• By: Ta Chen Peter Chang, MD; Sharon Freedman, MD
    Glaucoma

    The indication for intraocular pressure (IOP)-lowering medications in childhood glaucoma can vary with the context of diagnosis and disease course. When primary surgical intervention is advantageous (e.g., in primary congenital glaucoma, in which angle surgery has a high likelihood of success) or urgently necessary (e.g., angle-closure glaucoma, in which intervention can open the angle and allow it to regain function), medical therapy is adjunctive. In these cases, medications (topical and sometimes systemic) are used as a temporizing measure and often to help clear corneal edema ahead of surgery. Medications can also be used postoperatively if surgery has incompletely controlled the IOP.

    On the other hand, effective medical therapy is often used first-line and maintained long-term in open-angle forms of childhood glaucoma in which surgical intervention might not be needed (e.g., some cases of glaucoma after cataract removal or mild forms of juvenile open-angle glaucoma) or when surgical intervention poses substantial risk of complications (e.g., Sturge Weber–associated glaucoma with choroidal hemangioma, refractory cases in which angle surgery failed or is impossible).

    As in adult-onset glaucoma, long-term medication use in the management of pediatric glaucoma can be life-long, and each agent exposes the child to potentially undesirable side effects and incurs cost. The greater life expectancy in these young patients also means greater medication exposure and higher cumulative risk of potential side effects. Furthermore, in the pediatric population, the therapeutic window for glaucoma medications can vary widely with the patient's age, developmental status, and overall health. Although the eye of a child with glaucoma is often not much smaller, or in some cases, actually larger than the normal eye of an adult, the plasma volume of a small child is much lower than that of an adult (as much as a 10‑fold difference), leading to much higher systemic drug levels in smaller children than in adults after a topical glaucoma medication dose.

    Adherence to medical therapy in patients with childhood glaucoma can pose problems in certain situations, and often with teenage patients, but has been shown to be satisfactory under monitored circumstances. In a prospective, observational study of pediatric glaucoma patients using an electronic monitoring system over 30 days, about 93% of prescribed doses were taken, 72% of which were within a 25% window of the prescribed schedule. Poor adherence was associated with poor health literacy in parents, and both adherence and proportion of doses taken on schedule diminished with extended monitoring beyond 30 days.1

    The efficacy, safety, and clinical experiences of each pressure-lowering medication class are discussed below. Table 1 provides a summary of medications and their recommended uses.

    Alpha Agonists

    Nonselective alpha agonists such as epinephrine and dipivefrin (an epinephrine prodrug) are seldom, if ever, used in the treatment of pediatric glaucoma today due to their relatively modest IOP reduction, high risk of ocular side effects, and risk of systemic toxicity. More commonly used glaucoma drugs in this class are the selective alpha‑2 agonists, which reduce IOP by suppressing aqueous production and are commercially available as brimonidine (0.1%, 0.15%, and 0.2%) and apraclonidine (0.5% and 1%).

    Due its central nervous system suppressive effect, avoid brimonidine in young children. In a published study of children aged 7–14 years (mean age 10 years), brimonidine 0.2% accounted for the highest frequency of systemic side effects, with about 17% of patients experiencing somnolence and fatigue.2 Central nervous depression, bradycardia, hypotension, and cyanosis in infants younger than 2 years have been attributed to brimonidine,3,4 and extreme fatigue and unarousability were reported in a retrospective study on the safety and efficacy of brimonidine in older children with mean age of 10.5 years.5 In most cases, the systemic side effects resolved after discontinuation of the medication. Expert consensus guidelines recommend avoiding brimonidine in children younger than 6 years.6, 7 Brimonidine 0.1% can be used judiciously in selected children around the age of 5 years, but only with care to watch for systemic side effects.

    Apraclonidine 0.5% has a better safety profile in children, and can be useful in minimizing intra- and postoperative bleeding with angle surgery. In a retrospective series of infants and children (mean age 5.3 months) who received topical apraclonidine 0.5% perioperatively, 4% had reported lethargy.8 A retrospective series also reported a low (1.7%) incidence of systemic side effects in short-term apraclonidine use.2 This is likely due to apraclonidine's low permeability through the blood-aqueous barrier.9

    As monotherapy, brimonidine 0.2% appears to have little to no IOP-lowering effect and has a modest effect of 1.7–2.2 mm Hg mean IOP reduction when used in adjunct with other medications.2,5 These results demonstrate the limited benefits of brimonidine use in children.

