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Review Article

Primary Congenital Glaucoma: 2004 Update

Ching Lin Ho, FRCSEd; and David S. Walton, MD

ABSTRACT
Background: Primary congenital glaucoma is the most frequent childhood glaucoma and an important cause of blindness. We describe the current understanding regarding this disease, the evaluation of children with it, and its treatment. Patients and Methods: We accessed information derived from a review of 287 patients with primary congenital glaucoma and current published data related to primary congenital glaucoma. Results: The nomenclature for childhood glaucoma has been inconsistent, but is clarified for children with primary congenital glaucoma. The epidemiolDr. Ho is from the Singapore National Eye Centre, Singapore, Republic of Singapore. Dr. Walton is from the Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Originally submitted May 5, 2004. Accepted for publication June 3, 2004. Address reprint requests to David S. Walton, MD, 2 Longfellow Place, Suite 201, Boston, MA 02114-2224. The authors have no industry relationships to disclose. In accordance with ACCME policies, the audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. The material presented at or in any SLACK Incorporated continuing medical education activities does not necessarily reflect the views and opinions of SLACK Incorporated. Neither SLACK Incorporated nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the U.S. Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

EDUCATIONAL OBJECTIVES
1. To review current and new information of clinical value related to primary congenital glaucoma, including its genetic etiology, defining clinical features, and medical and surgical treatments. 2. To describe the clinical evaluation of patients with childhood glaucoma and the differential diagnosis of patients with signs and symptoms that suggest primary congenital glaucoma. 3. To describe the terminology, epidemiology, and pathogenesis of primary congenital glaucoma.

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ogy of primary congenital glaucoma notes its variable incidence worldwide. Familial occurrence supports autosomal recessive transmission; chromosomal loci have been identified, and the CYP1B1 gene has been identified and clinically correlated. The histopathology of eyes with primary congenital glaucoma confirms the presence of a variable trabecular meshwork anomaly and the absence of an imperforate membrane. Children with primary congenital glaucoma are diagnosed after recognition of corneal signs and symptoms of glaucoma.

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Conclusions: The examinations of patients with primary congenital glaucoma must be thorough to distinguish this glaucoma from other types of childhood glaucoma, to prepare for surgery, and to follow progress with treatment. Medical treatment must be tailored to the pediatric patient. Goniosurgery is the definitive procedure of choice for most children with primary congenital glaucoma, but other procedures are also used successfully after goniosurgery fails or is determined to be inappropriate. Future success will be determined by physicians who sustain continued progress for children with glaucoma. J Pediatr Ophthalmol Strabismus 2004;41:271-288.

INTRODUCTION
Primary congenital glaucoma is a hereditary childhood glaucoma secondary to abnormal development of the filtration angle, which occurs unassociated with systemic abnormalities. Glaucoma surgery has dramatically improved the visual prognosis of this important cause of childhood blindness; however, late recognition can result in permanent and severe visual morbidity. Associated amblyopia and secondary refractive errors are common. Clinical monitoring of primary congenital glaucoma is demanding and often performed for uncooperative patients. It is best treated by ophthalmologists who possess focused training, clinical experience with childhood glaucoma, and specialized surgical and examination skills. Its occurrence in young children makes its control a lifelong goal requiring motivation and perseverance by the patients, their parents, and their caregivers. In this article, we describe the progress made in understanding and caring for children with primary congenital glaucoma.

tal glaucomas anatomically related to involvement of the trabecular meshwork alone (isolated trabeculodysgenesis), combined with the iris (iridotrabeculodysgenesis), or combined with the cornea (corneotrabeculodysgenesis).1 Congenital glaucoma is a term broadly used when responsible developmental anomalies are suspected. Primary newborn glaucoma (isolated trabeculodysgenesis or iridotrabeculodysgenesis) is the term used when primary congenital glaucoma is clinically apparent at birth. When primary congenital glaucoma is recognized between 1 month and 2 years of age, it is termed primary infantile glaucoma, and is labeled late-recognized primary infantile glaucoma when recognized after 2 years of age. Primary congenital glaucoma is the term used in this article to refer to all three age groups with the clinical features, gonioscopic abnormalities, and genetics of isolated trabeculodysgenesis or iridotrabeculodysgenesis. The designation juvenile glaucoma is best reserved for patients with primary juvenile glaucoma who have normal gonioscopic findings, myopia, and acquired glaucoma associated with autosomal dominant inheritance. The glaucomas of infancy and childhood are classified into primary and secondary groups. The primary category is subclassified according to the presence or absence of systemic or other ocular anomalies, and the glaucomas in the secondary category are classifiable according to their etiologies (Appendix).

EPIDEMIOLOGY
Primary congenital glaucoma is hereditary, with a variable incidence in different populations but an overall occurrence of 1 in 10,000 births.2 A greater incidence occurs in populations with higher rates of consanguinity (eg, 1 in 2,500 in Saudi Arabia3 and 1 in 1,250 in Romanian gypsies), which supports autosomal recessive inheritance.4 It accounts for approximately 55% of primary pediatric glaucomas and is the most common type.5 Primary congenital glaucoma accounted for 5.7% and 10.9% of all patients with glaucoma seen in tertiary-care eye clinics during a 2-year period in China and Japan, respectively,6 and occurs worldwide with no racial or geographic predilection. Girls are more commonly affected in Japan, with a ratio of boys to girls of 2:3, whereas boys are more commonly affected in

DEFINITION AND TERMINOLOGY

The nomenclature for childhood glaucoma is plagued with confusing terminology. Developmental glaucoma is the term used to broadly encompass all glaucomas resulting from abnormal development of the aqueous outflow system, which may be associated with a systemic anomaly. Hoskins et al. classified the developmen-

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the United States and Europe, with a ratio of 3:2.7,8 Most (approximately 75%) of the cases of primary congenital glaucoma are bilateral, and asymmetric expression should be suspected in clinically apparent unilateral cases.9 More than 80% of the cases present within the first year of life, with 25% diagnosed in the neonatal period and 60% within the first 6 months of life.9

GENETICS
Most cases of primary congenital glaucoma are sporadic, but 10% to 40% are familial, frequently associated with consanguinity.10 In most familial cases, transmission is autosomal recessive, with expression and penetrance varying from 40% to 100%.10 Unequal gender distribution, a lower than expected number of affected siblings in familial cases, and transmission of the disease to successive generations challenge the autosomal recessive mode of inheritance.10 Genetic heterogeneity of primary congenital glaucoma confirmed by linkage studies has been postulated to explain these discrepancies.10,11 Three loci for primary congenital glaucoma have been found.10,12,13 The initial locus on chromosome 2p21 (GLC3A) was described in 1995 by Sarfarazi et al., who identified significant genetic linkage to this region in 11 of 17 Turkish families.10,14 Genetic heterogeneity was confirmed when a second locus on chromosome 1p36 (GLC3B) was found.12 Genetic family analysis identified a third locus (GLC3C) on chromosome 14q24.3.13 Although three chromosomal loci have been linked to primary congenital glaucoma, only the CYP1B1 gene in locus GLC3A has been identified.15 Mutations in this gene have been described as the predominant cause of primary congenital glaucoma in Turkish and Saudi Arabian families.16 The mutant alleles co-segregated with the disease phenotype in an autosomal recessive manner. In cases of parent-to-child transmission, molecular analysis invariably found homozygosity or compound heterozygosity for the mutant alleles in the affected parent and gene carrier status in the normal parent.17 These are examples of pseudo-dominance with an autosomal recessive trait. Mutations in the CYP1B1 gene were found to be responsible for 87% of familial cases, but were present in only 27% of sporadic cases of primary

congenital glaucoma.10 Approximately 45 mutations of this gene have been identified, including deletion; insertion; and point, missense, nonsense, frameshift, and terminator mutations.18 Genotypephenotype correlation has been reported to be related to the success of glaucoma management and abnormalities secondary to elevated intraocular pressure (IOP), and the most severe phenotype was associated with frameshift mutations.18 CYP1B1 is a member of the cytochrome P450 gene family of drug-metabolizing enzymes and is expressed in a wide range of tissues in the body, including the anterior uveal tract of the eye, the trabecular meshwork, the iris, and the ciliary body.19 This family of enzymes encodes monooxygenases and participates in the metabolism of exogenous hormones and drugs such as steroids. Its ocular substrate in the pathogenesis of primary congenital glaucoma has not been identified. A reasonable postulate is that the enzyme protein of CYP1B1 is involved in the metabolism of a molecule that plays an important role in the development of the anterior chamber angle. Primary congenital glaucoma is genetically distinct from a group of conditions classified as anterior segment dysgenesis or AxenfeldRieger syndrome or anomaly, which are transmitted by autosomal dominant inheritance resulting from mutations in the transcription factor genes PITX2 and FOXC1.20,21 Primary congenital glaucoma is also phenotypically unrelated to juvenile or adultonset, open-angle glaucoma, for which the MYOC (TIGR) gene has been identified at locus GLC1A on chromosome 1q25.22 In a small percentage of these cases, a CYP1B1 mutation has also been found, suggesting a modifier role.23

