Medical Therapy of Pediatric Glaucoma and Glaucoma in Pregnancy

Ophthalmol Clin N Am 18 (2005) 461 – 468
Medical Therapy of Pediatric Glaucoma and Glaucoma
in Pregnancy
Peter J.G. Maris, Jr, MDa, Anil K. Mandal, MDb, Peter A. Netland, MD, PhDa,*
a
Hamilton Eye Institute, University of Tennessee Health Science Center, 930 Madison Avenue, Suite 100,
Memphis, TN 38163, USA
b
Jasti V. Ramanamma Children’s Eye Care Center, L.V. Prasad Eye Institute, Hyderabad, India
Medical therapy is usually allocated to a supportive role in the management of pediatric glaucoma
patients. In children, medical therapy is used to reduce intraocular pressure temporarily or to clear the
cornea so that surgical therapy, the definitive treatment for primary congenital glaucoma, can be undertaken. Those patients who do require long-term
medical therapy usually have intractable disease that
has not responded adequately to surgical therapy. Our
purpose is to review medical therapy of pediatric
patients. We also review medical treatment of glaucoma in pregnant women, considering the risks and
benefits of treatment of the patient and potential adverse effects on the fetus.
Medical therapy of pediatric glaucoma
Some children with congenital glaucoma and elevated intraocular pressure respond well to medical
therapy. In 161 eyes with congenital glaucoma,
medical therapy by itself reduced the intraocular
pressure to less than 21 mm Hg in 12% of eyes in the
short term and 10% of eyes in the long term [1].
When considering medical therapy in pediatric patients, clinicians should evaluate the risks and benefits of specific medications, use the minimum dosages
P.A. Netland receives research support from Alcon,
Allergan, Merck, and Pfizer.
* Corresponding author.
E-mail address: [email protected] (P.A. Netland).
required for therapeutic efficacy, and follow the
patient closely for ocular and systemic side effects
[2,3]. Although regulatory agencies worldwide do not
typically include children in antiglaucoma drug
approval studies, clinicians have found several medications to be useful in treating children with elevated
intraocular pressure (Box 1). Evidence has appeared
in the literature regarding the efficacy and safety of
different classes of glaucoma medications.
Carbonic anhydrase inhibitors
In adult patients, the side effects of systemic
carbonic anhydrase inhibitors are well known to
clinicians. In children, growth suppression has been
associated with oral acetazolamide therapy, and infants may experience severe metabolic acidosis [4,5].
Side effects from the use of systemic carbonic anhydrase inhibitors in infants and young children are
not commonly reported, although these patients may
not verbalize the occurrence of side effects to their
parents or health care providers. Oral administration
of acetazolamide suspension at a dosage of 10 (range:
5 – 15) mg/kg/d in divided doses (three times daily) is
usually tolerated by children, reduces intraocular
pressure, and diminishes corneal edema before surgery [6,7].
Topical versus oral carbonic anhydrase inhibitor
therapy has been evaluated for pediatric glaucoma in
a crossover design study [8]. The mean intraocular
pressure was reduced by 36% and 27% compared
with baseline after treatment with oral acetazolamide
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462
maris et al
Box 1. Glaucoma medications commonly
used in childhood glaucoma
Beta-blockers
Betaxolol 0.25% (every day,
twice daily)
Levobunolol 0.25% (every day,
twice daily)
Timolol solution 0.25% (every day,
twice daily)
Timolol gel-forming solution 0.25%
(every day)
Carbonic anhydrase inhibitors
Acetazolamide elixir, 5 to15 mg/kg/d
in divided doses (twice daily,
three times daily)
Brinzolamide 1% (twice daily, three
times daily)
Dorzolamide 2% (twice daily, three
times daily)
Cholinergic drugs
Pilocarpine 1%, 2% (three times
daily, four times daily)
Prostaglandin-related drugs
Bimatoprost 0.03% (every day)
Latanoprost 0.005% (every day)
Travopost 0.004% (every day)
A
Beta-blockers
Adjunctive treatment with timolol has been
studied in patients with a variety of pediatric glaucomas. In 34 patients with childhood glaucoma,
timolol was combined with other medical therapy,
causing a definite improvement in 29%, a modest or
equivocal improvement in 32%, and no improvement
in 39% [9]. In 38 eyes being treated with timolol as
adjunctive therapy, 37% of eyes were controlled at
22 mm Hg or lower [10]. In 89% of eyes with various
types of pediatric glaucoma, lowering of intraocular
B
Dorzolamide (% Decrease IOP)
35
30
IOP (mmHg)
and topical dorzolamide, respectively (Fig. 1). Although not as effective as acetazolamide in this group
of patients, topical dorzolamide caused a significant
reduction in intraocular pressure [8]. Furthermore,
treatment with topical dorzolamide caused few side
effects. One patient noted a burning sensation after
installation during the first month of use, but none
experienced corneal toxicity or allergic symptoms.
