trabecular meshwork).
Use of topical corticosteroids or non-steroidal anti-inflammatory medication 3-4 times
daily for 4-7 days.
Effectiveness of laser trabeculoplasty:
ALT and SLT have the same efficacy153,158.
Laser trabeculoplasty is initially effective in 80 to 85% of treated eyes with a mean
IOP reduction of 20 to 25% (of 6 to 9 mmHg). The effect wears off over time, for both
ALT and SLT159.
LT versus medication: In the Glaucoma Laser Trial, after 7 years of follow-up, patients
with ALT had lower IOP (1.2 mmHg) than patients on medical treatment, and no difference
in progression of glaucoma160. SLT has shown to decrease IOP to a degree similar to
that of prostaglandin analogues after 9 to 12 months follow-up161 and appears to be
Predictors of efficacy:
Higher baseline IOP is associated with greater IOP reduction after SLT and ALT162,163.
The effectiveness of ALT is influenced by the treating surgeon, and success is better
when surgeons have more experience in ALT163,164.
Pigmentation of the trabecular meshwork (TM) is important. ALT is less successful
in eyes with no pigmentation of TM. SLT seems to be independent of the pigmentation
of TM. Younger subjects (less than 40 years old) usually respond less to ALT165.
3.5.3 Laser Iridoplasty166,167
Main Indication: [II,D]
Plateau iris syndrome confirmed by a patent iridotomy; the purpose is to enlarge the
peripheral angle approach after iridotomy, to decrease the chance of progressive synechial
Different types of continuous wave lasers can be used for photocoagulation, most frequently:
argon laser, diode laser (810 nm), and the frequency-doubled Nd:YAG laser (532 nm).
Preoperative preparation: [II,D]
Instillation of Pilocarpine followed by the same preoperative preparation as for laser
Lens: Abraham (+66 diopters), Wise (+103 diopters), CGI©LASAG CH lens or the central
non-mirrored part of the Goldmann lens.
Contraindications: [I,D] Flat anterior chamber
Extensive peripheral anterior synechiae.
Laser parameters for laser Iridoplasty [II,D]
Laser parameters [II,D]
Contraction burns (long duration-low power-large spot size)
Aiming beam should be directed at the most peripheral part of the iris
Visible contraction of the peripheral iris with flattening of the iris curvature (without
bubble formation or pigment release)
Number of spots
20-24 spots over 360° leaving 2 beam diameters between each spot and avoiding visible
Complications: Mild iritis
Corneal endothelial burns Transient elevation of IOP
Post-operative synechiae of the pupil Permanent pupil dilation
Topical corticosteroids or non-steroidal anti-inflammatory medication instilled for
Prevention of IOP spikes
When filtration surgery or tubes are likely to fail, have failed, or are not feasible
As an alternative to drainage devices
Diode laser (810 nm); Argon laser
Modes of laser delivery are: trans-scleral, endoscopic and transpupillary
Laser diode cyclophotocoagulation with the G probe is the cyclodestructive procedure
of choice because of the reduced incidence of complications compared with other cyclodestructive
Ultrasonic circular cyclocoagulation using high-intensity focused ultrasound delivered
by a circular miniaturized device was reported as a safe and effective technique to
reduce intraocular pressure in patients with refractory glaucoma171,172.
Retrobulbar or peribulbar injection of a 50:50 mixture of 2% lidocaine and 0.75% bupivicaine
G probe positioning
The G probe footplate is placed on the conjunctiva with the short side adjacent to
the limbus, which positions the fiberoptic tip 1.2 mm behind the limbus. The ciliary
body should be identified with transillumination as its position may vary and the
placement of the G probe is adjusted accordingly173
The fibre optic light source is directed approx. 4 mm posterior to corneoscleral limbus
to identify ciliary body by transillumination. The dark demarcation line indicates
the anterior margin of the ciliary body
Recommended setting: duration of 2 sec., from 1500 mW for dark to 2000 mW for light-coloured
irides and increase the energy until an audible »pop« is heard indicating tissue disruption.
If a »pop« sound occurs during two sequential subsequent laser applications, the power
is reduced by 150 mW and treatment completed at this power174
10-20 over 180°, energy 5-6 J per pulse, total treatment per session up to 270° of
circumference avoiding 3 and 9 o'clock positions (to avoid long posterior ciliary
nerves). Some surgeons prefer to use low energy and more applications. Retreatments
are often needed, but the incidence of severe complications is low [II,D].
