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Congenital Aniridia Congenital Aniridia

Congenital Aniridia Congenital Aniridia

JOCGP 10.5005/jp-journals-10008-1086 REVIEW ARTICLE Congenital Congenital Aniridia

Dewang Angmo, Bhaskar Jha, Anita Panda Services, Dr RP Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

Correspondence: Anita Panda, Glaucoma Services, Dr RP Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India, e-mail: [email protected]

ABSTRACT

Aniridia is a rare bilateral condition that may have life-threatening associations. It occurs as a result of abnormal neuroectodermal development secondary to a in the PAX6 gene linked to 11p13. This gene controls the development of a number of structures, hence the broad nature of ocular and systemic associations.This article presents a review of congenital aniridia including epidemiology, genetics, clinical features, ocular and systemic associations and management modalities. Keywords: Aniridia, Subluxation, Glaucoma filtering surgery, PAX6 gene.

INTRODUCTION Mortality/Morbidity: All patients with aniridia are visually Aniridia (Greek, absence of ) is an uncommon hereditary handicapped for their whole life. Complications like bilateral congenital, panocular disorder affecting not only the and glaucoma reduce the vision furthermore. The patients with iris but also the , anterior chamber angle, , , Wilms’ tumor have a reduced span of life. Aniridia itself is not and as well with life-threatening associations.6 Its a lethal disorder. However, miscarriages and a stillborn child first description was given by Barrata in 1818.1 It is charac- have been the only results of a consanguineous mating between terized by profound hypoplasia of the iris (Figs 1A and B) in individuals with aniridia. It is possible that a homozygous frequent association with multiple ocular anomalies, such as mutation of the aniridia gene may be lethal. The morbidity of peripheral corneal pannus and keratopathy, foveal hypoplasia, aniridia is significant because of the decreased vision and diffuse retinal dysfunction as seen on electroretinography, . impaired acuity with nystagmus, cataract and and Genetics: Aniridia can occur as the following: .7 These defects, in combination, usually cause a formidable barrier to normal visual function. • Autosomal disorder: Dominant and recessive Often, the iris is vestigial (little more than a margin is • Deletion of the short arm of , including band present) and the appears to have colorless (only a larger p13 than normal) . It may be associated with systemic defects • Sporadic case. consisting of mental retardation, genital anomalies and Wilms’ In the majority of cases with familial inheritance, an tumor.1 autosomal dominant inheritance pattern with almost complete Epidemiology: Incidence reported from studies are 1:64,000 penetrance has been demonstrated.1 However, variations in to 1:96,000.1,2 Pedigree analyses have shown that two-thirds expression have also been seen to occur. Rarely, it may be of children with aniridia have an affected parent.1,3 transmitted in an autosomal recessive manner.4,5 Consanguineous

Figs 1A and B: (A) The peripheral iris rim and a clear view of the lens equator, (B) total aniridia with inferiorly subluxated lens

Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 1 Dewang Angmo et al

Table 1: Classification of aniridia aniridia is unknown. Because the iris pigment epithelium, the iris musculature, the retina, and the optic nerve are derived AN-1 is autosomal dominant, accounts for 66% of cases and has no from neuroectoderm, there may be a common embryologic systemic implications. Penetrance is complete, but expressivity origin for these anomalies. The pathogenesis may involve variable. defective formation or excessive regression of various layers AN-2 () is sporadic and accounts for 33%. It carries of the anterior segment caused by cellular or biochemical 30% risk of Wilms’ tumor developing before the age of 5 years. aberrations. This explains the combined anterior and posterior AN-3 () is autosomal recessive and accounts for the remainder. It is associated with mental handicap and cerebellar segment, neural ectodermal and mesenchymal defects. The iris ataxia. stroma is hypoplastic, indicating an altered third neural crest wave of mesenchyme. marriages have also been implicated in some studies.30 Of the Clinical Presentations sporadic cases of aniridia, two-thirds represent a new autosomal dominant condition. Regarding racial predisposition it has been 1. Aniridia alone 2. Aniridia with other systemic abnormalities seen that it does not exist. • Wilms’ tumor (20% cases) As an isolated ocular malformation, aniridia is an autosomal • Genitourinary abnormalities dominant disorder, which is caused by a mutation in the PAX6 • Mental retardation (paired box gene family) gene. 3. Aniridia with other ocular disorders Patients with aniridia who have a positive family history • Albinism are not at an increased risk for Wilms’ tumor. Two genetic loci • Ectopia lentis (50%) for aniridia have been identified: one (AN1) on chromosome • Spontaneous lens dislocation arm 2p and one (AN2) on chromosome 11 (Table 1). • Arcus juvenilis • Miller Syndrome (WAGR Complex, 11p Syndrome) • Cataract (50-85%) The association between aniridia and Wilms’ tumor is referred • Glaucoma (30-50%) to as Miller syndrome. Approximately 30% of patients with • Nystagmus sporadic aniridia develop Wilms’ tumor, usually before age 5 • years. It is reported that 1.4% of patients with Wilms’ tumor • Optic nerve hypoplasia (75%) have aniridia compared to one in 64,000 to one in 100,000 of • Pupillary membrane remnants. Age: The age at presentations is generally infancy when the the general population. Other associated features are parents notice abnormally large pupil. Sometimes they may genitourinary abnormalities, craniofacial dysmorphism, also complain poor vision and in early childhood hemihypertrophy and severe mental retardation. These patients along with nystagmus. Congenital glaucoma and aniridia usually also have poorly lobulated low-set ears, prominent noses, and are not associated at birth. The glaucoma develops at either the long narrow faces. The acronym WAGR (Wilms’ tumor, preteen or the teenage level. aniridia, genitourinary anomalies and mental retardation) Significant may occur before puberty. The risk describes some of the features of Miller syndrome. for cataract increases with age with lens opacities observed in Miller syndrome has been attributed to a deletion of band 50 to 85% of patients during the first two decades of life. 11p13. Patients with sporadic aniridia should undergo a The clinical presentations/features are discussed one by one: thorough physical examination and work-up by a family practitioner or pediatrician. Decreased Vision It is the most common symptom of the aniridia. Many series Gillespie Syndrome report that as many as 86% of affected individuals have 20/ Gillespie syndrome is the association of aniridia, cerebellar 100 vision or worse in the better eye. ataxia and mental retardation. It is autosomal recessive, The causes of poor vision are: occurring in approximately 2% of patients with aniridia. These • Foveal hypoplasia patients have anatomical defects in the cerebellum and other • Cataract parts of the brain, and they are not predisposed to developing • Glaucoma Wilms’ tumor. • A study of the PAX6 gene in Gillespie syndrome failed to • Nystagmus find a mutation, suggesting that abnormalities in the PAX6 gene • Aberrations of light have also been indicated as a cause of are not responsible for this syndrome. early poor vision in aniridia • Strabismus Pathophysiology • Ectopia lentis • Optic nerve hypoplasia. Primary developmental arrest of the neuroectoderm and a secondary alteration of all three neural crest waves of the Photophobia mesenchyme have been implicated in the pathogenesis of It is often present in affected patients and considered secondary aniridia. The exact defect in iris morphogenesis giving rise to to excessive light stimulation because of poor pupillary 2 JAYPEE JOCGP

Congenital Aniridia constriction. A characteristic facial expression in many children consists of narrowing of the palpebral fissure and furrowing of the brow.1