Presently, topical carbonic anhydrase inhibitors
are more widely prescribed compared with systemic
carbonic anhydrase inhibitors. Many clinicians prefer
twice-daily dosing to minimize the discomfort and
inconvenience to the parent and the child associated
with three times daily dosing. Taking the fixed combination of dorzolamide with timolol twice a day can
simplify the medical regimen by reducing the number
of drops instilled per day and may be more appropriate for older children.
25
20
15
10
5
0
Baseline
Acetazolamide
Dorzolamide
55
45
35
25
15
5
-5
0
10
20
30
40
50
60
Acetazolamide (% Decrease IOP)
Fig. 1. Carbonic anhydrase inhibitors in pediatric patients treated with a beta-blocker at baseline. (A) Intraocular pressure (IOP)
was significantly reduced from baseline (on a topical beta-blocker alone) after addition of acetazolamide (mean ± standard
deviation decrease of 35.7% ± 15.6%) or dorzolamide (27.4% ± 17.1%). Y error bars indicate standard error of mean. Asterisk
indicates P < .01 compared with baseline. (B) Correlation between efficacy of oral and topical carbonic anhydrase inhibitor
therapy. The percentage reduction of IOP in eight eyes on topical beta-blocker therapy was similar after the addition of
acetazolamide (oral) or dorzolamide (topical) treatment (r = 0.94). (Adapted from Portellos M, Buckley EG, Freedman SF.
Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS 1998;2:43 – 7; with permission.)
pediatric glaucoma and glaucoma in pregnancy
pressure was achieved only in 20% of eyes [11].
Similarly, in 100 eyes with childhood glaucoma
treated with timolol, 31% experienced a reduction
of intraocular pressure (Fig. 2) [12]. After the initial
response, however, increased intraocular pressure
may occur over time [10].
Plasma timolol levels in children after treatment
with 0.25% timolol greatly exceed those in adults
after instillation of 0.5% timolol, particularly in infants [13]. Increased plasma timolol levels in children
are explained by the volume of distribution of the
drug, which is much smaller in children compared
with adults. The ocular volume of the neonate is approximately half that of the adult, reaching full size
by approximately 2 years, whereas the blood volume
of the neonate as a function of body weight is only a
small fraction of that of the adult. Thus, administering
the usual adult ocular dosage may be needed for the
eye; however, when it is systemically absorbed, the
dosage is diluted by a much smaller volume of blood.
A
Additional
treatment
required
No added
treatment
0
20
40
Percent Eyes
60
80
Change IOP (mmHg)
B
> 10
1 to 10
No Change
-1 to -10
< -10
0
10
20
30
40
50
Percent Eyes
Fig. 2. Timolol in pediatric glaucomas. (A) In a series of
100 eyes treated with timolol maleate, most (60%) required
additional surgery or medications. (B) The change from
baseline intraocular pressure (IOP) in the 40 eyes receiving
timolol therapy without additional surgery or medications.