PATHOGENESIS AND PATHOLOGY

Primary congenital glaucoma results from an abnormality of the trabecular meshwork, which may represent a developmental arrest or relative immaturity of the trabecular tissue, causing increased resistance to aqueous outflow.24,25 The defect was initially thought to be an imperforate membrane (Barkans membrane) lining the anterior chamber angle based on its gonioscopic appearance suggesting a clothed membrane with a shagreened surface.26,27 Evidence of this membrane has not been found.28

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Five features characterize the histopathology of primary congenital glaucoma. One such feature is an anterior insertion of the iris and ciliary body in an open-angle configuration with variable exposure of the trabecular meshwork to the anterior chamber.28 The anterior iris insertion may cover a variable amount of ciliary body band and trabecular meshwork. The anterior portion of the ciliary body overlaps the posterior portion of the trabecular meshwork with underdevelopment of the angle recess. The longitudinal fibers of the ciliary muscle insert directly into the corneoscleral meshwork, passing in front of the internal tip of an underdeveloped scleral spur. In one study, 77.8% of eyes with primary congenital glaucoma had either an invisible or a narrow ciliary body band compared with only 13.8% of eyes in the control group.29 Another characteristic is thickened and taut trabecular beams in the meshwork. Anderson found that the trabecular meshwork was perforate and the intertrabecular spaces were present, but the trabecular beams in between these spaces were abnormally thickened.28 Maul et al. found an increased amount of collagen fibrils in the core of the trabecular beams.30 A third characteristic of primary congenital glaucoma is a thicker and less porous juxtacanalicular meshwork. The juxtacanalicular meshwork in eyes with primary congenital glaucoma has been found to be thicker than that in normal eyes.28,30,31 Unlike the corneoscleral meshwork, this external layer of the meshwork is normally compact, with a lack of intertrabecular spaces.31 The cells in this layer are normally round with short cytoplasmic processes and are surrounded by extracellular materials composed of collagen, elastic fibers, and amorphous substances, giving them a compact appearance.30,31 Enucleated eyes of premature infants reveal that the trabecular sheets first appear on the anterior chamber side of the trabeculum and gradually progress with fetal age toward Schlemms canal.32 At 42 weeks of gestation, the trabecular meshwork shows intertrabecular spaces similar to those seen in adult eyes, with only a few layers of cells in the juxtacanalicular area. Hence, it has been postulated that the thicker, compact juxtacanalicular meshwork seen in primary congenital glaucoma is perhaps the result of relative immature differentiation.32 A paucity of vacuoles in the endothelium of

Schlemms canal occurs in congenital primary glaucoma. Decreased vacuoles, compared with normal functioning angles, have been described in eyes with primary congenital glaucoma and thought to be either an artifact or the result of reduced aqueous flow through the trabecular meshwork in glaucomatous eyes.28,30,31 Finally, an absence of Schlemms canal has also been described in cases of primary congenital glaucoma, but this is an exception and probably indicates more severe maldevelopment.32,33 Immaturity of the juxtacanalicular meshwork, underdevelopment of Schlemms canal or collector channels, or both may explain failure of goniotomy in some cases.34 Similarity of the angle histopathology in primary congenital glaucoma, glaucoma with SturgeWeber syndrome, and maternal rubella syndrome with glaucoma9 suggests that a common pathway for angle development is affected in diverse conditions. The underlying mechanism of trabecular dysgenesis is still unknown. The most probable postulated mechanism is offered by Anderson, who thought that the excessive formation of collagen in the trabecular tissue results in thickened and taut trabecular beams that prevent posterior sliding of the peripheral iris and ciliary body along the inner eye surface, resulting in the anterior location of the uveal tract and underdevelopment of the angle recess.28 The success of goniotomy in primary congenital glaucoma may be explained by the relief of tension in the thickened, compact trabecular meshwork, with resultant decreased resistance to the outflow of aqueous.28

CLINICAL FEATURES
The signs and symptoms of primary congenital glaucoma vary depending on the childs age and the severity of glaucoma and secondary corneal abnormalities (Table 1). Some children are asymptomatic, whereas others develop intense photophobia and blepharospasm. Infants are most likely to present with diffuse corneal opacification that will be recognized promptly by physicians or parents. The classic symptoms of epiphora, photophobia, and blepharospasm are secondary to corneal edema, opacification, and breaks in Descemets membrane. Some infants may exhibit irritable behavior, which may be mistakenly attributed to colic or formula intolerance. Acquired

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TABLE 1

TABLE 2

SIGNS AND SYMPTOMS OF GLAUCOMA INFANCY AND CHILDHOOD

Symptom Photophobia Epiphora Blepharospasm Red eye Irritability Cloudy cornea Enlarged cornea or eye Poor vision Asymptomatic Irritability Sign

IN

COMPONENTS OF A CLINICAL EXAMINATION PRIMARY CONGENITAL GLAUCOMA

FOR

Buphthalmos Corneal enlargement Corneal edema Corneal size asymmetry Breaks in Descemets membrane Iris and pupillary abnormalities Elevated intraocular pressure Visual impairment Myopia or astigmatism Optic nerve cupping

History and systemic examination General inspection (for photophobia, corneal size and asymmetry, and systemic defects) Vision assessment Tonometry Anterior segment examination (cornea, anterior chamber, iris, and pupil) Gonioscopy Funduscopy and optic nerve head evaluation Ultrasonography Retinoscopy

epiphora is commonly misinterpreted as evidence of a congenital nasolacrimal duct obstruction, or a red eye mimicking conjunctivitis may occur, leading to further delay in diagnosis. The corneas may be diffusely thick due to stromal edema or thin with buphthalmos. Alternatively, focal stromal thickening and opacification occur in association with breaks in Descemets membrane, which develop Haabs striae after endothelial cells form a new basement membrane and hyaline ridges. These defects are typically horizontal, curvilinear, and parallel to the limbus in the peripheral cornea. Corneal and ocular enlargements are usual presentations in toddlers. Progressive enlargement usually ceases by the age of 3 to 4 years. Both the parents and the physicians may accept corneal enlargement as a normal, aesthetically pleasing variation. The stretching of the cornea occurs mainly at the limbus and is associated with corneal thinning and a remarkably deep anterior chamber. The posterior segment also enlarges with an overall increase in axial length and the development of clinical buphthalmos in severe cases. In older children, astigmatism and progressive axial myopia cause symptomatic, decreased, uncorrected visual acuity and refractive amblyopia. Children with late-recognized primary congenital glaucoma may be asymptomatic and have been discovered to have elevated IOP or optic nerve cupping on routine ocular examination or when examined for unrelated ocular conditions. Although cupping of the optic nerve in glaucoma is generally a gradual process in older children and adults, it can occur rapidly in infants. Reversibility of the cupping with normalization of IOP in young chil-

dren occurs due to suspected relative immaturity and elasticity of the lamina cribrosa.

CLINICAL EXAMINATION
The clinical examination (Table 2) of a child with glaucoma requires a physicians patience, time, and skill. A detailed examination using a slit lamp for tonometry and biomicroscopy of the anterior segment and optic nerve head is not possible in most children younger than 5 years, but an informative office evaluation can still be obtained. Sedation of a particularly fractious child may be helpful. Oral chloral hydrate does not appear to alter the IOP levels and may be the safest choice for children 1 to 5 years old,35 but is still not risk free, and monitoring of the patient until recovery is necessary. An appropriate medical and family history is essential to diagnose each patient due to the genetic basis of some types of childhood glaucoma and the occurrence of primary and secondary childhood glaucomas with various systemic or ocular conditions. A general physical examination is also indicated when evidence of a systemic or ocular developmental defect suggests diagnoses other than isolated glaucoma or when general anesthesia is planned. Because children often resist being held down or touched in the eye region, clinical information must be obtained by careful inspection before laying on hands. The presence of glaucoma may be obvious on inspection alone by observing the presence of hazy, enlarged, or asymmetric corneas, light sensitivity, and abnormal visual behavior.