Endoscopic techniques combined with laser technology allow the photocoagulation of
ciliary processes not visible via the transpupillary route. The approach can be limbal
or through pars plana. Recently, endoscopic cyclophotocoagulation is most commonly
performed in conjunction with cataract surgery in cases with early glaucoma175.
This procedure is limited to eyes in which a sufficient number of ciliary processes
can be visualized gonioscopically, as in cases of aniridia, through a large surgical
iridectomy or when broad anterior synechiae cause anterior displacement of the iris.
New technology using ultra-sound cyclodestruction is currently under investigation.
Rates of complications are higher in neovascular glaucoma and with treatment protocols
using more than 80 J per session.
Hypotony and phthisis
Post-operative management: [II,D]
Consider analgesia. Topical corticosteroids and atropine instillation for 2-3 weeks.
In the immediate postoperative period IOP should be monitored and the anti-glaucoma
medication tapered accordingly.
The effectiveness of treatment is assessed after 4 weeks.
3.6 - Incisional Surgery
3.6.1 General Principles
The different techniques of incisional surgery have different indications depending
on the type of glaucoma. Their adoption depends on: [I,D]
the target IOP chosen for the individual situation
the previous history (surgery, medications, degree of visual field loss)
the risk profile (i.e. single eye, occupation, refractive status)
the preferences and experience of the surgeon
the patient opinion, expectation and postoperative compliance
The decision to recommend glaucoma surgery should be made in the light of published
clinical trials54,177. In the individual patient, a multitude of factors must be taken
into account when deciding treatment including compliance, stage of glaucoma etc.
Nevertheless, surgery should be considered whenever medical or laser treatment would
appear unlikely to maintain sight in the glaucomatous eye [I,D]. It should not be
left as a last resort (See Ch. 3.1). Angle-closure glaucoma is usually initially approached
by laser iridotomy or peripheral iridectomy. Primary congenital glaucoma is usually
treated with surgery, likely trabeculotomy or goniotomy, or combinations of filtration
surgery with antifibrotic agents.
For repeated surgery, cyclodestructive procedures and tube implants are more commonly
used (See FC VI).
Since glaucoma surgery is successfully practiced in different ways by different ophthalmologists,
a detailed description of surgical techniques is not within the scope of this text.
The primary goal of surgery is to achieve a Target IOP without additional medication.
Additional medications can be used if a Target IOP is not reached by surgery alone.
Success rates of a surgical method in terms of IOP lowering can be best evaluated
in the absence of adjunctive medical treatment. The number of preoperative versus
postoperative medications may also depend on the variable compliance of the individual
patient before and after surgery. Also, it is useful to count the percentage of “successes”
below a defined IOP level as in Fig. 3.3. It is also important to consider not just
the IOP but complications rates and, most importantly, functional outcomes.
22.214.171.124 Penetrating Glaucoma Surgery
The most widely used surgical procedure in OAG is the trabeculectomy, which produces
a ‘guarded’ fistula between the anterior chamber and the subconjunctival space178,179.
The introduction of improved operating microscopes, instruments and suture materials,
has led to numerous modifications and refinements of the original operation180. Modifications
include the size, shape and thickness of the scleral flap, limbal or fornix based
conjunctival flaps, fixed, releasable or adjustable sutures and the use of antimetabolites
and other antiscarring agents delivered in different ways to reduce wound healing181,182.
In the hands of experts the long-term success rate of filtering surgery alone, or
with adjunctive medical therapy in a previously unoperated eye has been reported at
up to 90%178; there are large differences however in the criteria used for the definition
of success and in the final success rates observed 183-192.
The use of stainless steel implants as facilitators for performing filtration surgery
should be weighted against the cost of the devices193-196.
Long-term IOP control is achieved in many cases, although some patients do require
further therapy or repeat surgery178,197,198.
The alternatives to trabeculectomy in OAG include non-penetrating surgeries and drainage
In cases where other forms of therapy, like medicines or laser, have failed.
In cases where other forms of therapy are not suitable (e.g. where compliance or side-effects
are a problem) or appropriate medical treatment is not available.
In cases where a Target Pressure is required to prevent clinically significant disease
progression that cannot be reached with topical medications and/or laser.
In cases which have such advanced glaucoma and high IOP at presentation that other
forms of treatment are unlikely to be successful.