Iris Abnormalities Aniridia is still considered by some to be one of the colobomatous disorders.10 The abnormalities can be: • Complete absence; as seen on oblique illumination • Hypoplasia with irregular pupillary margins (atypical of pupil) • Only root of the iris; visible on gonioscopy. Iris abnormalities from almost total absence to mild hypoplasia of the iris may occur in affected individuals. Since Fig. 2: Total aniridia with superiorly subluxated cataractous lens a small portion of iris tissue can almost always be found on (oblique illumination) gonioscopic examination, the term “irideremia” better describes the condition than does aniridia.8,9 In addition, ocular and aniridia have been reported among individuals in the same usually during the first two decades of life. Subtle changes may family in the patients with aniridia. It is now known that iris be present in the lens at birth, and these can progress to thinning with a round; normal-appearing pupil may be found in significant opacities by middle age. family members of aniridics who, on further examination, show Types of cataracts are as following: evidence of characteristic corneal or lenticular involvement of • Anterior polar aniridia.9 • Pyramidal • Nuclear Glaucoma • Lamellar Congenital glaucoma with or without is rare in • Cortical. infants with aniridia, but the reported incidence of glaucoma Anterior and posterior lens opacities noted after birth do 11-16 later in childhood is 6 to 75%. not usually cause significant visual difficulty. Cortical, Although some infants have congenital angle anomalies subcapsular, and lamellar opacities often develop by the teenage (trabeculodysgenic anomaly) and early glaucoma, most years and may require lens extraction. Areas of clear space may occur later in childhood or early adulthood with be present in the cataractous lens, which allows for relatively closure of the iridocorneal angle. As a result of its delayed onset, good vision. In these patients, cataract surgery is best delayed, the clinical findings of , buphthalmos and Haab’s since the risks of glaucoma, developing or progressing, and striae are not found. Routine gonioscopic examination is foveal hypoplasia in aniridic outweighs the small potential important to detect anatomical changes in the angle structures for visual improvement. that may progress to angle-closure. During the first few years of life, the trabecular meshwork appears open and is not covered Ectopia Lentis by iris tissue. Grant and Walton believe that a progressive change in the angle structures occurs during the first two decades Ectopia lentis (Figs 1B to 3) has been reported in up to 56% of of life in those patients who will develop glaucoma.14 These patients with aniridia. Segmental absence of zonules is a changes consist of extensions of iris stroma, somewhat possibility but zonules are morphologically normal. The high resembling anterior , that reach across and attach incidence of ectopia lentis in aniridia may eventually be anterior to the filtration area of the trabecular meshwork. These attributed to defects in their molecular structure.18,19 iris extensions may eventually form a sheet that covers most of the filtration area in patients who will develop glaucoma. The Corneal Defects lOP elevation is presumed to occur at a later developmental stage, usually after the age of 5, or often in adolescence. The These can be seen in the following forms: severity of glaucoma is directly correlated with the extent of • Pannus (Fig. 3) progressive synechial angle closure by the pulled-up residual • Epithelial ulcers iris stump. Glaucoma secondary to intumescent lens changes • Arcus juvenilis or ectopia lentis (Fig. 1B) has been reported in aniridia. • Microcornea. Progressive corneal opacification and pannus occur in most Cataract patients, developing as early as age of 2 years. In majority of Cataracts (Fig. 2) occur frequently and at a young age in individuals aniridic keratopathy manifests in the first decade of aniridics.17 Lens opacities develop in 50 to 85% of patients, life as thickened irregular epithelium of the peripheral cornea. Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 3 Dewang Angmo et al

inferior retinal arteriole prior to its bifurcation with the disk size. While the normal disk/arteriole ratio in an adult eye is 14.6 ± 2.4, in hypoplastic disks the range is from 6.1 to less than 14.6.21 True aplasia of the optic nerve is although rare in the general population, but can be found in these patients. The association between poor retinal development and aniridia is not surprising, since the iris epithelium and musculature, and the retina, are derived from neuroectoderm.

