Primary infantile glaucoma

INTRODUCTION — Glaucoma is a heterogenous group of eye disorders that are characterized by a progressive optic neuropathy, manifested by cupping of the optic disc (picture 1), and usually, but not always, associated with increased intraocular pressure (IOP). Primary infantile glaucoma refers to glaucoma with onset in the first years of life. Glaucoma can lead to optic nerve damage and consequent visual loss. Peripheral vision loss occurs first, but if glaucoma is untreated, central vision loss and complete blindness can occur [1]. In infants and toddlers, additional damage to the visual system, including large refractive error, astigmatism, strabismus, and amblyopia, may occur. Early diagnosis and referral are crucial to ensure optimal visual outcome.

The clinical features, diagnosis, and treatment of primary infantile glaucoma will be presented here. Other causes of glaucoma in children and glaucoma in adults are discussed separately. (See "Overview of glaucoma in infants and children" and "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis".)

EPIDEMIOLOGY — Primary infantile glaucoma occurs in 1:10,000 live births. It accounts for approximately 25 to 30 percent of cases of pediatric glaucoma seen in tertiary referral centers [2]. Primary infantile glaucoma is bilateral in more than two-thirds of affected patients but may be asymmetric in onset [3].

INHERITANCE — Primary infantile glaucoma is usually a sporadic disease. However, a number of reports have indicated that between 10 and 27 percent of cases are inherited. Inheritance is autosomal recessive in some cases and multifactorial in others; the penetrance is variable [4-7].

The molecular defect in the majority of familial cases is in the cytochrome P4501B1 gene (CYP1B1) on chromosome 2p21 [8]. The protein product of this gene is thought to affect a signaling pathway during the terminal stages of angle development [9]. A second locus for primary infantile glaucoma has been mapped to chromosome 1p36 [10].

PATHOGENESIS — Primary infantile glaucoma is caused by abnormal fetal development of the angle structures (figure 1), leading to impaired drainage of the aqueous fluid and elevated intraocular pressure (IOP) (figure 2). Elevated IOP causes damage to the optic nerve. In addition, in children younger than two to three years of age (who have more elastic ocular collagen), elevated IOP causes enlargement of the cornea and distention, enlargement, and thinning of the sclera.

The underlying cause of angle dysgenesis is not known. Proposed theories center on neural crest cell migration and development as neural crest cells are critical in the development of the trabecular meshwork [11,12]. Some angle abnormalities that have been observed on gonioscopy include an open angle with no recess, obstruction of the trabecular meshwork by the iris or ciliary body, an absent or rudimentary scleral spur, and fewer and smaller openings in the trabecular meshwork [1,4,6,13].

CLINICAL FEATURES

Timing of onset — Primary glaucoma may have onset at birth, in the first few years of life, or later in life. A distinction sometimes is made between glaucoma that is present at birth (true congenital glaucoma) and glaucoma that has onset in the first two to three years of life (infantile glaucoma) because the prognosis differs [1,4,14-16]. The later the onset, the less severe the structural anomaly and the more likely the glaucoma will respond to treatment [4]. However, an important caveat exists in that some of the "late-onset" cases are simply late-detection cases, where a great deal of damage may have already occurred.

Unilateral or asymmetric cases tend to present early as small differences in corneal diameter are detected easily on gross inspection. However, when the disease is bilateral and symmetric, increased corneal size may not be recognized or may even be viewed as an attractive trait, delaying presentation to medical attention until symptoms develop. Another potential cause of delay in diagnosis is the attribution of tearing to the more common nasolacrimal duct (NLD) obstruction. (See 'Differential diagnosis' below and "Congenital nasolacrimal duct obstruction (dacryostenosis) and dacryocystocele".)

Patients who present in early infancy are more likely to present with corneal edema and haze, whereas corneal enlargement and buphthalmos tend to occur at a somewhat later age [17]. The older the age of onset, the fewer the signs and symptoms. Onset after age four years may be insidious, with increased optic nerve cupping as the only sign. (See "Overview of glaucoma in infants and children", section on 'Juvenile glaucoma'.)