Some studies have indicated that in terms of field survival, primary trabeculectomy
was superior to medical treatment, but these studies may not be relevant to current
medical practice as the evaluation of visual field was not done using todays analyses,
and the medical treatment options were very limited206. More recent studies suggest
that visual field progression is not significantly different whether initial treatment
is medication or trabeculectomy207,208.
The ophthalmologist must assess the risks and benefits of early surgery in each individual
Long-term risks of trabeculectomy:
Accelerated progression of senile cataracts is frequently seen after filtration surgery209,210.
Patients undergoing trabeculectomy should be advised on the symptoms of a developing
blebitis/endophthalmitis including red eye, tearing, discharge or decreased vision,
and should be warned to immediately seek the help of an ophthalmologist if any of
symptoms develop in the operated eye211 [I,D]. Endophthalmitis is more common if the
bleb is thin and cystic - a situation more commonly found with the use of a small
treatment area of antimetabolites or full thickness filtration procedures. A long-tube
drainage device should be used if the bleb cannot be sited beneath the upper lid [I,D].
Trabeculotomy, alone or combined with trabeculectomy, is generally used for congenital
and paediatric glaucoma and is less effective in adults212-214 [I,B]. It also may
decrease the need for further filtering and shunting procedures215.
A novel glaucoma procedure of trabeculotomy by internal approach was recently introduced183,216,217.
126.96.36.199 Non-Penetrating Glaucoma Surgery
188.8.131.52.1 Deep Sclerectomy
In this technique, a deep lamella of corneosclera underneath the scleral flap is excised
thus removing the outer wall of Schlemm’s canal. The outer layer of the inner wall
of Schlemm’s canal is frequently also removed. Percolation of aqueous occurs through
the porosity of the remaining trabecular meshwork, possibly through micro-perforations.
When the scleral flap is repositioned, a “scleral lake” is created. A collagen implant
or a hyaluronic acid device is often used to keep this scleral lake open. In a number
of cases, a filtration bleb forms; long-term IOP levels appear higher than with trabeculectomy218-228.
In this technique, hyaluronic acid is injected into Schlemm’s canal in addition to
the dissection and excision of a deep lamella. The mechanism claimed to increase the
outflow is the widening of Schlemm’s canal and of the collector channels as well as
diffusion of aqueous from the “scleral lake”186,229,230.
The majority of randomised controlled trials suggests that the pressure lowering of
non-penetrating glaucoma surgery is not as marked as with trabeculectomy231-234.
Canaloplasty is a non-penetrating, bleb-independent, glaucoma surgery that combines
a 2-flap dissection to the trabeculo-Descemet’s membrane, like in viscocanalostomy
methods, with a circumferential catheterization and viscodilation of Schlemm’s canal.
In addition, a 10-0 polypropylene suture is placed within the canal to tension the
inner wall and the associated trabecular meshwork with the intention of preventing
the Schlemm’s canal collapse thus in theory restoring natural trabeculocanalicular
This technique is indicated in POAG, pigmentary glaucoma and pseudoexfoliative glaucoma
and permits combined procedures with cataract surgery [II,D].
Contraindications to canaloplasty are primary or secondary ACG, neovascular glaucoma
or cases needing a low target IOP.
Intraoperative or postoperative complications (hyphema, hypotony secondary to a break
in the trabeculo-descemetic window, hypertension, cataract, endophthalmitis) have
a lower incidence than trabeculectomy239-242.
Arguments in favour of non-penetrating glaucoma surgery:
minimal postoperative care (no bleb management)
reduced incidence of hypotony-related complications and cataract
reduced incidence of intraoperative complications (iris prolapse, expulsive haemorrhage)
Arguments against non-penetrating glaucoma surgery:
less efficient in IOP reduction (mean IOP 2-4 mmHg higher) than after trabeculectomy
difficult technique (learning curve)
Nd:YAG laser goniopuncture often needed for IOP control
Arguments in favour of trabeculectomy:
lower long-term postoperative IOP
fewer lOP-lowering medications needed postoperatively
Arguments against trabeculectomy:
possible higher rate of cataract formation
postoperative bleb complications
higher risk of postoperative hypotony and related complications (choroidal detachment)
3.6.3 Methods of Preventing Filtering Bleb Scarring
Wound healing is one of the main determinants of the long-term intraocular pressure
control after filtering surgery243,244. Excessive wound healing or repair leads to
scar formation in the conjunctiva. Risk factors for conjunctival scarring are young
age, afro- caribbean/hispanic race, inflammatory eye disease (e.g. uveitis, ocular
pemphigoid, Stevens-Johnson syndrome), long-term multiple topical medical therapy,
aphakia by intracapsular surgery, recent intraocular surgery (<3 months), previous
conjunctival incisional surgery, previous failed glaucoma filtration surgery, neovascular
glaucoma188,245. Antimetabolites such as 5-fluorouracil (5-FU) and mitomycin-C (MMC)
are frequently used in patients undergoing glaucoma filtration surgery in order to
reduce postoperative conjunctival scarring and improve drainage [I,A].