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The inspection and examination of the anterior segment is facilitated by the use of a penlight and a hand-held slit lamp, which allow maneuverability regardless of the childs position. Magnification obtained with loupes or with the oculars present on hand-held slit lamps is useful. The corneal size and clarity should be studied. Asymmetry in cornea size is usually more obvious on inspection than by measurement. Breaks in Descemets membrane should be identified and differentiated from other abnormalities such as the more vertically oriented defects observed after forceps-induced birth trauma or the irregular scattered defects seen with posterior polymorphous dystrophy. The iris and pupil should be carefully studied for abnormalities such as iris stromal hypoplasia, pupillary ectopia, and pupillary enlargement, as seen with newborn congenital glaucoma and aniridia. The anterior chambers are deep and the lenses are uniformly clear in patients with primary congenital glaucoma. Tonometry is an essential component of the examination and can be the most difficult part if the child is uncooperative. The best IOP measurements are taken when the child is sleeping or relaxed with the use of a topical anesthesia. IOP readings are variably altered by sedation and general anesthesia and are falsely elevated in a struggling patient. Time and patience are the most important requirements for success. Repeated measurements taken during the same or a return office visit may be necessary. Parents can help by holding the child to provide reassurance or by distracting the child with a toy or a bottle. Tonometry efforts should initially be directed to the eye that appears more normal, as IOP measurements are more critical in determining whether this eye has glaucoma. Various instruments have been used to measure IOP in children. The Perkins applanation tonometer probably ranks highest for accuracy and the Tono-Pen (Medtronic Solan, Jacksonville, FL) ranks highest for ease of use. The corneal thickness should be measured when possible and should always be estimated to assist with the interpretation of eye pressure measurements. The Schiotz tonometer is still useful to give an indication of the IOP in young or struggling children examined in the supine position, although its accuracy is most affected by corneal thickness and curvature and scleral rigidity. In older, cooperative children, the Goldmann tonometer mounted on a slit lamp may be used. Gonioscopy is indispensable for determining

the type of glaucoma and choice of surgery. When corneal clarity permits, simultaneous bilateral examination of the angles may be performed with Koeppe lenses. A hand-held microscope and a customized illuminator for gonioscopy are recommended. Direct gonioscopy by this method can often be performed in the office on a sleeping or feeding infant or a cooperative child lying supine after topical anesthesia has been administered. Older children may permit indirect gonioscopy at the slit lamp. However, a detailed gonioscopic examination of a young child most often requires the use of general anesthesia. Epithelial removal can be performed to obtain a clear view when the cornea is cloudy due to epithelial edema. The angle appearance in primary congenital glaucoma can vary according to the severity of angle anomalies. Typically, the iris inserts more anteriorly than usual, with variable obscuration of the ciliary body band. There is an altered translucency of the angle face causing indistinct definition of the different angle structures (ie, ciliary body band, scleral spur, and trabecular meshwork). The peripheral iris often appears hypoplastic with scalloping at its insertion and visibility of the peripheral iris pigment epithelium. In more severe variants, the angle may be so underdeveloped that minimal visible angle structures anterior to the iris insertion can be identified. The presence of multiple abnormal iris processes and iridocorneal bands suggests the diagnosis of anterior segment dysgenesis. Examination of the optic nerve head may be performed with a direct or indirect ophthalmoscope. Examination with an indirect ophthalmoscope allows a three-dimensional assessment of the optic disc as well as detection of posterior segment abnormalities, which are usually absent in primary congenital glaucoma. An A-scan ultrasound examination is useful to obtain the axial length of each eye, which increases with the severity and duration of the glaucoma. A B-scan ultrasound examination of the posterior segment may yield useful information when cloudy corneas preclude a good view of the fundus. Advanced cupping can be recognized and unexpected retinal defects ruled out.

EXAMINATION USING ANESTHESIA

A complete office examination is usually sufficient to exclude, diagnose, or suspect glaucoma and

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TABLE 3

TABLE 4

INFORMATION TO BE OBTAINED DURING AN EXAMINATION USING ANESTHESIA

Intraocular pressures Corneal diameters Anterior segment assessment Gonioscopic observations Retinoscopy measurements Optic nerve head assessment Photographic documentation

DIFFERENTIAL DIAGNOSES OF THE CLASSIC SIGNS AND SYMPTOMS OF PRIMARY CONGENITAL GLAUCOMA
Corneal edema or opacity Ocular Birth trauma Sclerocornea Keratitis Limbal dermoid Congenital hereditary endothelial dystrophy Posterior polymorphous corneal dystrophy Anterior staphyloma Peters anomaly Systemic Mucopolysaccharidoses I, II, III Mucolipidosis IV Cystinosis Generalized gangliosidosis I Infantile NiemannPick disease De Barsy syndrome Familial dysautonomia Corneal enlargement Axial myopia Hereditary megalocornea Keratoglobus Epiphora and red eye Conjunctivitis Corneal abrasion Congenital nasolacrimal duct obstruction Uveitis Keratitis Photophobia Ocular Keratitis Aniridia Iritis Cataract Achromatopsia Posterior polymorphous dystrophy Systemic Albinism Meningitis Posterior fossa tumor37

to justify general anesthesia for a more detailed examination and probable surgery. Using anesthesia during examination should enhance, rather than replace, the office examination. It should follow the office examination and precede any planned glaucoma surgery. The essential information that can be obtained during an examination using anesthesia is listed in Table 3. Unfortunately, most anesthetic agents, narcotics, and sedatives have a lowering effect on IOP measurements.36 Hence, IOP readings obtained with the use of anesthesia should never solely decide the diagnosis of glaucoma or its treatment without accounting for parameters such as corneal clarity and diameter and optic nerve head findings. Tonometry with a Schiotz, Perkins, or Tono-Pen tonometer is best performed as soon as possible after the induction of anesthesia. Corneal diameters are measured with a millimeter ruler or calipers and recorded for followup evaluation of glaucoma control. Detailed examination of the anterior segment using a hand-held slit lamp is followed by gonioscopy, which is most reliable and informative in young children with primary congenital glaucoma when performed during an examination using anesthesia. The view through the cornea for gonioscopy and for the posterior segment examination may be obscured by epithelial edema. Limited epithelial removal restores the view remarkably. The severity of the angle defect found on careful gonioscopy helps in the preparation for angle surgery, and the findings should be carefully recorded. The use of anesthesia during examination also provides a good opportunity for funduscopy that includes evaluation of the optic nerve head, which can be viewed through the gonioscopy lens, and retinoscopy.

DIFFERENTIAL DIAGNOSIS
Primary congenital glaucoma is diagnosed when signs and symptoms of glaucoma, including a persistently elevated IOP, are observed in a child who has no other related ocular or systemic abnormalities and no other ocular disorders that can result in glaucoma. The differential diagnoses include other childhood glaucomas (Appendix) as well as disorders presenting

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with the signs and symptoms of primary congenital glaucoma (Table 4). Other Primary and Secondary Glaucomas Primary congenital glaucoma is diagnosed after other causes of glaucoma have been excluded (Appendix). Other primary glaucomas are excluded by the presence of associated congenital systemic or ocular abnormalities. A careful ocular history, examination, and systemic assessment should also detect cases of secondary glaucoma; hence, a complete general physical examination and ocular examination are important for all patients suspected to have pediatric glaucoma. Differential diagnosis of glaucoma is accomplished by considering the anterior segment findings. The presence of glaucoma-related corneal abnormalities supports the diagnosis and may suggest its severity and duration. Enlargement of the cornea may be exaggerated with early infantile glaucoma associated with neurofibromatosis or with a nevus flammeus. A small cornea may be seen at the onset of aphakic glaucoma or glaucoma complicating advanced retinopathy of prematurity. The anterior becomes abnormally deep with early childhood glaucoma, but will be shallow in the presence of a pupillary block secondary glaucoma. Evaluation of the iris can be helpful in differentiating the glaucomas. Recognition of the newborn variant of primary congenital glaucoma may depend on this because the angle features typically may not be seen well in the presence of the corneal opacity. In this condition, iridotrabeculodysgenesis, the iris is thin and flat, associated with abnormally large pupils often large enough to suggest aniridia. Examination of the iris should be continued during the gonioscopic assessment of the anterior segment. When iris and other anterior segment abnormalities exist, as in anterior segment dysgenesis, differentiation from primary congenital glaucoma is relatively easy. In AxenfeldRieger syndrome, for instance, associated iris atrophy, iris processes in the angle, anterior termination of the Schwalbes line, and characteristic faces make the diagnosis clear cut. In aniridic glaucoma, there are conspicuous iris defects as well as prominent angle abnormalities consisting of progressive shifting of the iris stump onto the angle face. Severe underdevelopment of the filtration angles and pupillary iris ectropion occur in glaucoma associated with neu-