    In summary, brimonidine and apraclonidine can be adjunctive medications in selected cases of pediatric glaucoma, but should not be considered first- or second-line therapy for most cases requiring medical therapy. Do not use Brimonidine in infants and small children due to its central nervous system suppression, which can be exacerbated by concurrent topical beta blocker use; apraclonidine has a better systemic safety profile, but be cautious with this drug in infants.

    Beta Blockers

    Topical beta-adrenergic antagonists (beta blockers) work by reducing aqueous production. Topical beta blockers are often chosen as first-line medical therapy, but have well-documented systemic side effects that limit their use in infants, in children with reactive airways, and in some with cardiac disease. Several drugs and formulations are available, as are many combination therapies. The most widely used nonselective beta blocker in children is timolol, whereas betaxolol is the most widely used relatively beta‑1 selective beta blocker; both of these are most often available as 0.25% and 0.5% solutions, with viscous gel-forming versions also sold. These drugs are dosed twice daily, but can often be used once every morning with similar IOP control.

    As monotherapy, topical timolol (0.25% and 0.5%) lowers IOP about 5 mm Hg,2,10 whereas betaxolol 0.25% and levobetaxolol suspension 0.5% each has a less robust effect at about 3 mm Hg.11, 12 IOP control was achieved with timolol monotherapy in about 75% of children through a 3‑month prospective trial, with 0.25% concentration prescribed to those younger than 2 years and 0.5% prescribed to older children.13 Gel-forming formulations of timolol used once daily lower IOP similarly to solution formulations of the same strength dosed twice daily and can confer better adherence and decrease systemic absorption14 while being relatively contraindicated with contact lens use.

    The plasma timolol concentration in adults rises rapidly after topical administration and can be diminished with punctal occlusion. Random plasma timolol concentrations in children are in general higher than those of adults and can be greater than 30 times higher in infants, reaching levels above those desired for clinical (systemic) beta blockade.15 Ocular side effects of topical beta blockers include ocular hyperemia and discomfort, which is present in about 5%–7% of patients regardless of agent, formulation or strength.2, 11, 12 Systemic side effects such as bradycardia, fatigue, and hypotension are seen in 3%–6% of children.11, 12 In a retrospective series, 2 of the 10 adverse events in 106 patients were reported as "wheezing," underscoring the beta‑2 mediated bronchopulmonary side effects in susceptible children.2

    In summary, topical timolol lowers IOP about 5 mm Hg, with betaxolol and levobetaxolol slightly less effective. Topical beta blockers can be used once or twice daily and in combination with most other drug classes and can be good first- or second-line drugs in most pediatric glaucomas. About 75% of patients can achieve short-term IOP control with topical beta blocker therapy alone. Gel-forming formulations might be preferred in young patients due to easier dosing schedule and theoretically lower systemic absorption. Plasma concentration of topical timolol in children can be much higher than that of adults, and the medication must be used with caution in infants and in children with a history of respiratory (especially reactive airways/asthma) and cardiac problems. Topical beta blockers are generally well tolerated, with 3%­–6% of children at risk of developing systemic side effects. Beta‑1-selective agents might be appropriate, but not entirely without risk for side effects, for those at high risk of bronchopulmonary events.

    Carbonic Anhydrase Inhibitors

    Carbonic anhydrase inhibitors (CAIs) work by reducing aqueous production; both oral and topical formulations are available and have been widely used in children with glaucoma. The topical CAIs are generally second-line medication for children, but might be preferred in small infants and in those with contraindications to beta blockers, alpha agonists, and prostaglandin analogs. CAIs lack the convenience of once-daily drugs, but add well to all other drug classes.