Presentation — Primary infantile glaucoma typically presents with a classic triad of chronic or intermittent tearing (epiphora), photophobia, and some degree of blepharospasm. Parents or pediatric health care providers also may notice a large cornea or asymmetry in the corneal diameters.

Findings on physical examination include the following:

●Corneal enlargement and Haab striae – Increased intraocular pressure (IOP) causes stretching of the cornea and increased corneal diameter in children younger than three years of age (picture 2). The normal newborn corneal diameter ranges from 9.5 to 10.5 mm. At one year of age, a diameter of 11 mm is typical, with the cornea reaching adult size (12 mm) by two or three years. As a general rule, a corneal diameter that is more than 1 mm greater than average is cause for concern, and more than 2 mm is definitely abnormal [6]. Thus, a corneal diameter of 12 mm or more in an infant younger than one year of age should prompt urgent referral to an ophthalmologist [18,19].

Corneal enlargement has little effect on the epithelium and stroma but injures the endothelium and basement membrane (Descemet membrane). The corneal endothelium is a relatively static cell layer; the cells lack the ability to divide after birth, so it does not regenerate. Thus, as corneal stretching progresses, it causes breaks (called Haab striae) in the basement membrane, which leave permanent scars (picture 3). Haab striae may be linear or arcuate and are typically horizontally oriented. They are an important cause of permanent visual impairment in infantile glaucoma. Vision loss from central scars will persist despite adequate treatment of the glaucomatous nerve damage. Haab striae are an important diagnostic feature, though they may be difficult to see without a slit lamp. They occur in approximately 25 of patients who present at birth and approximately 60 percent of patients who present in later infancy [20,21].

Changes in the cornea can also lead to refractive error [1]. In one series of 59 patients with 102 eyes affected by primary infantile glaucoma, 24 percent had at least 2 diopters of astigmatism [22]. The astigmatism may be regular (meaning unidirectional and correctable with glasses) or irregular (multidirectional and uncorrectable with glasses). Both forms can lead to amblyopia and may persist despite adequate treatment of the glaucoma. (See "Refractive errors in children", section on 'Astigmatism' and "Amblyopia in children: Classification, screening, and evaluation", section on 'Refractive amblyopia'.)

●Corneal edema – Corneal edema causes many of the symptoms of infantile glaucoma. It is irritating, painful, and produces light scattering. The irritation causes tearing (epiphora), ocular discharge, conjunctival injection, and blepharospasm. Corneal edema is manifest as clouding and occurs less frequently after the barrier function of the corneal endothelium matures (ie, after six months of age) [6,17]. Epithelial and stromal edema results from the absorption of aqueous fluid through Haab striae.

Corneal clouding may result in unilateral or bilateral pattern deprivation, contributing to the development of amblyopia. (See "Amblyopia in children: Classification, screening, and evaluation", section on 'Deprivation amblyopia'.)

●Optic nerve cupping – The central depression in the optic nerve head is called the cup. The cup is characterized by the ratio between the cup diameter and the disc diameter. Thus, a cup that has a diameter that is 50 percent of the disc diameter would be 0.5. The term "cupping" refers to an increase in this ratio from normal. Eyes with a high degree of cupping have a hollowed-out appearance on funduscopic examination (picture 1).

In healthy infants, the optic nerves are symmetric with little cupping. In fact, a 0.3 cup, which generally is considered normal for an adult, is uncommon in infants. Cups >0.3 are seen in <2 percent of healthy infants [23]. Asymmetry of cupping from eye to eye also may be a sign of infantile glaucoma. Between-eye differences of >0.2 are seen in approximately two-thirds of infants with glaucoma and is very uncommon in healthy infants [23].

Cupping occurs due to optic nerve damage caused by elevated IOP. Axons at the superior and inferior poles of the disc are preferentially affected. Thus, the cup tends to be elongated on the vertical axis in glaucomatous eyes (picture 1).

At a given IOP elevation, cupping increases more rapidly in infants than in adults [24]. However, in contrast with adults, infants with glaucoma may have a reduction in optic nerve cupping when IOP is controlled. The reversal of cupping seen in these cases is due to a change in the displacement of the axons within the optic nerve, not an improvement in the loss of viable nerve fibers, which occurs in glaucomatous vision loss and is not reversible. (See "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis".)