rofibromatosis and in congenital iris ectropion syndrome. An angle anomaly resembling that found in primary congenital glaucoma may be present with glaucoma associated with certain systemic syndromes such as SturgeWeber syndrome, cutis marmorata telangiectatica congenita, maternal rubella syndrome, Lowe oculocerebrorenal syndrome, Down syndrome, cranio-cerebello-cardiac syndrome, and Stickler syndrome. Hence, these conditions and others must be recognized by their nonocular features. Disorders With Corneal Edema or Opacity Corneal haze or opacification is a sign that most often initiates an evaluation for childhood glaucoma, but is also seen in other conditions in the newborn or infant (Table 4). The differential diagnosis includes obstetric trauma induced by forceps with resultant Descemets membrane tears, corneal edema, and clouding; this is differentiated from primary congenital glaucoma by the presence of periorbital soft tissue trauma, a normal IOP, frequently vertical orientation of the Descemets tears, the absence of corneal enlargement, an abnormally deep anterior chamber, and an abnormal filtration angle. Viral keratitis such as herpetic or rubella keratitis can result in a cloudy cornea in the newborn. Rubella keratitis in the newborn may particularly resemble primary congenital glaucoma because it can be bilateral and associated with glaucoma. Peters anomaly is characterized by corneal opacities that may coexist with glaucoma, but characteristic corneal abnormalities and associated anterior segment anomalies help distinguish them from primary congenital glaucoma. Diffuse stromal thickening with the absence of corneal enlargement help to distinguish the congenital endothelial dystrophies.38 Corneal clouding secondary to storage diseases seldom causes confusion due to the plethora of associated systemic signs. Disorders With Corneal Enlargement An infant with corneal enlargement should be evaluated for glaucoma (Fig. 1) and repetitively examined for an elevated IOP in cases of doubt. Axial myopia is both in the differential diagnosis and a presenting sign of glaucoma in childhood; signs such as peripapillary crescent, tilted optic nerve head insertion, choroidal mottling, or retinal

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tessellation in the posterior pole are helpful distinguishing features not seen in primary congenital glaucoma. In hereditary megalocornea, the strikingly enlarged corneas are associated with deep anterior chambers at the expense of the posterior segments; the absence of Descemets membrane breaks or corneal opacities; and the presence of iris transillumination and pigment dispersion on the lens, cornea, or iris surfaces and in the angle. In most cases, it is transmitted by X-linked recessive inheritance.39 Disorders With Epiphora and a Red Eye The ocular examination must distinguish conditions showing epiphora or red eye from glaucoma. Congenital nasolacrimal duct obstruction is a common early cause of persistent epiphora and is always associated with discharge. Acute onset of epiphora with a red eye should also suggest a corneal injury, infection, or intraocular inflammation.

Figure 1. Eight-month-old patient with primary congenital glaucoma and symptomatic secondary asymmetric anterior segment enlargement.

PRINCIPLES

OF

MANAGEMENT

The treatment of a child with glaucoma is challenging. Primary congenital glaucoma is a chronic disease affecting infants and young children with normal life expectancies. The IOP-reducing benefit of each treatment modality may not persist. Treatments should be carefully tailored with the goal of long-term control of the IOP with minimum risk to the eye to enable meaningful vision for life. Surgery constitutes the mainstay of therapy for primary congenital glaucoma. Medications alone are rarely effective but play an important secondary role as adjunctive treatment. Because angle surgery enjoys striking success rates in primary congenital glaucoma, it should be considered first and will often be the initial procedure of choice. Other surgical procedures must be considered when appropriate angle surgery has failed or is unlikely to succeed because of gonioscopic evidence of a severe filtration angle anomaly. Medical Treatment Primary congenital glaucoma responds poorly to medical therapy alone. However, medications are important and are used before surgery as a temporizing measure in infants who are unfit for surgery

or anesthesia, to prepare a patient for goniosurgery by clearing the cornea, and mainly for adjunctive therapy in complicated cases unsuitable for or only partially controlled by surgical therapy. Medications can have different risk and benefit profiles in children compared with adults, and ophthalmologists using them in infants and children should be aware of these differences. Ocular surface toxicity and allergy are also real problems complicating continuous topical treatment started at a young age. Children are also often unable to communicate adverse effects, making it important for parents and physicians to assess the appearance of the eye, systemic signs, behavior, appetite, and growth. Oral carbonic anhydrase inhibitors (CAIs), such as acetazolamide and methazolamide, are the most effective and potent IOP-lowering drugs for children with primary congenital glaucoma. At doses of 10 to 15 mg/kg/d administered orally, acetazolamide is generally safe for use in the short term and often reduces IOP by one-third.40 It is useful to clear the cornea before goniosurgery and to improve IOP control after a surgical procedure has failed to lower IOP satisfactorily prior to further glaucoma surgery. Acetazolamide is administered orally using a mixture prepared from pulverized tablets and is usually well tolerated by young children. Inhibition of carbonic anhydrase in the kidneys results in decreased hydrogen ions and increased bicarbonate in the urine. The resultant metabolic acidosis may be associated with noticeable hyperpnea, decreased appetite, increased fatigue, and failure to thrive with prolonged use. These symptoms can be reduced by decreasing the acetazolamide dose and by adding oral sodium bicarbonate at 1 to 2 mEq/kg/d.38 Renal calculi formation secondary to the alkaline urine potentiated

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by acetazolamide may complicate long-term use, and this risk is increased with the use of sodium bicarbonate.41 Myelosuppression is a rare, idiosyncratic, life-threatening complication of CAI use and has not been reported in children younger than 6 years.42 If the CAI is prescribed for more than 1 month, blood counts should be obtained and the drug immediately ceased if a decrease in the level of any single formed blood element is observed. Topical CAIs, such as dorzolamide and brinzolamide, constitute a welcome alternative with less risk of systemic side effects compared with oral CAIs. They are generally less effective than oral CAIs, as they reduce IOP by 25%, but are better tolerated43,44 and are therefore used extensively in children with glaucoma. They are administered topically 3 times a day for maximum effectiveness and can be expected to have an additive benefit when used in conjunction with beta-blockers, although both drugs are suppressors of aqueous production.45 Beta-adrenergic antagonists (beta-blockers) have been used extensively for the treatment of glaucoma in infancy to adolescence and adulthood. Studies have found an IOP-lowering efficacy of 20% to 30% in responsive cases of childhood glaucoma, but none has examined its efficacy in primary congenital glaucoma.46,47 Severe systemic side effects from topical timolol are rare in infants and children, but bronchospasm and bradycardia have been reported,47-49 especially with the higher concentration of 0.5%. Apnea has been described in neonates and toddlers, although other factors such as coexistent congenital disorders could also have contributed to the apneic spells.49,50 Passo et al. have demonstrated that plasma timolol levels are much higher in children receiving timolol 0.25% compared with adults receiving timolol 0.5% and range from 10 times higher in a 5-year-old child (3.5 ng/mL) to up to 100 times higher in a neonate (34 ng/mL).51 Punctal occlusion after topical timolol decreased the mean 1-hour plasma timolol level by approximately 40%.51 Hence, in the treatment of glaucoma in the young, it is prudent to start with a lower concentration of timolol (0.25%) at a lower frequency of once daily, to begin treatment with only one eye initially in bilateral glaucoma, and to advise single-drop application with the use of punctal occlusion after every application. It is wise to avoid beta-blockers in patients who have

significant asthma and bradycardia and to use them with caution in neonates. Brimonidine, a relatively selective alphaagonist, reduces IOP by decreasing aqueous production and increasing uveoscleral outflow.52 Brimonidine passes through the bloodbrain barrier, potentially causing central nervous system toxicity.53 There have been reports of bradycardia, hypotension, hypothermia, hypotonia, apnea, and unresponsiveness in infants after having received topical brimonidine.54-57 A study regarding the safety and efficacy of brimonidine in children 2.4 to 16.8 years old reported somnolence and extreme fatigue following its administration and also showed a 6.7% average IOP reduction, which is much less than that shown in adult studies.58 Brimonidine should be avoided in infants and toddlers and should be used with caution in older children. The prostaglandin analogues latanoprost, travoprost, and bimatoprost have been shown to be effective in the treatment of adult glaucoma, have similar chemical structures, and reduce IOP primarily by enhancing uveoscleral outflow.59 They also have similar side effects, the most prominent of which are conjunctival hyperemia, iris and skin pigmentation, and accelerated eyelash growth.59 Their use and efficacy in children has not been widely reported. Disappointingly, little IOP reduction and a high nonresponse rate in children have been reported, although these drugs are systemically safe.60,61 A significant IOP-lowering effect was found in some older children with primary juvenile glaucoma or glaucoma related to SturgeWeber syndrome.60,61 The average age of nonresponders was 5 years versus 11 years for responders.61 Miotics such as pilocarpine are ineffective for primary congenital glaucoma. Symptoms of ciliary spasm and visual blurring from the induced myopia occur in older children. They can be useful for aphakic glaucoma and are helpful to produce miosis before goniosurgery. Goniotomy Barkan developed the goniotomy technique and described its successful use for infants with glaucoma.62,63 This seminal accomplishment offered for the first time a successful therapy for infantile glaucoma, heretofore considered a hopeless disease. Indications. Goniotomy is the procedure of choice for children with primary congenital glauco-