Of the 40 eyes that received timolol therapy without
additional surgery or medications, 31 (78%) demonstrated
reduced intraocular pressure (IOP) after timolol treatment. (Adapted from Hoskins Jr HD, Hetherington Jr J,
Magee SD, et al. Clinical experience with timolol in
childhood glaucoma. Arch Ophthalmol 1985;103:1163 – 5;
with permission.)
463
In addition, the infant’s immature metabolic enzyme
systems may prolong the half-life of drugs in the
neonate from two to six times beyond that of the
typical adult [14]. Higher plasma levels of drug
in infants and children would be expected to increase the risk of systemic side effects as compared
with adults.
In children older than 5 years of age, a reduction
in resting pulse rates has been associated with timolol
use and is comparable to that of adults [9]. Side effects have occurred in 4% to 13% of children [10,11],
and timolol therapy has been discontinued in 3% to
7% of patients [9,10]. Alarming side effects of
timolol therapy, such as Cheyne-Stokes breathing
and apneic spells, have been reported, especially in
infants and younger children [15 – 17]. Provocation of
asthma has been associated with timolol treatment.
Betaxolol, a selective b1 antagonist, reduces the risk
of pulmonary side effects in adults as compared with
timolol, but its effect on children is not known. Likewise, the effects of long-term use of any of the topical
beta-blockers in children have not been reported.
Timolol in 0.25% and 0.5% solutions should be
used cautiously in young glaucoma patients. Because
of the possibility of apnea, the drug should be used
with extreme caution in neonates. A detailed pediatric
history and examination to elicit the presence of systemic abnormalities, such as bronchial asthma and
cardiac disease, should precede the use of timolol. In
such cases, therapy with a beta-blocker is contraindicated. The use of 0.25% timolol instead of 0.5%
timolol is strongly recommended to reduce the risk of
side effects. Additionally, a significant reduction in
the systemic absorption of timolol has been observed
when performing punctal occlusion and simple eyelid
closure after drop administration [13]. Although the
practice of punctal occlusion with the eyelids closed
for at least 1 minute may be considerably more
difficult to execute in children than in adults, simply
blotting off excess drops from the child’s lids may
help to minimize unwanted systemic absorption [13].
Once-daily dosing with timolol 0.25% in a gelforming solution may similarly help to simplify the
medical regimen.
a2 Agonists
Several noncomparative case series describing the
use of brimonidine in pediatric glaucoma patients
exist in the ophthalmic literature, whereas the
pediatric use of apraclonidine has not been described.
In 30 patients with a mean age of 10 years,
brimonidine treatment achieved a mean 7% reduction
in intraocular pressure from baseline [18]. Two young
464
maris et al
children (aged 2 and 4 years) were transiently unarousable after administration of brimonidine, and
five other children experienced severe fatigue [18]. In
a study of 23 patients with a mean age of 8 years,
18% experienced serious systemic adverse effects
necessitating cessation of the drug [19]. Four pediatric patients have been reported to develop somnolence after treatment with brimonidine [20].
Additionally, a 1-month-old infant experienced repeated episodes of ‘‘coma,’’ characterized by unresponsiveness, hypotension, hypotonia, hypothermia
and bradycardia after treatment with brimonidine [21].
The a2 agonists are less often used in pediatric
patients compared with adult patients. The possibility
of central nervous system – mediated side effects is
greater with lipophilic drugs (eg, brimonidine)
than for more hydrophilic drugs (eg, apraclonidine),
which are less likely to cross the blood-brain barrier.
Iopidine may help to minimize intraoperative hyphema precipitated by goniotomy [22]. Brimonidine
should be used cautiously in pediatric patients, and its
use should be restricted to older children.
Other adrenergic agonists
Although uncommonly prescribed at present as an
ocular hypotensive agent in the adult population,
epinephrine (1%) has been used in children [23].