●Ocular enlargement – Increased IOP causes stretching of the sclera in children <3 years old. Stretching of the sclera increases the size of the globe, also called buphthalmos or "ox eye." The increased anterior-posterior diameter of the eye causes secondary axial myopia. In one series of 102 eyes from 59 patients with primary infantile glaucoma, almost two-thirds had at least 3 diopters of myopia [22]. (See "Refractive errors in children", section on 'Myopia'.)

Myopic or astigmatic anisometropia (unequal refractive error between the eyes) occurs in approximately one-third of children with primary infantile glaucoma (either unilateral or bilateral) [22]. Anisometropia occurs in bilateral cases because the eyes are rarely symmetrically affected. Anisometropia, if left untreated, can cause amblyopia. Amblyopia is a leading cause of blindness and visual loss in infantile glaucoma, even in children whose glaucoma has been well controlled surgically. Amblyopia can be either refractive or deprivational (from Haab striae, corneal edema, or extremely asymmetric refractive error). Careful attention must be paid to amblyopia superimposed over the glaucoma. If identified, it should be treated aggressively with patching and/or atropine. (See "Amblyopia in children: Classification, screening, and evaluation" and "Amblyopia in children: Management and outcome".)

DIAGNOSIS — The diagnosis of infantile glaucoma is based upon a constellation of findings that includes enlarged cornea, corneal edema, and optic nerve cupping. Infants with these findings should be referred for urgent ophthalmologic evaluation. Referral should not be delayed pending progression (eg, of optic nerve cupping), as such delay can result in permanent visual loss.

Most patients with infantile glaucoma can be diagnosed in the ophthalmologist's office, although some require an examination under anesthesia. The diagnosis usually is based upon the clinical features described above. Measuring intraocular pressure (IOP) is often not a vital part of the diagnostic process since the other findings are usually readily apparent in children. However, measuring the IOP is helpful for following the treatment response. In addition to widely accepted methods of tonometry, rebound tonometry, performed without the need for topical anesthetic drops, has been shown to be reliable and may significantly reduce the number of examinations under anesthesia [25,26].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of infantile glaucoma differs depends upon the cardinal sign(s) and/or symptom(s). When the constellation of tearing, blepharospasm, photophobia, and enlarged cornea occur together, infantile glaucoma should be the first consideration.

Tearing — Common causes of tearing (epiphora) in infants include nasolacrimal duct (NLD) obstruction, infectious or allergic conjunctivitis, and corneal abrasions. The distinction between these disorders can usually be made on the basis of clinical findings. Unlike patients with infantile glaucoma, children with NLD obstruction do not have blepharospasm or photophobia. Nasal discharge is another finding that helps to distinguish glaucoma from NLD (during episodes of tearing, the nose runs in patients with glaucoma but not in those with NLD obstruction). (See "Congenital nasolacrimal duct obstruction (dacryostenosis) and dacryocystocele".)

Rare causes of persistent tearing in infancy include metabolic diseases such as cystinosis and tyrosinemia. Children with cystinosis may have corneal deposits that cause photophobia, tearing, and blepharospasm (in addition to corneal clouding). Children with cystinosis also have extraocular manifestation (eg, growth failure, rickets). The characteristic ocular findings of tyrosinemia are corneal ulcers or dendritic keratitis, which cause photophobia, pain, excessive lacrimation, and conjunctival injection. Patients with tyrosinemia also have characteristic skin lesions. (See "Cystinosis" and "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 2'.)

Among the other causes of tearing, infantile glaucoma is the only one in which enlarged cornea, corneal clouding, and optic disc cupping occur.

The diagnostic approach to infants and children with persistent tearing is discussed in greater detail separately. (See "Approach to the child with persistent tearing".)

Corneal clouding — Cloudy corneas can be caused by congenital hereditary endothelial dystrophy, mucopolysaccharidoses, sclerocornea, and trauma.

●Congenital hereditary endothelial dystrophy presents with corneal edema at birth. Associated epiphora and photophobia are uncommon. Nystagmus is very common. The cornea is of normal size horizontally and very thickened (up to two to three times), the intraocular pressure (IOP) is usually normal, and the optic nerve and angle are normal (albeit difficult to visualize). Congenital hereditary endothelial dystrophy is inherited in an autosomal recessive pattern [27].