    Topical CAIs include dorzolamide 2% and brinzolamide 1% formulations, as well as combination drugs (see Fixed-Dose Combinations below). These drugs are ideally dosed 3 times daily, but practically speaking, usually are prescribed twice daily. As monotherapy, the effect of topical CAIs is modest. In a 3‑month randomized trial of children younger than 6 years, dorzolamide 2% monotherapy was maintained through the study period in 28 of 50 (56%) of children younger than 2 years before switching to open-label combinations of dorzolamide and timolol medications, as prompted by the study protocol (compared to 27 of 35, or 77%, of patients randomized to timolol 0.25% monotherapy). In children aged 2–6 years, dorzolamide 2% monotherapy was maintained in 66 of 85 patients (78%), compared to 35 of 46 (76%) of patients randomized to timolol 0.5% monotherapy.13 However, the study design included an open-label phase and the mean IOP reduction during monotherapy phase was not reported. As monotherapy, dorzolamide achieved mean IOP reduction of 2.7 + 5.3 mm Hg in a small retrospective series,2 whereas brinzolamide lowered IOP 4–5 mm Hg (16%–20%) in a prospective randomized study.12 When used in conjunction with other medications, reports of dorzolamide effect vary between about 2 mm Hg and 27.4% reduction from baseline in retrospective studies.2,16

    Topical CAI therapy is safe and generally well tolerated by children. Burning/stinging on instillation (more commonly with dorzolamide than with brinzolamide), ocular hyperemia, and discharge are the most frequently reported side effects, affecting about 5% of children younger than 2 years and 12% of children aged 2–6 years.2, 13 The topical CAIs are relatively contraindicated in eyes with impaired corneas or corneal transplant, although they can be used in these eyes if clinically required. Rarely, systemic side effects such as fatigue and bradycardia have been reported.12 Although both topical and oral CAIs are renally excreted, topical CAIs are generally considered safe even in situations in which oral CAIs would be contraindicated.17

    Oral CAIs are rarely used as monotherapy in children, rather being reserved for refractory glaucoma cases. The available agents include acetazolamide and methazolamide, with acetazolamide much more widely used in children than methazolamide. Available formulations of acetazolamide include tablets (125 mg and 250 mg) and sustained-release capsules (500 mg). Dosing ranges 10–20 mg/kg/day divided in 2–4 daily doses, best taken with food. Acetazolamide suspensions must be prepared by a pharmacy. Less information is available on the recommended dosing and effectiveness of methazolamide in children.

    When added to topical therapies, the additional IOP-lowering effect of oral CAI ranges 30%–36%16,18 even when topical CAIs are in use. The pediatric neurology literature offers most of the reports on side-effect frequency and severity because oral acetazolamide is the first-line treatment for idiopathic intracranial hypertension (IIH). Metabolic acidosis and compensatory respiratory alkalosis is a well-recognized adverse effect, but is in general well tolerated and asymptomatic, although infants can demonstrate rapid respiratory rates. Other systemic side effects can include increased risk of renal calculi and hypokalemia. In contrast, paresthesia, gastrointestinal symptoms, loss of appetite, lethargy, and metallic taste can make therapy intolerable to patients.19 Blood dyscrasias have been associated with long-term acetazolamide exposure in adults, but the incidence in the pediatric population is unknown and the value of routine hematologic screening is uncertain.20 Oral carbonic anhydrase inhibitors are generally considered relatively contraindicated in patients with sulfonamide allergy, although a retrospective review of patients with self-reported "sulfa allergy" and concurrent acetazolamide use suggests low cross-reactivity.21

    In summary, topical carbonic anhydrase inhibitors are well tolerated and moderately effective in lowering IOP. They are best dosed 2–3 times daily, can be used in combination with most other drug classes, and can be good first- or second-line drugs in most pediatric glaucomas. Oral CAIs reduce IOP more effectively than topical agents and can be added to topical CAIs when needed, but often produce systemic side effects that limit their long-term use in children.

    Miotics

    Miotics, including pilocarpine and echothiophate iodide, stimulate the longitudinal ciliary muscle to pull open the trabecular meshwork and increase trabecular outflow and at the same time close intramuscular spaces and decrease uveoscleral outflow. Pilocarpine, the most commonly used miotic, comes in a wide variety of concentrations (0.25%–4%) dosed 2–4 times daily. In children, pilocarpine has modest IOP-lowering effects when used as monotherapy and minimal additional effect in conjunction with other IOP-lowering agents (‑2.2 mm Hg and ‑0.3 mm Hg, respectively in retrospective studies). It appears well tolerated in children, with about 4% reporting soreness, stinging, and coughs.2