Foveal Hypoplasia Foveal hypoplasia is a devastating feature of some cases of aniridia , with patients having nystagmus from an early age, and a visual acuity potential of only about 20/200. This should Fig. 3: Total aniridia with inferiorly subluxated lens with pannus and make the physician cautious about the visual results from 360° limbal stem cell deficiency cataract extraction or penetrating keratoplasty. In some patients, foveal hypoplasia may be so subtle that fluorescein angiography The epitheliopathy is typically accompanied by fine superficial may be necessary to demonstrate lack of the foveal avascular neovascularization (Fig. 3). Initially, fine radial vessels invade zone. Approximately, 75% of patients with aniridia have some the superficial layers of the peripheral cornea at the 6 and degree of optic nerve hypoplasia. The macula and optic nerve 12 o’clock positions, and then involve the whole circumference. are usually normal in patients with Gillespie syndrome. This process may initially involve epithelial and subepithelial layers, and later on may progress to involve the entire thickness Strabismus and Refractive Errors of cornea. Overtime subepithelial fibrosis and stromal scarring predisposes aniridic patients to recurrent erosions, corneal Strabismus is common in aniridic patients and mostly it is ulceration and chronic pain. This corneal “dystrophy” associated .1,15 Asymmetric visual loss in aniridic children may with aniridia may progress in a variable manner to completely occur from secondary to strabismus or cover the cornea, further compromise vision requiring corneal . High refractive errors are not uncommon and a transplantation. Since, the corneal abnormality is vascularized careful cycloplegic refraction is necessary in affected children. and inflamed, it cannot be included among the group of diseases This can be either or hypermetropia. Visual acuity may known as dystrophies. improve if clinical suspicion is high for amblyopia and Microcornea has been reported in association with appropriate optical correction and occlusion therapy begins 19 aniridia. early in the child’s visual development. The cause for the keratopathy is still not clear. It is thought to be resulting from dysfunction of limbal stem cells which Nystagmus originates from following observations: 1. The clinical morphology of the limbus in aniridic patients Pendular nystagmus is present in the majority of aniridics. Most has been shown to be abnormal. These patients lack the investigators believe that nystagmus is secondary to macular palisades of Vogt. These palisades serve as a marker for hypoplasia.13,17 The presence of nystagmus should alert the phy- corneal stem cell differentiation. The absence of this sician to the likelihood of foveal hypoplasia. The other causes important limbal structure suggests localization of the of nystagmus and poor vision in infancy are the characteristic epithelial abnormalities in aniridic patients to the limbus. iris defect and lack of foveal reflex in aniridia. Mild cases may 2. Healthy corneal epithelium is a stratified squamous be difficult to detect because of nystagmus, and corneal or lens epithelium that contains no goblet cells or other conjunctival opacities. specific elements. In aniridic patients, goblet cells are present in significant numbers in the peripheral corneal Differential Diagnosis epithelium. • Rieger syndrome with iridocorneal dysgenesis • Congenital coloboma of the iris Posterior Segment Disorder • Surgical iris coloboma It consists of optic nerve hypoplasia and foveal hypoplasia; • Hereditary iris hypoplasia optic nerve hypoplasia has rarely been reported in aniridic • Traumatic iris injury patients. True aplasia to even mild anomalies can be seen in the • Bilateral congenital patients with aniridia.20 Mild cases can be noted if careful • AGR triad—sporadic (bilateral or unilateral) aniridia, comparisons are made between the widths of the superior or genitourinary abnormalities and mental retardation

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• Corectopia Schirmer’s test: To find out associated dry eye. • ICE syndromes Ultrasound biomicroscopy:26 This is helpful in imaging, • Anterior cleavage syndromes especially in cases of opaque cornea. Ultrasound biomicroscopy • Colobomatous . imaging demonstrates shallow anterior chamber, irregular Investigations corneal thickness, hyperechoic lesion of the corneal stroma and Gonioscopy short, thin (ciliary body hypoplasia). It also shows peripheral residual iris stump. Ultrasound biomicroscopic Grant and Walton studied detailed angles assessement in aniridic imaging demonstrated that not only iris hypoplasia but also children.25 They noted that the angles of aniridic patients without ciliary body hypoplasia exist in aniridia. Anterior inclination glaucoma are free from iris attachments to the trabecular of the ciliary process was also found, which was thought to be meshwork and that the iris remnant is in the normal iris plane, at least partly responsible for the shallow anterior chamber. which is perpendicular to the axis of the eye. The angles of aniridic patients developing glaucoma show increased Impression cytology: To find out abnormal cells in the confluence of irregular attachments from the iris stroma to the epithelium. The presence of caliciform cells in corneal angle wall. They found that in most of the eyes the peripheral impression cytology defines the instability of the lacrimal film stump of iris gradually extended anteriorly to cover the filtration and an epithelial defect. portion of the trabecular meshwork (Figs 4A and B) eventually leading to synechial angle closure. Typically, later in childhood FFA the filtration area of the trabecular meshwork is covered by extension of abnormal iris tissue forward on to the trabecular Intravenous fluorescein angiography shows an early vascular meshwork, and therefore rising the intraocular pressures.25 loop in the remaining iris and late leakage from the pupillary Therefore, gonioscopy is must to find out the progression of margin; this may be a helpful finding in those cases where the angle closure glaucoma. If the iris stump is enlarging it is an diagnosis of aniridia is not apparent because of a round, more indication of prophylactic goniotomy. normal-appearing pupil. The posterior pole of aniridic patients shows persistence of vessels in the normally avascular zone of the macula.

Electrophysiological Tests The electroretinographic (ERG) signal amplitudes in patients with visual acuity of 20/60 or worse are abnormally low, while some patients with better acuities may have abnormally high a:b wave ratios. Prolonged latencies of the b wave peaks (implicit times) were also demonstrated in some patents; no ERG findings have been consistent enough to be useful diagnostically. The electrooculogram (EOG) has usually been normal.