The use of these substances continues to be refined. Indications and techniques need
to be carefully considered, particularly the use of larger antimetabolite treatment
areas to minimise thin cystic blebs246,247 [I,D].
The risk of corneal epithelial erosions, epitheliopathy, late hypotony, bleb leaks,
and blebitis/endophthalmitis must be considered [I,D]. The use of antimetabolites,
especially MMC, is potentially hazardous, and requires careful surgical technique
to prevent over drainage and hypotony, or a thin focal drainage bleb with a higher
risk of infection [I,D]. New antifibrotic agents and techniques are under investigation
to more specifically target and modulate the biological processes of wound healing
after filtration surgery, aiming for a lower risk of complications243,248-250.
184.108.40.206.1 General Precautions
The use of antimetabolites will enhance the unfavourable effect of any imprecision
during surgery. It is important to assess each individual case for risk factors, and/or
for the need of low target IOP and titrate the substance and dosage used accordingly
based on local experience.
If aqueous flow is not well controlled persistent hypotony will occur. Strategies
to increase control of flow include smaller sclerostomies, larger and/or thicker scleral
flaps, tighter suturing of the scleral flap, and releasable or adjustable sutures
Research studies suggest that a large surface area of cytotoxic treatment together
with large scleral flaps and accurately sutured fornix-based conjunctival flaps lead
to more diffuse, posteriorly extended non-cystic blebs giving a considerable reduction
in bleb- related complications such as blebitis and endophthalmitis197,247,251,252
It is advisable for a surgeon not familiar with these drugs to start with weaker agents
(e.g. 5-FU rather than MMC) or lower concentrations of MMC [II,D].
Antimetabolites should not enter the eye [I,D]. 5-FU has a pH of 9.0 and one drop
(0.05 ml) of MMC is enough to cause irreversible endothelial damage: precautions for
use and disposal of cytotoxic substances should be observed [I,D].
5-FU and MMC are not officially approved for ocular applications. Their use in many
cases as adjunctive in filtration surgery, however, has become standard clinical practice.
Intraoperative use [II,D]
Concentration: 25 or 50 mg/ml undiluted solution. Administration: intraoperatively
on a filter paper or a sponge.
Time of exposure: usually 5 minutes (shorter time has minimal effect). Rinse: with
at least 20 ml of balanced salt solution.
Postoperative use [II,D]
Relative contraindication if epithelial problems present. Concentration: 0.1 ml injection
of 50 mg/ml undiluted solution.
Administration: adjacent to but not into bleb (pH 9), with a small calibre needle
(e.g. 30 G needle on insulin syringe). Reflux from the injection site over the ocular
surface should be prevented253. Repeated injections are often necessary.
Intraoperative use [II,D]
Concentration: 0.1-0.5 mg/ml (care must be taken in diluting it to the desired concentration).
Administration: intraoperatively on a filter paper or a sponge. Avoid contact with
cut edge of conjunctive flap.
Time of exposure: 1-5 minutes.
Rinse: with at least 20 ml of balanced salt solution.
Postoperative use [II,D]
Concentration: 0.1 ml injection of 0.02 mg/ml solution.
Administration: adjacent to but not into bleb, with a small calibre needle (e.g. 30
G needle on insulin syringe). Reflux from the injection site over the ocular surface
should be prevented253. A very small amount of MMC entering the eye will irreversibly
damage the endothelium. It is useful for some needling procedures but recommended
only in experienced hands.
220.127.116.11 Alternative Methods of Preventing Filtering Bleb Scarring
Irradiation, PDT and inhibition of growth factors have been used, but no long-term
clinical studies to support their use are yet available243,249.