Lack of efficacy as well as the potential for systemic
toxicity, including cardiac tachyarrhythmia and
hypertension, limit the use of this drug. When used,
a reactive conjunctival hyperemia may occur after the
initial a1-mediated vasoconstriction. After prolonged
use of topical epinephrine (1%), melanin-like adrenochrome deposits consisting of oxidation products
of the compound may be noted in the conjunctiva and
occasionally in the cornea. Dipivefrin hydrochloride
0.1%, a prodrug of epinephrine, may also be used
in pediatric patients. Given its prodrug composition,
side effects may be attenuated compared with epinephrine. Still, local allergic reactions occur frequently. These drops are administered every 12 to
24 hours. Epinephrine (1%) and dipivefrin hydrochloride 0.1% should be avoided in aphakic or pseudophakic pediatric patients because of the risk of
cystoid macular edema.
Cholinergic drugs
Although miotic drugs enhance aqueous outflow
through the trabecular meshwork in normal patients
as well as in glaucoma patients, thereby lowering
intraocular pressure, these drugs are likely not as
effective in developmental glaucoma. This reduced
efficacy in developmental glaucoma is believed to be
attributable to the abnormal insertion of the ciliary
muscle into the trabecular meshwork. In pediatric
patients, the use of pilocarpine (2% applied every
6 – 8 hours) has been limited [6]. These drugs may
benefit aphakic and pseudophakic children with elevated intraocular pressure, however. In addition,
cholinergic drugs serve a useful purpose in the surgical management of pediatric glaucoma by causing
pupillary miosis before and after goniotomy [22].
The induced myopia produced by miotic therapy
can cause disabling visual difficulties. A slow-release
pilocarpine membrane delivery system, Ocusert (Alza
Pharmaceuticals, Palo Alto, California), currently not
available from the manufacturer, was helpful in some
young patients [24], and the sudden release of pilocarpine (burst effect) seldom induced myopic spasms.
The long-acting anticholinesterase drugs are not
readily available, are associated with serious adverse
effects, and offer no advantages over pilocarpine for
use in pediatric glaucoma. Echothiophate iodide
(phospholine iodide), usually administered topically
every 12 to 24 hours, is a potent and relatively irreversible inhibitor of the enzyme cholinesterase.
Ciliary spasm and angle-closure glaucoma have been
precipitated by the use of echothiophate iodide to
treat esotropia in a child [25]. Also, the systemic absorption of anticholinesterase agents can significantly
reduce the serum cholinesterase and pseudocholinesterase levels. Affected patients, particularly children,
may show signs of excessive parasympathetic nervous system activation. These signs can include
generalized weakness, diarrhea, nausea, vomiting,
excessive salivation, and decreased heart rate.
Significantly reduced systemic levels of cholinesterase and pseudocholinesterase can be particularly
dangerous when surgery is contemplated, because succinylcholine is commonly used as a muscle relaxant
during general anesthesia. Succinylcholine is normally quickly hydrolyzed by systemic cholinesterase
at nerve endings. When serum cholinesterase levels
are low, however, prolonged apnea can result because
of this excess of unhydrolyzed succinylcholine.
Prostaglandin-related drugs
Prostaglandin-related drugs, specifically latanoprost, have been evaluated in studies of a variety of
glaucoma diagnoses, including glaucoma associated
with Sturge-Weber syndrome [26 – 30]. In 31 eyes
with a variety of glaucoma diagnoses, 6 (19%) of the
treated eyes responded with a mean reduction in
intraocular pressure of 8.5 mm Hg, which represented
a 34% decrease from baseline. Most eyes were
pediatric glaucoma and glaucoma in pregnancy
A
465
25
Number Eyes
25
20
15
10
6
5
0
Nonresponders
B
Responders
35
IOP (mmHg)
30
25
Nonresponders
Responders
20
15
10
Baseline
Latanoprost
Fig. 3. Latanoprost in pediatric glaucomas. (A) In a series of 31 eyes, most children (n = 25) were nonresponders (defined as
<15% decrease in intraocular pressure [IOP]). Medical therapy using any particular drug is usually effective in a few pediatric
glaucoma patients. (B) In 31 eyes, latanoprost was effective in six responders (defined as 15% decrease in IOP). The average
IOP reduction in latanoprost responders was 8.5 ± 3.6 mm Hg (34.0% ± 10.9%; asterisk denotes P = .002). Y error bars indicate
standard deviation. (Adapted from Enyedi LB, Freeman SF, Buckley EG. The effectiveness of latanoprost for the treatment of
pediatric glaucoma. J AAPOS 1999;3:33 – 9; with permission.)