Lab Studies Chromosomal deletion is detected by cytogenetic testing with the use of high-resolution banding. Submicroscopic deletions of the Wilms’ tumor gene are recognized with a fluorescent in situ hybridization (FISH) technique. High-resolution chromosome studies are obtained in sporadic cases to determine if there is a deletion of band 11p13. Serial renal ultrasound examinations are indicated in patients through age 7 years, especially for those with a deletion of band 11p13 or those with a negative family history of aniridia and normal chromosomes.

Histologic Findings Figs 4A and B: Gonioscopy of superior (A) and inferior (B) angle in aniridia showing peripheral stump of iris gradually extended anteriorly Histologically, small portions of the iris are always present; the to cover the filtration portion of the trabecular meshwork ciliary body is usually hypoplastic; and the anterior chamber

Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 5 Dewang Angmo et al angle may be normal, immature (i.e. incompletely developed), procedures for the treatment of aniridic glaucoma include the or malformed. Histopathologic examination of advanced cases following: of aniridia reveals only stubs of iris tissue that lack dilator and 1. Goniotomy is useful if performed before the development sphincter muscles, both neuroectodermal derivatives. In eyes of irreversible synechial closure. This early surgical therapy enucleated from older patients, extensive peripheral anterior has some risk to the crystalline lens and zonules because synechia that cause the iris stump to adhere to the posterior the surgery is performed from the anterior approach. It was corneal surface have been observed. reported by Barkan11 in the 1950s to control IOP in one Retinal lipoidal deposits in the peripheral retina have been patient with aniridia followed for 9 months. Since that time, reported in three patients suggests that the underlying defect however, multiple authors have reported disappointing may be in the metabolic pathway of fats, which results in storage outcomes with IOP control from goniotomy.25,27 of an abnormal lipid compound in the tissues. 2. Trabeculotomy may be safer than goniotomy since it relies on the posterior approach (ab externo). The tissues can be Systemic Investigations defined more clearly, and accurate surgery can be 41 Abdominal ultrasound: To rule out associated Wilms’ tumor performed. However, failures are common. Adachi et al found that in 12 eyes, which initially underwent Genitourinary referral: To find out associated anomaly trabeculotomy, 10 eyes (83%) obtained good IOP control IQ evaluation: For mental retardation. (defined as an IOP of 21 mm Hg or lower) after the first or second trabeculotomy with a mean follow-up of 9.5 years. TREATMENT In eyes that underwent other procedures first (i.e. goniotomy, trabeculectomy, trabeculectomy with trabeculotomy and Glaucoma Molteno implant), only three of 17 eyes (18%) obtained This is difficult and the prognosis guarded. Prophylaxis is good IOP control. They concluded that in eyes with aniridia directed toward the prevention of glaucoma, which includes and uncontrolled glaucoma, trabeculotomy is the preferred the following: initial surgical intervention. Their patient population, • Medical treatment with miotics however, developed glaucoma and underwent surgery at • Surgical separation of the iris from the trabecular meshwork an earlier age than most patients with aniridia. Of the 29 in selected cases. eyes that had glaucoma surgery, 14 eyes had glaucoma Medical treatment is frequently the initial approach, although surgery in the first year of life. This is inconsistent with the it is usually eventually inadequate. The medical treatment is general belief that many patients with aniridia develop glaucoma later in childhood (i.e. between ages 5 and 15) directed toward control of intraocular pressure, which includes the topical use of the following: because of progressive angle closure, and that glaucoma in infancy is rare in aniridic patients. The success rate reported Miotics: Miotics often are tried first; they improve aqueous by Adachi et al includes patients who had an IOP of 21 or outflow by contracting the ciliary muscle. However, the induced lower, with or without medications. In fact, only three of myopia may not be well-tolerated by young patients. Adrenergic 12 eyes (25%) treated with initial trabeculotomy achieved agonists, beta-blockers, and carbonic anhydrase inhibitors also IOP control without medications. Wiggins and Tomey27 did may be tried, but they often are ineffective long-term as the not have as much success with trabeculotomy in treating patient becomes refractory to them. Whenever a new medication aniridic glaucoma as the two eyes that underwent this is to be instituted, a trial should be performed, adding and procedure in their large series did not achieve successful removing only one medication at a time. IOP control. 3. Filtering procedures: Most surgeons operate for Beta-blockers trabeculectomy after a few attempts at goniotomy or • Sympathomimetics trabeculotomy. There is a greater danger of injury to the • Carbonic anhydrase inhibitors. crystalline lens and to disturbance of the vitreous along with vitreous loss in trabeculectomy because of the absence of Argon laser trabeculoplasty: It has been described in the patients iris. The surgical complications of direct lens injury, lens with aniridia. Nelson performed the procedure in four of his or vitreous incarceration in filtration sites can be 1 patients and all had good control of IOP. Poor results have considerably reduced with the use of intracameral 1 been obtained with laser trabeculoplasty. viscoelastic perioperatively. Several other studies, however, have reported poor IOP control after trabeculectomy in eyes Surgical Procedures with glaucoma associated with aniridia. Grant and Walton No convincing opinion exists as to which surgical procedure is reported poor IOP control (defined as pressure > 22 mm the treatment of choice for aniridic glaucoma; none has been Hg or the need for further surgery) in nine eyes of seven considered reliable and predictable in efficacy. Surgical patients treated with filtering surgery for glaucoma