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ma when planned by a physician familiar with the technique and when the cornea is clear enough to enable confident viewing of the filtration angle. Preoperative gonioscopic evaluation is essential preparation for goniosurgery and may reveal encouraging or potentially discouraging findings. Inadequate pressure control after an initial goniotomy often indicates the need for repeat goniosurgery. Repeat goniotomy should also be considered with a recurrence of glaucoma even if the patient is an adult. The severe angle anomaly with extreme forward insertion of the iris and minimal development of the trabeculum typically seen with primary newborn glaucoma decreases the potential for a successful goniotomy. The indication for goniotomy is also much less certain for other primary glaucomas including glaucoma with a nevus flammeus, AxenfeldRieger syndrome, and neurofibromatosis. Therefore, late-recognized primary congenital glaucoma can be difficult to distinguish from primary juvenile glaucoma, but, fortunately, goniotomy is indicated for both of these conditions. Results. Overall, the expected outcome of goniotomy surgery for primary congenital glaucoma is favorable, with a reported success rate greater than 80%.64 Patients recognized to have glaucoma between birth and 2 months of age have a lower success rate with goniotomy,65-68 which may correlate with their severe filtration angle anomaly. In one study, goniotomy surgery was performed on 335 eyes; glaucoma control was achieved with a single goniotomy in 71% (239) of the eyes and with one or more goniotomies in 93% (313) of the eyes.69 Relapse following successful goniotomy is unusual68 and occurred more frequently when the glaucoma was first recognized at birth (36%) than before 6 months of age (16%).68 History of repeat goniotomy procedures and glaucoma bilaterality were also found to be risk factors for relapse.68 Review of the functional results in patients with successful goniotomy determined that only 47% (34 of 72) of the eyes achieved an acuity of 20/50 or better, associated with an increased incidence of anisometropia and strabismus.70 Technique. Goniotomy is performed using a light source, a magnification instrument, fixation forceps, an operating gonioscopic lens, and a suitable goniotomy needle or knife. Following the positioning of the globe and with the trabecular meshwork in view through an operating lens, the cutting

Figure 2. Gonioscopic view of the filtration angle following successful goniotomy.

instrument enters the anterior chamber through the peripheral cornea and is brought into contact with the midsection of the trabeculum. A circumferential incision is then made in the trabeculum (Fig. 2), and the instrument is removed without causing injury to the cornea or lens.71 Surgical complications after goniotomy are rare. A postoperative hyphema is a constant finding, but is usually of no clinical significance. Occasionally, a significant amount of blood will reflux into the anterior chamber during the first 72 hours after surgery, and when this becomes complicated by an elevated IOP, washout of the blood should be considered. Endoscopic goniotomy has been successfully performed using a coaxial ocular endoscope in the presence of corneal opacification that prevented standard goniotomy.72 Trabeculotomy Trabeculotomy ab externo is an alternative procedure to goniotomy for primary congenital glaucoma. Its successful use for infantile glaucoma was recognized early, and favorable results have been reported.73,74 The efficacy of this newer operation has been compared favorably with that of goniotomy.74 Trabeculotomy and goniotomy for infantile glaucoma were compared and found to be equally effective and safe.75 The significant advantage of trabeculotomy for those cases with a cloudy cornea

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limiting visualization of the angle has been described.75 In one study, primary combined trabeculotomytrabeculectomy was performed for 144 eyes with primary congenital glaucoma and, based on a success rate greater than 90% at 6 months, has been recommended for cases with significant corneal edema.76 Trabeculotomy, rather than goniotomy, may be a more appropriate choice for surgeons not experienced with goniotomy, especially when the cornea is so cloudy secondary to edema or scarring that the angle cannot be comfortably visualized. It requires more operating time than does goniotomy, and a quadrant of the limbus must be used for this surgery. The operative technique for trabeculotomy has been modified little.77 The superior quadrants are best saved for alternative surgery. A limbus-based scleral flap is created to expose the sclerolimbal junction, followed by a radial incision centered over this landmark to unroof and expose Schlemms canal. Trabeculotomy probes are then introduced into Schlemms canal and brought into the anterior chamber in a plane parallel to the iris to create a fistula between the canal and the anterior chamber.78 Following removal of the probes, the scleral flap and conjunctiva are repositioned. An alternative variation of this procedure is to thread a suture circumferentially through Schlemms canal, pulling it across and then out of the anterior chamber, creating a communication between these structures.79 Study of the long-term effectiveness of trabeculotomy has confirmed its efficacy for primary congenital glaucoma. In a study of trabeculotomy for 99 eyes, the probability of success after one or more surgeries at 5 and 10 years was reported to be 92% and 82%, respectively.80 Trabeculotomy for 46 children with primary congenital glaucoma and a mean age of approximately 4 years (range, 13 to 88 months) achieved success in 87% (68) of the eyes using custom probes for 102 procedures.81 Complications after standard trabeculotomy are unusual. A small reflux hyphema of no consequence is common. Trabeculectomy Before the use of goniosurgery for primary congenital glaucoma, filtering surgery was performed with little expectation for success. Procedures performed included limboscleral trephine and posterior lip sclerectomy. Beauchamp and Parks studied

the use of trabeculectomy in 7 children with refractory primary congenital glaucoma following angle surgery; 4 patients were observed, and 3 of the 8 operated on eyes were adequately controlled.82 Introduction of trabeculectomy lessened the risk of filtration surgery in young children but had not significantly improved glaucoma control. The addition of antimetabolite during trabeculectomy in children followed and improved the surgical outcome in terms of more effective IOP control.83 The indication for trabeculectomy for primary congenital glaucoma is persistence of an unacceptable elevation of eye pressure following an appropriate number of angle incision operations. The condition of the superior conjunctiva related to previous surgery, patient age, potential for follow-up examinations, postoperative contact lens use, and the risk of postoperative infection must be considered. Children younger than 1 year show a significantly lower success rate than do older patients.84 An explanation for this is not clear. The surgery is not more complicated, and the use of an antimetabolite has not improved the outcomes. Postoperative care is difficult for young patients. Their postoperative course is characterized by decreasing evidence of external filtration, even if improved IOP control is achieved following trabeculectomy. Favorable outcome with combined trabeculotomytrabeculectomy for patients younger than 1 month with primary congenital glaucoma has been described.85 The trabeculectomy surgical procedure for primary congenital glaucoma does not vary significantly from that performed for adults. A limbusbased or fornix-based flap is manufactured. The fornix-based flap spares the surgeon the need to enter through the youthful conjunctiva and Tenons layers, which are substantially thicker than those found in adult eyes. If used, 0.2 to 0.4 mg/cc of mitomycin C is applied to the scleral flap region and broadly more posteriorly.86 A scleral flap is created with adequate extension anteriorly to facilitate entry into the anterior chamber in front of the abnormal anterior insertion of the iris. After removal of a small section of trabeculum, the iridectomy is performed. The flap is closed with nylon or absorbable sutures, and the conjunctiva is closed tightly. Absorbable 10-0 sutures allow tension on the scleral flap to be released at a time 2 to 4 weeks following the procedure. The results of trabeculectomy are encouraging,

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with 60% to 70% of patients having their primary congenital glaucoma successfully controlled during the first 2 years after surgery.83,84,87 Continued failures are to be expected with continued observation. Complications after trabeculectomy with the use of adjunctive antifibrosis agents are frequent.83,84,87 After surgery, shallowing of the anterior is frequent, and choroidal expansion occurs variably in proportion to the degree and duration of hypotony. Chronic postoperative hypotony with maculopathy occurs infrequently. Nonprogressive subcapsular lens opacities occur even after only a few weeks of hypotony. Failure is associated with decreasing evidence of subconjunctival filtration often without internal evidence of blockage of the sclerostomy. Ciliary processes can be seen in the internal sclerostomy with both functioning and nonfunctioning results. Late-onset, bleb-related endophthalmitis happens acutely with an expected occurrence rate of 7% to 17%83,84,88 within a 3-year period following surgery.88 Candidate patients remain at risk when thin avascular blebs are present even in the absence of leakage. In one study, following trabeculectomy for primary congenital glaucoma, thin avascular blebs were observed after 18 months in 33% and 67% of eyes following the use of 0.2 and 0.4 mg/cc of mitomycin C, respectively.89 Bleb excision followed by conjunctival advancement is necessary for blebs that become at risk for infection and is fortunately associated with a low incidence of failure.90 Aqueous Drainage Devices Implant surgery is an important alternative treatment for patients with primary congenital glaucoma who are poor candidates for angle incision therapy and trabeculectomy or whose conditions have proven to be refractory to these procedures. Molteno pioneered the contemporary translimbal glaucoma implant and reported favorable results. The use of Molteno implants for primary congenital glaucoma has been widely adopted and their efficacy and complications have been better understood.91,92 Introduction of the Baerveldt implant (Pharmacia & Upjohn, Inc., Kalamazoo, MI) in 1990 made available a silicone, non-valved implant, and the Ahmed Glaucoma Valve implant (New World Medical, Inc., Rancho Cucamonga, CA) was designed with a valve to lessen the occurrence of immediate postoperative hypotony.