    In a retrospective series of 32 eyes with glaucoma after infantile cataract surgery, the addition of echothiophate iodide 0.125% in combination with other medications reduced IOP about 33% over long-term follow-up and was well tolerated.23 Chronic echothiophate iodide therapy results in cholinesterase and pseudocholinesterase depletion, which can limit the metabolism of succinylcholine, a muscle relaxant sometimes used in general anesthesia, and can result in prolonged respiratory paralysis.9 Furthermore, abrupt discontinuation of echothiophate iodide can result in rebound IOP elevation, and this drug's commercial availability is limited at times due to shortage of raw material.22

    Prostaglandin and Prostamide Analogs

    Prostaglandin analogs reduce IOP by enhancing uveoscleral outflow of the eye. There are four prostaglandin analogs available in the United States as topical therapy for glaucoma: latanoprost, bimatoprost, travoprost, and tafluprost. When used in adults and dosed once nightly, latanoprost 0.005%, travoprost 0.004%, tafluprost 0.0015%, and bimatoprost 0.03% or 0.01% have similar efficacy: lower IOP about 30% from baseline.9

    In children, latanoprost has modest IOP-lowering effect as monotherapy (3.5 + 5 mm Hg, 14.7%).23 When used in conjunction with other medications, the addition of topical latanoprost resulted in little additional IOP-lowering in younger children, but was effective in the subgroup of older children (aged 9–13 years) carrying the diagnosis of juvenile open-angle glaucoma (JOAG).23 In cohort with mean age of 8.8 years, addition of latanoprost resulted in mean IOP reduction of 7.2 mm Hg, with higher responder rate in children carrying nonprimary congenital glaucoma diagnoses.10 A retrospective review of JOAG patients showed a treatment response of ‑5.0  + 3.6 mm Hg (20.7 + 12.4%) from baseline.24

    Topical latanoprost is generally well tolerated, but reported side effects have included transient hyperemia, irritation, sleep disturbance, and increased eyelash thickness and pigmentation.24, 25, 26 Iris pigmentation and hyperhidrosis have been reported, but are thought to be very uncommon.25

    Latanoprost and bimatoprost are both preserved with benzalkonium chloride, whereas travoprost is preserved by a trademarked preservative containing boric acid, propylene glycol, sorbitol, and zinc chloride. The effect of alternative preservatives on hyperemic symptoms is not well studied in children. The recently recognized periorbital skin hyperpigmentation and fat atrophy associated with some prostaglandin analogs in adults has yet to be proven in pediatric exposure, but should be considered as potential with the stronger agents.27 The prostaglandin groups of drugs are relatively contraindicated in the presence of uveitis and are not recommended in children with any active uveitis.28 Tafluprost is exclusively marketed as preservative-free, with no reported information on pediatric exposure.

    In 2015, latanoprost and travoprost (with benzalkonium chloride) both have generic formulations and are likely to be less expensive than the other prostaglandin analogs.

    In summary, latanoprost is moderately effective as monotherapy and provides little additional pressure-lowering effect in young children. In older children, especially those carrying diagnoses of JOAG, addition of latanoprost can provide substantial additional IOP-lowering. The safety profile of latanoprost seems excellent. The other drugs in this class might be appropriate for selected cases, with tafluprost useful in cases in which preservative-free drugs are needed.

    Fixed-Dose Combinations

    When monotherapy fails, fixed-dose combinations can offer added IOP-lowering benefits while keeping the prescribed medication schedule simple. In the United States, several fixed-dose combination medications are available including dorzolamide 2.0%/timolol 0.5% (Cosopt), brimonidine 0.2%/timolol 0.5% (Combigan), and brinzolamide 1%/brimonidine 0.2% (Simbrinza). None of these fixed-dose combination medications have been extensively studied in the pediatric population, and clinical experience with brimonidine 0.2%/timolol 0.5% and brinzolamide 1%/brimonidine 0.2% are lacking given the relative contraindication of brimonidine use in young children.

    A dorzolamide-timolol combination offered a mean IOP reduction of 4.3 mm Hg when used as monotherapy and as adjunct to other medication. It also has the greatest persistence when compared to the other glaucoma medications.2 About 4%–6% of children experienced respiratory side effects.2

    Preservative-Free Glaucoma Drugs

    Several commonly used glaucoma drops are available in the United States in preservative-free form including timolol (Ocudose 0.25% and 0.50% packets), Cosopt PF (dorzolamide 2%/timolol 0.5%), and Zioptan PF. Some patients might benefit from using preservative-free formulations of long-term glaucoma drugs including those with aniridia, allergic tendencies, and corneal pathology. Cost often makes these drugs difficult for patients to use in place of more affordable preservative-containing formulations.