nonresponders, however (Fig. 3). Subjects who responded favorably were more likely to have juvenileonset open-angle glaucoma and to be older than
nonresponders [26]. The drug was well tolerated in
this short-term study.
In glaucoma associated with Sturge-Weber syndrome, 17% to 28% of eyes treated with latanoprost
responded with a reduction in intraocular pressure
[27,28]. Increased episcleral venous engorgement
was noted, and one patient (6%) discontinued latanoprost therapy because of intolerable hyperemia of
the conjunctiva [28]. Although a decline in success over time was noted, half of the patients were
controlled at 1 year of follow-up after a trial of
latanoprost as adjunctive therapy [29].
Although most children do not respond well to
latanoprost therapy, some children may experience an
appreciable hypotensive effect with treatment [30].
Likewise, the once-daily dosing schedule for latanoprost is convenient. Although local side effects are
infrequent and mild, parents and patients should be
warned about them, including iris pigmentation
changes, eyelash growth, and hyperemia. When
short-term medical therapy is planned, such as before
surgery, these local side effects are usually not a
problem. The prevalence and types of side effects
associated with long-term latanoprost use are not
known, however.
Osmotic drugs
Glycerol is administered orally at a dose of 0.75 to
1.5 g/kg of body weight in a 50% solution [31]. The
excessively sweet taste may be partially masked by
chilling the solution over ice or by using fruit juice
(commonly lemon or orange) or flavored water as a
diluent. This drug is not commonly used in the
treatment of developmental glaucoma. Mannitol
(20% solution) is dosed intravenously at 0.5 to
1.5 g/kg of body weight at approximately 60 drops
per minute. A rapid fall in intraocular pressure occurs
in 20 to 30 minutes after drug administration and can
last for 4 to 10 hours. Mannitol may also be used to
reduce markedly elevated intraocular pressure before
surgery in patients with developmental glaucomas
refractory to standard medical therapy.
466
maris et al
Glaucoma in pregnancy
Although glaucoma in adults is primarily a disease
of the older population, it can affect women of
childbearing age. In managing the pregnant glaucoma
patient with medical therapy, one must consider not
only the systemic side effects on the mother but any
potentially harmful effects on the developing fetus.
Based on the limited available literature on the
subject, the risk associated with prescribing ophthalmic drops to pregnant women is low [32]. Clinicians
should consult experts in the field when in doubt
about any deleterious effects of ophthalmic medications, however.
Glaucoma is rarely first discovered during pregnancy because intraocular pressure is usually noted to
decrease during pregnancy and stays decreased for
several months postpartum [33,34]. This reduction in
intraocular pressure has been proposed to be caused
by several factors: an increase in uveoscleral outflow
based on changes in the mother’s endogenous hormone levels, a decrease in episcleral venous pressure
reflecting an overall reduction of venous pressure in
the upper extremities, and a slight metabolic acidosis
induced by the mother’s pregnant state [35]. This
hypotensive effect is believed to increase slightly
during the course of the pregnancy. In one study of a
group of pregnant women, the mean intraocular
pressure in the third trimester was demonstrated to
be 1.5 mm Hg lower than in the first trimester [36].