The indications for implant surgery for primary congenital glaucoma have expanded beyond its being an option to consider only after other procedures have failed. Implant surgery can follow trabeculectomy at the same preferred superior site but should not be planned to precede it. Most patients with primary congenital glaucoma will have initial goniosurgery, and, if unsuccessful, trabeculectomy will be considered followed by implant surgery. When preoperative gonioscopy reveals a severe angle anomaly in a newborn, goniosurgery has only a minimal chance of success, and the outcome of trabeculectomy at this age even with antimetabolite augmentation is poor; hence, these patients are strong candidates for primary glaucoma implant surgery. When the outcome of 32 patients with a mean age of 7 months treated with glaucoma implants was compared with the outcome of 19 patients with a mean age of 5 months treated with trabeculectomy, the probability of success at 77 months was 53% and 19%, respectively.93 The surgical technique is similar for all glaucoma implants.80 The superior temporal quadrant is the preferred site to maximize the distance of the drainage plate from the optic nerve. Following a peritomy, the implant device is placed with its anterior edge approximately 6 to 7 mm from the limbus. The tube is shortened and beveled, and an incision is made into the anterior chamber to allow entry of the tube parallel to the iris, taking into account the frequent anterior insertion of the iris in infants with primary congenital glaucoma. Contact between the iris and the tube will result in corectopia. The tube can be tied with a 7-0 absorbable suture to impede flow and decrease the risk of hypotony. The tube is then protected with the autogenous sclera or pericardium, and the limbal peritomy is closed.94 The results of implant surgery for pediatric glaucoma and primary congenital glaucoma are favorable.95,96 In a cohort of 14 eyes with primary congenital glaucoma, including 9 eyes with a history of previous cycloablation, success was achieved in 93% (13) of the eyes with the continued use of medications.96 Importantly, the potential success of implant surgery for refractory primary congenital glaucoma has greatly decreased the use of destructive cycloablative procedures. With the use of the Ahmed implant in 60 pediatric eyes with glaucoma, including 25 with primary congenital glaucoma, IOP control was achieved in 73% (44) of the eyes at

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last examination with the continued use of medications in 77%; however, complications occurred in 50% (30) of the eyes.97 The complications of pediatric glaucoma implant surgery are varied and frequent.96,97 Early hypotony and tube-related problems are most common and often require intervention.96 Glaucoma implant tube exposure puts an eye at significant risk for infection and postoperative endophthalmitis and must be corrected promptly by recovering the tube.98 Cyclodestruction Cyclodestructive procedures are selectively used for primary congenital glaucoma that has proven refractory to medical therapy and conventional surgical procedures to improve aqueous outflow, and work by decreasing aqueous production. The required ciliary epithelial ablation can be clinically produced by cyclocryotherapy or by transscleral or endoscopic diode laser cyclophotocoagulation. The indications for using any of these intentionally damaging procedures must also consider the long-term visual and anatomic prognosis and parents expectations for the affected eye. The ocular indications include a blind painful eye, a blind eye with a high pressure and rapidly deteriorating cornea, an eye proven to be refractory to all more conservative treatment alternatives, an eye with anatomic defects that preclude other glaucoma procedures, and not being a candidate for either prolonged general anesthesia or intraocular surgery. The cycloablation surgical procedures differ, but have in common the direction of destructive energy targeted for the ciliary epithelium and the need for general anesthesia. The cyclocryotreatment and the transscleral laser probes are applied externally to the retrolimbal conjunctiva, whereas the laser endoscope enters through the anterior chamber to approximate the ciliary processes. The results of cyclodestructive procedures for patients with primary congenital glaucoma are difficult to interpret because of the limited number of reported cases and because of their use primarily for eyes with advanced disease. The results of cyclocryotherapy for 37 eyes with primary congenital glaucoma with a history of previous eye surgery were compared with those of 12 eyes without prior procedures, and control was achieved in 31% and

30%, respectively.99 Twenty-five eyes with primary congenital glaucoma were in a cohort of 64 pediatric eyes with glaucoma treated with cyclocryotreatment, which achieved success in 44% (28) of the eyes at last examination (mean, 4.8 3.3 years) with an average of 4.1 4.0 treatments for each eye.100 Twenty-six eyes with primary congenital glaucoma were in a series of 77 pediatric eyes with refractory glaucoma treated with laser diode cyclophotocoagulation that collectively achieved a success rate of 30% after approximately 4 years.101 Four eyes of 3 patients with primary congenital glaucoma and a history of multiple previous conventional glaucoma procedures were treated with endoscopic diode laser photocoagulation, and success was achieved in 1 eye.102 Nineteen eyes with primary congenital glaucoma were included in a series of 69 pediatric eyes with glaucoma treated with a mean of 2.1 sessions per eye; at 1 year, 79% were controlled below 21 mm Hg, and 48% were controlled at 5 years.103 Cyclodestructive operations are followed by many complications, including phthisis,100,101 retinal detachment,100,101,103 chronic hypotony, and cataracts.99 Not yet reported is the chronic postcyclodestruction anterior segment syndrome, seen frequently in children with primary congenital glaucoma that has been successfully controlled by these procedures, which is characterized by band keratopathy, corneal edema and endothelial cell drop out, chronic anterior chamber flare, posterior synechia and microcoria, and slowly progressive cataracts.

THE FUTURE
The potential therapeutic use of knowing the genetic basis for primary congenital glaucoma is appreciated. Continued progress in the development of techniques to target and alter genetic expression of the outflow pathways is crucial to make such beneficial intervention a therapeutic reality.104 Spontaneous resolution of primary congenital glaucoma is clinical evidence that supports the hope that intervention could be successful. Evidence that outflow pathway anomalies that are genetically determined can be qualitatively influenced by pharmacologic agents provides additional information to support medical therapy for prima-

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ry congenital glaucoma in the future.105 The possibility of a degenerative component in primary congenital glaucoma is suggested by the progressive iris stromal abnormalities seen in some patients and the impaired outflow acquired in primary juvenile glaucoma, which may possess a related genetic basis.106 Inhibition of this unidentified mechanism may also prove beneficial. Inevitably, children will present with glaucoma that requires treatment. Continued development and use of goniosurgery will be required. Filtration surgery for children who are unresponsive to angle therapies must be done with greater confidence for a favorable outcome without progressive conjunctival deterioration. Implants have been successful for resistant primary congenital glaucoma, but new devices that are both smaller and more biocompatible will control IOP even more reliably. Efforts must continue to define the pediatric safety and efficacy of glaucoma drugs, which have been developed for adults, to make these agents more quickly available for children and to allow them to be used more confidently. Increased exposure of ophthalmology residents to the challenge and rewards of caring for children with glaucoma should be encouraged. Support must become more available to enable this work to be continued after training by the best of those who are motivated and possess the necessary skills, endurance, and a love of children.

10. 11. 12. 13.

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19. 20. 21. 22. 23. 24. 25. 26.