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associated with aniridia. Nelson and Spaeth1 noted that in devastating complications, in that three eyes went on to five of 14 patients with glaucoma associated with aniridia, develop phthisis and one eye had a IOP remained uncontrolled after trabeculectomy. Okada and followed by phthisis.37 Wallace et al38 reported good IOP associates28 reported successful IOP control in young control in six of nine aniridic eyes treated with one or more aniridic patients after filtering surgery. In their study, 17 sessions of cyclocryotherapy, but over half of the eyes trabeculectomies and three trabeculectomies with treated experienced a decline in vision. Wiggins and mitomycin C were performed on 10 eyes of six patients Tomey27 reported a success rate of 25% in eyes with aniridic younger than 40 years, followed up for a mean of 14.6 glaucoma undergoing cyclocryotherapy, but they also months (range, 2-54 months). The mean duration of observed complications of cataract and phthisis. Kirwan et successful IOP control (defined as pressure lower than 20 al39 studied the use of diode laser cyclophotocoagulation in mm Hg with or without glaucoma medications) after filtering 77 eyes with uncontrolled pediatric glaucoma, including surgery was 14.6 months. five eyes with aniridia. They found that cyclodiode therapy 4. Glaucoma drainage devices: The choice of the techniques could provide effective IOP control with repeat treatments and the order, in which they are used, depends upon the in the pediatric glaucoma population, but the results are not peculiarities of the case and the perception of the surgeon. broken down to detail the aniridic patients in particular. Use of luminal occlusive suture, which can be removed later, They do comment that the aniridic patients did not have a has greatly improved the success of this procedure and higher rate of adverse events from cyclophotocoagulation enhanced the safety. Arroyave et al22 studied five patients compared with the other patients in their study, in contrast with aniridia (8 eyes) who underwent placement of to the findings of Wagle et al.37 In 1992, Wiggins and glaucoma drainage devices (7 eyes had Baerveldt implants Tomey27 reported the outcomes of glaucoma surgery in 17 and 1 a double plate Molteno implant) at an average age of eyes of 10 patients with aniridia. Forty-five procedures were 92 months and who were followed up for an average of 19 performed, and 11 eyes achieved IOP control with a mean months. Insertion of the glaucoma drainage implant was of 2.8 surgeries. They observed that trabeculectomy and the initial glaucoma surgery in six of the eight eyes in this cyclocryotherapy controlled the IOP in 9% (one of 11 eyes) study. They reported a success rate of 100% at 6 months and 25% (five of 20 eyes). and 88% at 1 year, with success defined as IOP < 21 mmHg, 6. Goniosurgery: Chen and Walton24,40 described a different with or without medications, with no visually devastating approach to aniridic glaucoma, using goniosurgery to complications or need for reoperation for glaucoma. The prevent the development of glaucoma in selected young patients experienced a decrease in average IOP from 35 patients with aniridia. They reported the use of a modified mm Hg preoperatively on an average of one glaucoma goniosurgery in 55 eyes of 33 patients with aniridia, all of medication to 14.9 mm Hg postoperatively with no eye whom met inclusion criteria (i.e. age greater than 1 year of drops. Vision remained stable in 25% of eyes, improved in life and the presence of particular gonioscopic findings). 63% of eyes, and decreased in the one eye that experienced Eyes that were felt to be good candidates for prophylactic a complication, retinal detachment.22 Wiggins and Tomey goniosurgery included aniridic eyes with greater than half also reported a high rate of success with glaucoma drainage the circumference of the posterior trabecular meshwork implants in advanced cases of aniridic glaucoma, in that covered by extensions of tissue from the peripheral iris, or 83% of the eyes that underwent this procedure had a eyes with progressive covering of the trabecular meshwork postoperative IOP < 21 mm Hg with no visually devastating by iris tissue. Eyes with aniridia and IOP mm Hg, or eyes complications. Many of these eyes had multiple prior IOP with less severe gonioscopic changes were not considered lowering procedures including trabeculectomy, good candidates for prophylactic goniosurgery. These trabeculotomy, laser trabeculoplasty, and cyclocryo- selected eyes that were felt to be at high-risk for the therapy.27 Thus, glaucoma drainage implants have a role in development of glaucoma because of progressive iris aniridic glaucoma and can be used as an initial surgical changes then underwent a modified goniosurgery. In this approach or in advanced cases with extensive prior surgical modified goniosurgery, a goniotomy knife was used to attempts at IOP lowering. remove the abnormal tissue spanning between the iris and 5. Cyclodestructive procedures have also been reported in the the trabecular meshwork. Care was taken to avoid injury to treatment of aniridic glaucoma, with limited success and the trabecular meshwork. Similar to goniosynechialysis frequent complications. Wagle et al37 described the surgery, this iris tissue is peeled away from the wall of the combined experience of two institutions in treating eight angle. Unlike goniotomy surgery, no incision through the eyes with aniridia with cyclocryotherapy. Two of eight eyes trabecular meshwork or into Schlemm canal is made. Chen (25%) were in the success group, defined as an IOP of 21 and Walton reported successful prevention of glaucoma in mm Hg or less without devastating complications or the 89% of patients treated with this prophylactic goniosurgery need for further glaucoma surgery. However, 50% of the (i.e. IOPs were < 22 mm Hg without medications at last eyes with aniridia treated with cyclocryotherapy developed follow-up). Additionally, the remaining 11% of patients who

Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 7 Dewang Angmo et al

underwent the procedure subsequently developed glaucoma Cataract with elevations of IOP that could be controlled with two Lens opacification may require cataract extraction. Before glaucoma medications or less. These results were based on operating, however, the ophthalmologist should attempt an average follow-up of 9.5 years, and there were no 40 refraction through the aphakic portion of the pupil if the lens is complications of surgery. This is in contrast to the subluxated. Either extracapsular or phacoemulsification surgery literature, which reports the incidence of glaucoma in may be used, depending on the stability of the zonules. aniridia to be about 50%. Glaucoma occurs in about half of all cases of aniridia and Management of Cataract is difficult to control with medications and surgery. Different • In-the-bag lens implantation in cases without lens dislocation surgical approaches have been attempted with only limited • In-the-bag IOL placement with intracapsular ring, when success. The most successful approach may be to prevent there is slight lens displacement aniridic glaucoma by performing goniosurgery in selected eyes • Lens extraction followed by correction, if the with progressive angle changes. For aniridic glaucoma, lens is grossly out of place. glaucoma drainage devices may be more successful in lowering Cataract extraction can be difficult and is often accompanied IOP and may have fewer complications than trabeculectomy by vitreous loss or further deterioration of the cornea. Dense and cyclodestructive procedures. cataract removal may result in some improvement in visual acuity. Lensectomy performed with an aspiration-cutting Corneal Problems instrument has been recommended. Capsule-supported 1. Penetrating keratoplasty may be indicated for that intraocular are not appropriate for patients with ectopia have opacified from pannus or in the cornea that becomes lentis. The use of intraocular lens implants in children is an sufficiently opaque. Surgical results from penetrating evolving field, and their use in patients with aniridia is still not keratoplasty are quite poor because of the abnormal stem very clear. cells and highly vascular host. Therefore, visual results are A combined approach for both glaucoma and cataractous marginal (one to two lines improvement in Snellen acuity) subluxated lens: In the bag limbal lensectomy with Ahmed and the prognosis is guarded because of rejection and glaucoma valve implantation. underlying amblyopia or other structural defects. Kremer et al reported recurrence of ocular surface abnormalities in Surgical Technique 91% of treated eyes and rejection of corneal grafts in 64% “In the Bag” Limbal Lensectomy42-44 of patients.30 Gomes documented graft failure in 100% of patients requiring repeat penetrating keratoplasty for The surgery is done through limbal ports, which are made using recurrent aniridic epithelial disease.31 20 G microvitreoretinal (MVR) blade, at 9 and 2’o clock 2. Keratolimbal allograft: These have been tried to address position for superiorly subluxated lens (Fig. 5). A third port is the problem of limbal stem cell deficiency. Results have made at 4 and 5’o clock position for the anterior chamber been found encouraging.32 maintainer. 