●Corneal clouding from structural changes in the stroma (picture 4) is a characteristic feature of mucopolysaccharidosis type 1. Affected infants appear normal at birth; during the first year, they develop the characteristic coarse facial features, wide nasal bridge, and flattened midface. Other signs include hepatosplenomegaly, umbilical or inguinal hernias, and typical skeletal abnormalities. These infants typically present between six months and two years of age with developmental delay, recurrent respiratory infections, and chronic nasal discharge. (See "Mucopolysaccharidoses: Clinical features and diagnosis".)

●Sclerocornea is a congenital malformation of the cornea in which the limits of the cornea and sclera are indistinct (picture 5). The cornea is hazy because its collagen fibrils are irregularly arranged. Additional ocular anomalies (eg, aniridia, cataracts, coloboma) usually are present.

Corneal enlargement — Primary megalocornea (picture 6) is an inherited eye disorder that may be confused with infantile glaucoma. Megalocornea usually is inherited as an X-linked recessive trait and occurs almost exclusively in males. In patients with primary megalocornea, the IOP is normal; corneal edema, epiphora, and photophobia are absent; and the optic nerve is normal.

Unilateral high myopia, proptosis, lid retraction, microphthalmos, enophthalmos, or ptosis can give the appearance of an enlarged cornea because one eye is larger, more prominent, or more visible than the other [1].

Cupping — In addition to glaucoma, cupping of the optic nerve can be physiologic (picture 7) or due to optic nerve anomaly (ie, coloboma (picture 8)). Premature infants, especially those falling within the screening criteria for retinopathy of prematurity, also tend to have larger cups [28]. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Cupping'.)

TREATMENT — The goal of infantile glaucoma therapy is preservation of vision and prevention of progression of the optic neuropathy, rather than control of intraocular pressure (IOP), although IOP is used to monitor treatment success [29]. Treatment is almost always surgical, although medications have an adjunctive role, both pre- and postsurgery.

Surgery — Surgical intervention is the mainstay of therapy for primary infantile glaucoma and most pediatric glaucomas. The first-line procedures include goniotomy and trabeculotomy. Clinical trials have found no difference in success rates between these procedures [30].

●Goniotomy – Internal goniotomy involves cutting into the abnormal trabecular meshwork, which causes the iris to drop back, deepening the angle recess [31,32]. A surgical cleft is left in the area of the trabecular meshwork, decreasing resistance to outflow. Goniotomy is performed with a surgical goniolens with direct visualization of the trabecular meshwork and is thus limited by the need for adequate visualization, which may be impeded by corneal clouding. This limitation may be overcome with the development of endoscopic technology that provides direct visualization of the anterior chamber angle [33].

●Trabeculotomy – Trabeculotomy is the procedure of choice when corneal clouding precludes visualization of angle structures [34]. It involves the creation of a flap, an incision through scleral to access Schlemm canal, followed by the insertion of a trabeculotome into Schlemm canal with rotation into the anterior chamber to create an opening in the abnormal trabecular meshwork [35,36]. Treatment of the entire angle can be performed using a suture or illuminated catheter in some cases [37-40]. Treatment of the entire angle was shown to provide improved long-term outcomes in one study [41]. Gonioscopy-assisted transluminal trabeculotomy is a relatively new procedure that has the advantage of sparing the conjunctiva for possible future surgery if needed. It has shown some promise in the treatment of infantile glaucoma in a preliminary report [42].

Success rates (defined as IOP <20 mmHg) with goniotomy and trabeculotomy for treatment of true primary infantile glaucoma are approximately 80 to 90 percent. Success rates are lower for more complicated forms (anterior segment dysgenesis). Success rates in the available reports reflect outcomes over a relatively short follow-up period. Relapse can occur years after the initial surgery and, as such, lifetime monitoring is necessary.

Complications of goniotomy and trabeculotomy include hemorrhage and hyphema, inflammation, cataract formation, uveal or vitreous incarceration, endophthalmitis, retinal or choroidal detachment, hypotony (abnormally low IOP), irido- or cyclodialysis, and Urrets-Zavalia syndrome, in which the pupil remains fixed and dilated after a procedure [43].