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56. Mungan NK, Wilson TW, Nischal KK, Koren G, Levin AV. Hypotension and bradycardia in infants after the use of topical brimonidine and beta-blockers. J AAPOS 2003;7:69-70. 57. Berlin RJ, Lee UT, Samples JR, et al. Ophthalmic drops causing coma in an infant. J Pediatr 2001;138:441-443. 58. Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. J AAPOS 2001;5:281-284. 59. Parrish RK, Palmberg P, Sheu WP, XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, maskedevaluator multicenter study. Am J Ophthalmol 2003;135:688-703. 60. Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Surv Ophthalmol 2002;47(suppl 1):S129-S132. 61. Enyedi LB, Freedman SF, Buckley EG. The effectiveness of latanoprost for the treatment of pediatric glaucoma. J AAPOS 1999;3:33-39. 62. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217-223. 63. Barkan O. Operation for congenital glaucoma. Am J Ophthalmol 1942;25:552-568. 64. de Luise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983;28:1-19. 65. Haas J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968;7:140-146. 66. Boughton WI, Parks MM. An analysis of treatment of congenital glaucoma by goniotomy. Am J Ophthalmol 1981;91:566-572. 67. Mandal AK, Gothwal VK, Bagga H, Nutheti R, Mansoori T. Outcome of surgery on infants younger than 1 month with congenital glaucoma. Ophthalmology 2003;110:1909-1915. 68. Shaffer RN. Prognosis of goniotomy in primary infantile glaucoma (trabeculodysgenesis). Trans Am Ophthalmol Soc 1982;80:321-325. 69. Russell-Eggitt IM, Rice NSC, Barrie J, Wyse RKH. Relapse following goniotomy for congenital glaucoma due to trabecular dysgenesis. Eye 1992;6:197-200. 70. Richardson KL, Ferguson WJ, Schaffer RN. Long-term functional results in infantile glaucoma. Transactions of the American Academy of Ophthalmology and Otolaryngology 1967;71:833836. 71. Walton DS. Goniotomy. In: Thomas JV, ed. Glaucoma Surgery. St. Louis: Mosby-Yearbook; 1992:107-121. 72. Joos KM, Shen JH. An ocular endoscope enables a goniotomy despite a cloudy cornea. Arch Ophthalmol 2001;119:134-135. 73. McPherson SD Jr. Results of external trabeculotomy. Trans Am Ophthalmol Soc 1973;71:163-170. 74. McPherson SD Jr, MacFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980;87:302-305. 75. McPherson SD Jr, Berry DP. Goniotomy vs external trabeculotomy for developmental glaucoma. Ophthalmology 1980;87:302-305. 76. Mandal A, Naduvilath TJ, Jayagandan DO. Surgical results of combined trabeculotomy-trabeculectomy for developmental glaucoma. Ophthalmology 1998;105:974-982. 77. Harms H, Dannheim R. Epicritical consideration of 300 cases of trabeculotomy ab externo. Transactions Ophthalmological Society of the United Kingdom 1969;89:491-499. 78. Shrader CE, Cibis GW. Trabeculotomy. In: Thomas JV, ed. Glaucoma Surgery. St. Louis: Mosby-Yearbook; 1992:123-131. 79. Mendicino ME, Lynch MG, Drack A, et al. Long-term surgical and visual outcomes in primary congenital glaucoma: 360 degrees trabeculotomy versus goniotomy. J AAPOS 2000;4:205-210. 80. Akimoto M, Tamihara H, Negi A, Nagata M. Surgical results of trabeculotomy ab externo for developmental glaucoma. Arch Ophthalmol 1994;112:1540-1544. 81. Filous A, Brunova B. Results of the modified trabeculotomy in the treatment of primary congenital glaucoma. J AAPOS 2002;6:182-186. 82. Beauchamp GR, Parks MM. Filtering surgery in children: barriers to success. Ophthalmology 1979;86:170-180. 83. Beck AD, Wilson WR, Lynch MG, Lynn MJ, Noe R. Trabeculectomy with adjunctive mitomycin C in pediatric glaucoma. Am J Ophthalmol 1998;126:648-657. 84. Freedman S, McCormick K, Cox T. Mitomycin C-augmented

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trabeculectomy with postoperative wound modulation in pediatric glaucoma. J AAPOS 1999;3:117-124. Mandal AK, Gothwal VK, Bagga H, Nutheti R, Mansoori T. Outcome of surgery on infants younger than 1 month with congenital glaucoma. Ophthalmology 2003;110:1909-1915. Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C. Ophthalmology 2003;110:2192-2197. Susanna R, Oltrogge EW, Carani JE, Nicolela MT. Mitomycin as adjunct chemotherapy with trabeculectomy in congenital and developmental glaucomas. J Glaucoma 1995;4:151-157. Sidoti PA, Belmonte SJ, Liebmann JM, Ritch R. Trabeculectomy with mitomycin-C in the treatment of pediatric glaucoma. Ophthalmology 2000;107:422-429. Agarwal HC, Sood NN, Sihota R, Sanga L, Honavar SG. Mitomycin-C in congenital glaucoma. Ophthalmic Surg Lasers 1997;28:979-985. Tannenbaum DP, Hoffman D, Greaney MJ, Caprioli J. Outcomes of bleb excision and conjunctival advancement for leaking or hypotonous eyes after glaucoma filtering surgery. Br J Ophthalmol 2004;88:99-103. Hill R, Heur D, Baerveldt G, Minckler D, Martone J. Molteno implantation for glaucoma in young patients. Ophthalmology 1991;98:1042-1046. Nesher R, Sherwood M, Kass M, Hines J, Kolker A. Molteno implants in children. J Glaucoma 1992;1:228-232. Beck AD, Freedman S, Kammer J, Jin J. Aqueous shunt devices compared with trabeculectomy with Mitomycin-c for children in the first two years of life. Am J Ophthalmol 2003;136:994-1000. Melamed S. Aqueous drainage implants. In: Thomas JV, ed. Glaucoma Surgery. St. Louis: Mosby-Yearbook; 1992:83-85. Coleman A, Smyth R, Wilson R, Tam M. Initial clinical experience with the Ahmed Glaucoma Valve implant in pediatric

patients. Arch Ophthalmol 1997;115:186-191. 96. Englert J, Freedman S, Cox T. The Ahmed valve in refractory pediatric glaucoma. Am J Ophthalmol 1999;127:34-42. 97. Morod Y, Donaldson C, Kim Y, Abdolell M, Levin A. The Ahmed drainage implant in the treatment of pediatric glaucoma. Am J Ophthalmol 2003;135:821-829. 98. Al-Torbaq AA, Edward DP. Delayed endophthalmitis in a child following an Ahmed glaucoma valve implant. J AAPOS 2002;6:123-125. 99. Al Faran MF, Tomey KF, Mutlaq FA. Cyclocryotherapy in selected cases of congenital glaucoma. Ophthalmic Surg 1990;21:794-798. 100. Wagle NS, Freedman SF, Buckley EG, Davis JS, Biglan AW. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology 1998;105:1921-1927. 101. Kirwan JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas. Ophthalmology 2002;109:316-323. 102. Plager DA, Neely DE. Intermediate-term results of endoscopic diode laser cyclophotocoagulation for pediatric glaucoma. J AAPOS 1999;3:131-137. 103. Autrata R, Rehurek J. Long-term results of transscleral cyclophotocoagulation in refractory pediatric glaucoma patients. Ophthalmologica 2003;217:393-400. 104. Gonzalez P, Caballero M, Liton PB, Stamer WD, Epstein DL. Expression analysis of the matrix GLA protein and VE-cadherin gene promoters in the outflow pathways. Invest Ophthalmol Vis Sci 2004;45:1389-1396. 105. Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003;299:1578-1581. 106. Vincent AL, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002;70:448-460.

APPENDIX
PRIMARY PEDIATRIC GLAUCOMAS
Primary congenital glaucoma Congenital newborn glaucoma (iridotrabeculodysgenesis) Infantile glaucoma (trabeculodysgenesis) Late-recognized infantile glaucoma Primary juvenile glaucoma Primary angle closure glaucoma Associated with systemic abnormalities SturgeWeber syndrome Neurofibromatosis Stickler syndrome Lowe oculocerebrorenal syndrome AxenfeldRieger syndrome SHORT syndrome Hepatocerebrorenal syndrome Marfan syndrome RubinsteinTaybi syndrome Infantile glaucoma with retardation and paralysis Oculodentodigital dysplasia Open angle glaucoma associated with microcornea and absent frontal sinuses

SECONDARY PEDIATRIC GLAUCOMAS

Traumatic glaucoma Acute glaucoma Angle concussion Hyphema Ghost cell glaucoma Glaucoma following angle recession Arteriovenous fistula Secondary to intraocular neoplasm Retinoblastoma Juvenile xanthogranuloma Leukemia Melanoma of ciliary body Melanocytoma Iris rhabdomyosarcoma Aggressive iris nevi Medulloepithelioma Secondary to uveitis Open angle glaucoma Angle blockage glaucoma Synechial angle closure Iris bombe with pupillary block

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PRIMARY PEDIATRIC GLAUCOMAS (CONTD)