Alternative Glaucoma Surgery
New alternative surgical techniques with the aim obtaining a higher safety profile
than filtration surgery were proposed during the last several years. Under the acronym
of M.I.G.S. “Minimally Invasive Glaucoma Surgery” are now collectively grouped both
ab-interno and ab-externo procedures, not necessarily involving the use of an implantable
device, not always bleb-independent for efficacy. The general aim would be to entail
significantly less tissue manipulation than filtration surgery, with less side effects
and sizeable IOP-lowering efficacy. There are no well controlled comparative
trials available to support the superiority among any of these procedures nor versus
trabeculectomy, for both safety and efficacy254,255. These techniques are currently
performed in selected glaucoma patients with early to moderate disease and preferably
in combination with cataract surgery [II,D].
ALTERNATIVE GLAUCOMA SURGERY (*)
Based on subconjunctival filtration
trans-scleral filtration, ab-interno device (AqueSys Xen)
trans-scleral filtration, ab-externo device (InnFocus Microshunt)
Based on suprachoroidal drainage
suprachoroidal stents, ab-interno (Glaukos iStent Supra, Transcend CyPass)
Based on Schlemm’s canal drainage/bypass/expansion
trabecular bypass stents/canal expanders (Glaukos iStent, Ivantis Hydrus)
ab-Interno trabeculectomy (Trabectome)
ab-externo canaloplasty/trabeculotomy (iScience catheter)
(*) THIS LIST IS NOT ALL INCLUSIVE. The EGS does not endorse any product or procedures.
3.6.4 Complex Cases
Complicated glaucoma cases such as those that have failed previous surgery, secondary
glaucomas, congenital glaucomas, et cetera require specialist treatment. In addition
to trabeculectomy, other forms of therapy may be necessary such as drainage devices
and ciliary body ablation.
3.6.5 Long-Tube Drainage Devices
The use of long-tube drainage devices such as those described by Molteno256-263, Krupin264-266
, Baer veldt 267-272, Ahmed268, 273-280 or Schocket 281-284 are generally reserved
for patients with risk factors for a poor result with trabeculectomy with antimetabolite
[II,D], although recent trials established their efficacy and safety as a primary
surgical procedure258,285 [II,B].
Factors that decrease the chances of successful trabeculectomies and, therefore, make
tube surgery attractive, include previous failed filtering surgery with antimetabolites,
excessive conjunctival scarring due to previous ocular surgery with severe conjunctival
or surface disease, active neovascular disease, paediatric aphakia, or where filtration
surgery is going to be technically difficult286,287 [II,D].
3.7 - Cataract and Glaucoma Surgery
When glaucoma surgery is indicated and there is a visually significant cataract the
two procedures can be performed combined or sequentially. The decision is to be made
according to the clinical findings, after discussing with the patients advantages
and disadvantages of each approach [I,D].
In case of angle closure or narrow angle approach, it is important to evaluate the
lens as a component of the raised IOP [I,D] (See also Ch 2.4)
Small-incision phacoemulsification cataract extraction is one of the most relevant
surgical advances for our glaucoma patients. It allows faster and better visual recovery,
and with appropriate techniques it is safely applicable in cases with small pupil,
shallow AC or pre-existing filtering blebs. Futhermore it can be combined effectively
and safely with filtering procedures, including trabeculectomy, miniature drainage
implants and deep sclerectomy205,288-290.
Different new glaucoma surgical techniques which can be combined with phacoemulsification
(i.e endoscopic cyclophotocoagulation, trabecular bypass stents, ab interno trabeculectomy
and canaloplasty) have been proposed in the last years291. Randomized clinical trials
are presently needed to clarify this topic.
Despite the improved results of small incision phacoemulsification and of filtration
surgery with anti-metabolites there is no evidence to support a generalized switch
from sequential to combined surgery and viceversa [I,D].
Modern phacoemulsification with clear cornea incisions does not interfere with subsequent
glaucoma surgical procedures292
The development or worsening of a visually significant cataract is common after glaucoma
Cataract surgery performed after trabeculectomy can affect the IOP control209,293
Cataract surgery alone may be of limited benefit in lowering the IOP in open angle
glaucoma and the effect appears to be proportional to the preoperative IOP values;
such effect may be greater in angle closure glaucoma / narrow angles and appears to
be proportional to the degree of anterior chamber opening294-296
Combined procedures allow for greater IOP reduction and fewer IOP spikes in the immediate
postoperative period than phacoemulsification alone297-299
The success rate of combined phacoemulsification and filtration surgery is usually
not as favourable as filtration surgery alone and the use of antimetabolites is recommended
in all cases.