Second-line surgical therapies include trabeculectomy, implantation of drainage devices, and cyclodestructive procedures.

●Trabeculectomy – Trabeculectomy, or filtering surgery, usually is attempted if goniotomy or trabeculotomy fail. This procedure involves creation of an artificial drainage pathway through the sclera to allow excess aqueous humor to leak out of the eye through a conjunctival filtering "bleb." The long-term success rate of trabeculectomy in children is usually cited as 50 percent [44]; success has been found to increase with the use of antifibrotic agents such as topical mitomycin C and fluorouracil [23,29,45]. Antifibrotic agents should be used with caution as they increase the risk of leakage and late-onset endophthalmitis [23]. Severe complications (eg, infection, bleb leak, collapse of the anterior chamber) are much more common after trabeculectomy than trabeculotomy or goniotomy. Use of fornix-based conjunctival dissection and a wide area of anti-scarring application may reduce the risk of complications [46]. Just as in adults, trabeculectomy carriers a lifetime increased risk of endophthalmitis, which is a particularly important consideration in pediatric cases since the overall duration of risk is considerably longer and may be increased further, owing to hygiene and activity level in children [23]. (See "Bacterial endophthalmitis", section on 'Bleb-related endophthalmitis'.)

●Drainage devices – Drainage devices are a secondary choice for infantile glaucoma after failure of angle surgery, just as for trabeculectomy. Glaucoma drainage devices consist of a small tube that is placed inside the eye, leading to a "reservoir" placed under the conjunctiva posteriorly. The tube must be placed well into the anterior chamber so that it does not cause corneal decompensation and is not too posterior to cause iris damage or cataract. Some advocate for tube placement in the sulcus or pars plana to minimize the risk of corneal decompensation over time. However, pars plana implantation requires a pars plana vitrectomy with its associated risks. Compared with other methods of surgical treatment, drainage devices have a higher risk of early and persistent hypotony. Success rates (defined as IOP <20 mmHg) at two to five years following surgery have been reported to be 55 to 65 percent [29,47]. Most patients require supplemental medication after surgery [48]. Complications include tube failure, encapsulation, vitreous hemorrhage, hyphema, malignant glaucoma, retinal detachment, erosion or recession of the implant, endophthalmitis, corneal edema, corneal failure, and cataract formation [49-54].

●Cyclodestructive procedures – Cyclodestructive procedures aim to decrease aqueous fluid production by destroying the ciliary processes. Cyclodestructive procedures are usually recommended when other methods of control have failed or when the vision is poor [55]. Cyclodestruction is performed with cryotherapy or diode laser application and has a success rate (defined as IOP <20 mmHg) of approximately 50 percent [56-58]. Complications include hypotony, retinal or choroidal detachment, phthisis, cataract formation if not already aphakic, and inflammation. Both transscleral laser and endolaser have been used in infantile glaucoma.

Medical therapy — The use of topical or oral preparations of pressure-lowering agents has a limited role in primary infantile glaucoma because nearly all cases require surgery. Surgery is required because of the rapidity of ocular damage and the difficulties inherent in monitoring the disease parameters (eg, IOP, visual acuity) in young children. However, medical therapy may be used as a temporizing measure prior to surgery to clear the corneal edema prior to attempted goniotomy and postoperatively to prevent or postpone the need for a second surgical procedure.

Medications used in the treatment of glaucoma include beta blockers, alpha-2 adrenergic agonists, carbonic anhydrase inhibitors, prostaglandin analogs, miotics, and sympathomimetics [1].

●Beta blockers (eg, betaxolol, carteolol, levobunolol, metipranolol, timolol) work by decreasing aqueous production. Side effects include bronchospasm, apnea, and bradycardia.

●Prostaglandin analogs (eg, bimatoprost, latanoprost, travoprost, unoprostone) improve aqueous outflow, primarily via the uveoscleral pathway. Side effects include iris and eyelid pigmentation, eyelash growth, and cystoid macular edema.

●Carbonic anhydrase inhibitors (eg, acetazolamide, brinzolamide, dichlorphenamide, dorzolamide, methazolamide) also work by decreasing aqueous production. Side effects include paresthesias, loss of appetite, nausea, diarrhea, polyuria, and metabolic acidosis. These side effects are far less common with topical administration compared with oral.