Mucopolysaccharidoses Trisomy 13 Caudal regression syndrome Trisomy 21 (Down syndrome) Cutis marmorata telangiectatica congenita Warburg syndrome Kniest syndrome (skeletal dysplasia) Michels syndrome Nonprogressive hemiatrophy PHACE syndrome Soto syndrome Linear scleroderma Growth retardationalopeciapseudoanodontia optic atrophy (GAPO) syndrome Roberts pseudothalidomide syndrome WolfHirschhorn (4p-) syndrome Robinows syndrome Nail-patella syndrome Proteus syndrome Fetal hydantoin syndrome Cranio-cerebello-cardiac (3C) syndrome Brachmannde Lange syndrome Associated with ocular abnormalities Primary newborn glaucoma with iris anomalies Aniridia Congenital onset Acquired onset Congenital ocular melanosis Sclerocornea Congenital iris ectropion syndrome Peters syndrome Iridotrabecular dysgenesis (iris hypoplasia) Posterior polymorphous dystrophy Idiopathic or familial elevated episcleral venous pressure Anterior corneal staphyloma Congenital microcoria with myopia Congenital hereditary endothelial dystrophy Iridocorneal endothelial syndrome

SECONDARY PEDIATRIC GLAUCOMAS (CONTD)

Trabecular endothelialization Lens-related glaucoma Subluxationdislocation and pupillary block Marfan syndrome Homocystinuria WeillMarchesani syndrome Axial subluxation progressive myopia syndrome Ectopia lentis et pupillae Spherophakia and pupillary block Phacolytic glaucoma Aphakic glaucoma Lens tissue trabecular obstruction Pupillary block Glaucoma following infantile lensectomy Steroid glaucoma Secondary to rubeosis Retinoblastoma Coats disease Medulloepithelioma Familial exudative vitreoretinopathy Chronic retinal detachment Secondary angle closure glaucoma Retinopathy of prematurity Microphthalmos Nanophthalmos Retinoblastoma Persistent hyperplastic primary vitreous Congenital pupillary irislens membrane Topiramate Central retinal vein occlusion Ciliary body cysts Malignant glaucoma Glaucoma associated with increased venous pressure Cavernous or dural arteriovenous shunt Orbital disease Maternal rubella syndrome Intraocular infection Acute recurrent toxoplasmosis Acute herpetic iritis Endogenous endophthalmitis

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1. Review the stated learning objectives on the first page of the CME article and determine if these objectives match your individual learning needs. 2. Read the article carefully. Do not neglect the tables and other illustrative materials, as they have been selected to enhance your knowledge and understanding. 3. The following quiz questions have been designed to provide a useful link between the CME article in the issue and your everyday practice. Read each question, choose the correct answer, and record your answer on the CME REGISTRATION FORM at the end of the quiz. 4. Type or print your full name and address and your date of birth in the space provided on the CME REGISTRATION FORM. 5. Complete the Evaluation portion of the CME Registration Form. Forms and quizzes cannot be processed if the Evaluation portion is incomplete. The Evaluation portion of the CME Registration Form will be separated from the quiz upon receipt at JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS. Your evaluation of this activity will in no way affect the scoring of your quiz. NO PAYMENT REQUIRED. You may be contacted at a future date with a follow-up survey to this activity. 6. Send the completed form to: JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS CME Quiz, PO Box 36, Thorofare, NJ 08086. 7. Your answers will be graded, and you will be advised whether you have passed or failed. Unanswered questions will be considered incorrect. A score of at least 80% is required to pass. 8. Be sure to mail the CME Registration Form on or before the deadline listed. After that date, the quiz will close. CME Registration Forms received after the date listed will not be processed. CME ACCREDITATION SLACK Incorporated is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. SLACK Incorporated designates this educational activity for a maximum of one (1) hour category 1 credit toward the AMA Physicians Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. FULL DISCLOSURE POLICY Current ACCME policies state that participants in CME activities should be made aware of a faculty members significant financial or other relationships. Therefore, all faculty members participating in any SLACK Incorporated-sponsored activity are expected to disclose to the activity audience their relationships (1) with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial service(s) discussed in an educational presentation and (2) with any commercial supporters of the activity. (Such relationships can include grants or research support, employee, consultant, major stockholder, member of speakers bureau, etc.) The intent of this disclosure is not to prevent a presenter with a significant financial interest or other relationship from making a presentation, but rather to provide participants with information on which they can make their own judgments. It remains for the audience to determine whether the presenters interests or relationships may influence the presentation with regard to exposition or conclusion. In accordance with ACCME policies, the audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. This CME activity is primarily targeted to pediatric ophthalmologists and ophthalmic surgeons. There are no specific background requirements for participants taking this activity.

Primary Congenital Glaucoma: 2004 Update

1. Which one of the following childhood glaucomas has autosomal recessive inheritance: A. B. C. D. Glaucoma with a nevus flammeus. Glaucoma in Lowe syndrome. Primary congenital glaucoma. Glaucoma with Stickler syndrome.

2. A gene locus and the related responsible gene, CYP1B1, have been identified for which one of the following primary childhood glaucomas: A. B. C. D. Juvenile open-angle glaucoma. SturgeWeber syndrome. Primary congenital glaucoma. AxenfeldRieger syndrome.

3. The clinical success of a goniotomy for primary congenital glaucoma is related to: A. B. C. D. Lysis of peripheral anterior synechiae. Incision of Barkans membrane. Creation of a peripheral iridotomy. Relief of tension on thickened and compact trabecular beams.

4. Inspection of the corneas of a child with glaucoma may reveal bilateral Haabs striae, which are: A. A specific sign of primary congenital glaucoma. B. An indication that abnormal enlargement of the cornea occurred before 3 years of age. C. An indication of birth trauma. D. A sign of glaucoma associated with polymorphous dystrophy. 5. The essential examination step for determining the diagnostic type of childhood glaucoma and the patients candidacy for a successful goniotomy is: A. Early tonometry after the induction of general anesthesia. B. A positive family history for childhood glaucoma. C. Review of serial disc photographs. D. Gonioscopic examination of the filtration angle and the iris. 6. Goniosurgery has been found to be efficacious for which of the following conditions with childhood glaucoma: A. SturgeWeber syndrome and neurofibromatosis type 1. B. Primary congenital glaucoma and juvenile open-

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angle glaucoma. C. AxenfeldRieger syndrome and congenital iris ectropion syndrome. D. Congenital newborn glaucoma and Lowe syndrome. 7. Which of the following preoperative findings is a risk factor for failure of trabeculectomy for primary congenital glaucoma: A. B. C. D. Patient age younger than 1 year. History of failed goniosurgery. Corneal diameter greater than 13.5 mm. Absent ciliary body band on gonioscopy.

R E G I S T R A T I O N

F O R M

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Primary Congenital Glaucoma: 2004 Update

Black out the correct answers
1. 2. 3. 4. 5. A A A A A B B B B B C C C C C D D D D D 6. 7. 8. 9. 10. A A A A A B B B B B C C C C C D D D D D

8. For patients with primary congenital glaucoma whose conditions are refractory to goniosurgery and trabeculectomy, implant surgery should: A. Never be used before 18 months of age. B. Be used only when the globe diameter is greater than 20 mm. C. Be considered the next surgical procedure of choice. D. Always be used in conjunction with a cycloablation procedure. 9. Cyclodestructive procedures for childhood glaucoma are characterized by: A. Frequent immediate and long-term complications. B. Expected control of the intraocular pressure following the initial procedure. C. Infrequent loss of acuity following surgery. D. Unexpected development of cataracts, corneal opacification, or phthisis. 10. The visual prognosis of a child with primary congenital glaucoma is NOT significantly improved by: A. Early recognition of glaucoma. B. A less severe angle anomaly. C. Absence of central corneal breaks in Descemets membranes. D. Uncertain follow-up examinations following surgery.

Number of hours you spent on this activity _________________________ (reading article and completing quiz) Forms can be sent by fax to 856-853-5991 Deadline for mailing: For credit to be received, the envelope must be postmarked no later than October 15, 2005. Evaluation (must be completed in order for your CME Quiz to be scored) SEPTEMBER/OCTOBER 2004 Check the appropriate box below. Yes No 1. The content of the article was accurately described by the learning objectives. a. To review current and new information of clinical value related to primary congenital glaucoma, including its genetic etiology, defining clinical features, and medical and surgical treatments. ____ ____ b. To describe the clinical evaluation of patients with childhood glaucoma and the differential diagnosis of patients with signs and symptoms that suggest primary congenital glaucoma. ____ ____ c. To describe the terminology, epidemiology, and pathogenesis of primary congenital glaucoma. ____ ____ 2. This activity will influence how I practice ophthalmology. ____ ____ a. If you answered yes, list one new thing you learned as a result of this activity _______________________________________________. 3. The quiz questions were appropriate for assessing my learning. ____ ____ 4. Please rate the degree to which the content presented in this activity was free from commercial bias. No bias Significant bias 5 4 3 2 1 Comments regarding commercial bias _______________________________ ________________________________________________________________ 5. Please list topics you would like to see future CME activities address: _________________________________________________________.

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