    Suggested Approach

    The approach to medical therapy in childhood glaucoma centers on the child's age, systemic comorbidities, and prior treatment response and side effects. Goals of medication use in children with glaucoma include simplifying the schedule, minimizing side effects, and maximizing adherence. We suggest the following general approaches.

    Birth to 6 Years

    Start with beta blockers or topical CAIs, whichever is not contraindicated, as first-line treatment, and augment with beta blocker or topical CAIs, respectively. If IOP is controlled on both beta blocker and topical CAI, consider switching to fixed-dose combinations in the child who can tolerate the 0.5% timolol. Third-line and additional treatment includes latanoprost followed by topical apraclonidine, oral CAIs, or in the case of glaucoma after infantile cataract surgery, echothiophate iodide.

    Older than 6 Years

    Start with beta blockers or topical CAIs, or in the case of JOAG, a prostaglandin analog. Second- and third-line therapy would be the addition of a beta blocker, topical CAI or prostaglandin analog that is not already in use, with the additional of prostaglandin analog more likely to be effective in older children with JOAG. Consider fixed dose combination medication whenever possible to improve adherence. Brimonidine can be used judiciously with careful monitoring for systemic side effects, and echothiophate iodide can be considered in cases of glaucoma after infantile cataract surgery. Oral CAI can provide substantial IOP-lowering in older children, but long-term adherence and tolerability can be limited.

    Table 1. Medication use in pediatric glaucoma.

    Medication Type

    Indications

    Contraindications, Side Effects

    Adrenergic Agonists

    Epinephrine compounds

    Rarely used, limited effectiveness.

    Systemic effects: hypertension, tachycardia in small children.

    Alpha Agonists

    Apraclonidine 0.5%; Brimonidine: In smaller children, use lowest concentration, e.g., 0.10%.

    Apraclonidine helps during and after angle surgery; useful in the short-term in infants and after corneal transplantation. Use Brimonidine only in older children; 2nd‑ or 3rd‑line therapy with JOAG, aphakia, and older children with other glaucoma types.

    Apraclonidine is systemically safe; effect can wear off; rarely, local allergy or red eye. Brimonidine can cause bradycardia, hypotension, hypothermia, hypotonia, apnea — especially if used with β-blocker — so do not use in children weighing less than about 40 pounds.

    Beta Blockers

    Nonselective: timolol, levobunolol, carteolol

    β1-selective: betaxolol

    1st-line therapy for many, 2nd‑line for some older children; nonselective are more effective than selective, but selective are relatively safer in children with asthma.

    Systemic effects: bronchospasm, bradycardia. Avoid in premature or tiny infants and in children with history of reactive airways. Start with 0.1% or 0.25% in smaller children.

    Carbonic Anhydrase Inhibitors

    Topical: dorzolamide, brinzolamide 2–3 x/day

    Oral: acetazolamide 10–20 mg/kg/day, methazolamide 2–4 x/day

    1st- or 2nd-line in young children; add well to other classes. Topical therapy is better tolerated, but not as effective, so use both if needed.

    Topical systemically safe. In children with compromised corneas, especially with corneal transplant, reserve as later option. Dorzolamide stings. Metabolic acidosis can occur with oral therapy, rarely in newborns with topical.

    Miotics

    Echothiophate iodide, pilocarpine

    Echothiophate is rarely used, sometimes in aphakia. Pilocarpine is used after angle surgery and sometimes with JOAG. In congenital glaucoma, pilocarpine is less effective at reducing IOP.

    Echothiophate systemic effects: sometimes diarrhea, possibly inflammatory, warn about use with succinyl choline. Echothiophate and pilocarpine: headache; can induce myopic shift.

    Prostaglandins and Similar

    Latanoprost, travoprost, bimatoprost, tafluprost

    1st–3rd-line with JOAG; in others usually 2nd- or 3rd-line after β‑blockers and topical CAIs

    Systemically safe in children; long eyelashes will result, so beware unilateral use; redness is common, especially with bimatoprost; trial use with uveitic glaucoma only as last resort.

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