●Alpha-2 adrenergic agonists (eg, apraclonidine, brimonidine) work by decreasing aqueous production. Side effects include central nervous system depression and ocular injection [59-61]. In older children, they may cause somnolence. Alpha-2 adrenergic agonists are rarely used in young children and should be avoided in children <2 years old because of reports of sudden death owing to central respiratory depression.

●Miotics (eg, carbachol, echothiophate, pilocarpine) improve aqueous outflow through the trabecular meshwork. Side effects include headache, myopia, and prolonged paralysis (with echothiophate after pharmacologic depolarizing agents were used during anesthesia). The induction of the accommodation reflex limits their use in the pediatric population, except in pseudo or aphakic patients.

●Sympathomimetics (eg, dipivefrin, epinephrine) improve aqueous outflow. Side effects include eye pain, headache, macular edema, and conjunctival deposits. With the availability of other, better-tolerated medications (listed above), sympathomimetics are rarely used for treatment of pediatric glaucoma in contemporary practice.

OUTCOME

Surgical success — Goniotomy and trabeculotomy are successful in controlling intraocular pressure (IOP; <20 mmHg) in 80 to 90 percent of cases of primary infantile glaucoma when patients present between 1 and 24 months of age [4]. Reported success rates of the second-line procedures (ie, trabeculectomy, drainage devices, and cyclodestructive procedures) range from 50 to 65 percent [29,44,56-58].

Some studies have reported lower success rates (55 to 60 percent) in patients who present before two months of age [14,62]; however, other studies found no association between age at presentation and success rate [63,64].

Reoperation — A second procedure is necessary in 20 to 30 percent of cases [29,64]. Critical ages when further glaucoma surgery is required appear to be at approximately two and five years of age [64].

Visual outcome — The visual prognosis for children treated for primary infantile glaucoma is good. In the available reports, 50 to 80 percent of affected patients have visual acuity of 20/60 or better [63,65,66]. Children diagnosed at <3 months of age tend to have worse visual outcomes [64]. Poor vision usually results from amblyopia or presence of other ocular abnormalities or syndromes rather than glaucomatous optic neuropathy [2].

SUMMARY AND RECOMMENDATIONS

●Definition and importance – Glaucoma is a group of eye diseases that are characterized by a progressive optic neuropathy, usually associated with elevated intraocular pressure (IOP). Primary infantile glaucoma refers to glaucoma with onset in the first years of life. Increased IOP leads to optic nerve damage and consequent visual loss. Early diagnosis and referral are crucial to ensuring optimal visual outcome. (See 'Introduction' above.)

●Clinical features – Primary infantile glaucoma typically presents with chronic or intermittent tearing (ie, epiphora), photophobia, and some degree of blepharospasm. Parents or pediatric health care providers also may notice a large cornea or asymmetry in the corneal diameters. (See 'Clinical features' above.)

Findings on physical examination include corneal enlargement (picture 2), corneal clouding, conjunctival injection, tearing, discharge, blepharospasm, optic nerve cupping (picture 1), and ocular enlargement (buphthalmos). (See 'Clinical features' above.)

●Diagnosis – The diagnosis of infantile glaucoma is based upon a constellation of findings that includes enlarged cornea, corneal edema, and optic nerve cupping. Infants with these findings should be referred for urgent ophthalmologic evaluation. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of infantile glaucoma includes other disorders that cause tearing, photophobia, corneal clouding, and/or corneal enlargement. (See 'Differential diagnosis' above.)

●Treatment – The goal of infantile glaucoma therapy is preservation of vision rather than control of IOP, although IOP is used to monitor treatment success. Treatment is almost always surgical, although medications have an adjunctive role. (See 'Treatment' above.)

●Outcome – Success rates for the first-line surgical procedures (ie, goniotomy and trabeculotomy) are 80 to 90 percent. Approximately 20 to 30 percent of patients require a second procedure later in childhood, typically at age two to five years. Most children treated for primary infantile glaucoma have visual acuity of 20/60 or better; approximately 30 percent require glasses or contact lenses. (See 'Outcome' above.)