Little is known regarding the teratogenic effects of
the commonly prescribed glaucoma medications, and
few human studies have specifically examined the
potential for harm rendered by the topically applied
glaucoma medications. The information that does
exist on the subject has been extrapolated from
studies of adverse effects attributable to systemic
treatment with various agents. For example, a large
collaborative study examining the use of systemic
cholinergic drugs (eg, pilocarpine) found no association between their use during the first 4 months of
gestation and congenital abnormalities [37]. Systemic
adrenergic compounds (analogues of topical epinephrine 1% and dipivefrin) have been shown to inhibit
the spontaneous and oxytocin-induced contractions
of the human uterus, however, and may delay the
second stage of labor or cause a prolonged period of
uterine atony with hemorrhage [37].
The US Food and Drug Administration (FDA)
and other groups specify safety in pregnancy according to categories or classes based on human and
animal studies. Class A indicates that safety is established using human studies. Class B indicates
presumed safety based on animal studies. Class C
indicates uncertain safety, with no human studies and
animal studies showing an adverse effect. Class D
indicates unsafe, with evidence of risk that may be
justifiable in certain clinical circumstances. Class X
indicates highly unsafe, with the risk of use outweighing any possible benefit. No topical ophthalmic
drugs are placed in category A or X.
Most topical glaucoma medications belong to the
pregnancy category C (Fig. 4), deemed as having
uncertain safety because of adverse fetal effects in
animals. Brimonidine and dipivefrin have been ascribed class B status, which presumes safety based on
animal studies only. What specifically may confer the
additional safety of these two compounds, although
similar agents, such as apraclonidine, remain class C,
is not apparent when reviewing the literature, however. The fixed-combination timolol 0.5%/dorzolamide 2% has been designated category D.
Prostaglandin-related drugs are in pregnancy
category C because of adverse fetal effects in animals. Use of the prostaglandin-F2 a analogues during
pregnancy arouses concern because of their presumed
abortifacient actions [38]. Manufacturer reports indicate that 25% of pregnant rabbits exposed to 80 times
the human dose of latanoprost delivered no viable
fetus at term (FDA latanoprost prescribing information [NDA 20-597/S-023]; available at: http//www.
fda.gov/cder/approval/x.htm). One observational
study of 11 pregnant women revealed no systemic
side effects threatening abortion or preterm delivery
as a consequence of topical exposure, however [39].
Although this series was too small to achieve statistical significance, the study found no evidence
of adverse effects of topical once-daily latanoprost
therapy on pregnancy or neonatal outcomes.
If the new mother plans on nursing her infant, it is
important to consider the excretion of any maternally
administered glaucoma medications in her breast
milk and their effect on the infant. Clinical evidence
Fig. 4. These glaucoma medications are designated pregnancy class C (uncertain safety; adverse fetal effects demonstrated in animals).
pediatric glaucoma and glaucoma in pregnancy
does exist for the excretion of timolol 0.5% and
betaxolol in a nursing mother’s breast milk [37]. In
the case of timolol 0.5%, the concentration of timolol
in the mother’s milk was determined to be a factor of
one eightieth of the cardiac-effective dose [40]. This
level of timolol should probably not cause concern
unless the infant’s hepatic or renal function is impaired. Nevertheless, if timolol treatment in a nursing
mother is deemed absolutely necessary, the infant
should be closely observed for signs of beta-blockade
or should be weaned altogether.
Summary
The primary goals of medical therapy in pediatric
glaucoma are to decrease intraocular pressure temporarily, to clear an edematous cornea, and to facilitate surgical intervention. Most pediatric patients
who require long-term medical therapy have severe
disease that has not responded sufficiently to surgical
therapy, and these patients may experience additional
intraocular pressure reduction with a medical regimen. Before commencing medical glaucoma therapy
in a child, clinicians need to consider the potential for
side effects carefully. During treatment, children need
to be closely monitored because they may be at increased risk of systemic side effects compared with
adults as a result of their reduced body mass and
blood volume for drug distribution. Similar caution
should be exercised when treating the pregnant
glaucoma patient or the nursing mother.
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