3. Amniotic membrane transplantation is a very effective MVR blade is used to make an opening in the anterior lens procedure, although its effect is transitory, for restoring the capsule followed by hydrodissection with hydrodissection ocular surface integrity in patients with congenital aniridia cannula. Vitrectomy cutter of phacoemulsification system is and moderate limbal deficiency.23 used in I/A-Cut mode (in which irrigation and aspiration comes 4. Stem cell transplantation: Ocular surface stem cell before cutting). Vitrectomy probe is inserted into the anterior transplantation is a new therapy aimed at correcting stem chamber and then through the opening in anterior capsule into cell deficiency and has been highly successful in treating the lens (Fig. 6). the corneal disease associated with aniridia. The goal of Second port is used for irrigation cannula to maintain the surgery is to transplant normal stem cells from donor chamber. All the cortical matter is aspirated and then capsular eyes to the stem cell deficient aniridic eye. bag is taken with the help of vitrectomy cutter in the same mode. 5. A recent analysis of patients treated demonstrates the Now a thorough anterior vitrectomy is done in Cut-I/A mode establishment of a stable ocular surface in 90.5% of aniridic (Fig. 7). patients treated with appropriate immunosuppression. Of these patients, approximately one-third were spared the need Ahmed Glaucoma Valve Implantation for subsequent corneal transplantation. In those patient in which significant scarring had already occurred prior to stem Adequate surgical exposure is dependent on proper placement cell transplantation, corneal transplantation was performed of a traction suture. A 6-0 polyglactin (Vicryl) or silk traction and was successful in 85% of patients on appropriate suture on a spatulated needle is placed through superficial cornea immunosuppression. near the superior limbus and attached to the drape beneath the 6. Autologous serum has also been proved in these patients. eye.45

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Fig. 5: Superiorly subluxated lens Fig. 7: Viscoelastic is injected in the anterior chamber after a thorough anterior vitrectomy has been done

Fig. 6: MVR blade is used to make an opening in the anterior lens Fig. 8: Creation of subconjunctival space in the superotemporal capsule with anterior chamber maintainer in situ quadrant

A fornix-based conjunctival–Tenon capsule flap is created, With Ahmed valved implants, balanced salt solution must usually in the superotemporal quadrant to expose the be irrigated through the tube using 27 gauge cannula (Fig. 10), bed (Figs 8 and 9A). The flap is slightly elevated to allow for before the insertion into the anterior chamber, to ensure that blunt dissection between Tenon and episclera with blunt the valve opens properly. Westcott scissors. Radial relaxing incisions on one or both sides The external plate is then tucked posteriorly into the sub- of the conjunctival flap can improve surgical exposure. Tenon space (Fig. 9C) and is sutured to sclera with Whenever possible, the superonasal quadrant should be nonabsorbable 9-0 Prolene or nylon sutures through the anterior avoided to reduce the risk for strabismus/motility problems. positional holes of the plate, with the anterior border at 8 to The Ahmed drainage device, when placed in the superonasal 10 mm posterior to the limbus. quadrant, has also been shown to come within 1 mm of the The tube is then cut, bevel up, to permit its extension 2 to optic nerve.46 3 mm into the anterior chamber (Fig. 9C). It is best to maintain

Figs 9A to C: (A) Creation of subconjunctival space in the superotemporal quadrant, (B) insertion of plate into subconjunctival space and (C) cutting the tube to the appropriate length

Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 9 Dewang Angmo et al

Fig. 10: Priming of AGV—balanced salt solution in 27G cannula is used and it is injected through the end of the tube, a jet of BSS comes out of the valve which indicates it is primed

Figs 12A and B: (A) Colored photograph and (B) sketch: Showing tube insertion into the anterior chamber via the needle track, using nontoothed or specially designed tube-insertion forceps

through this needle track, is positioned between cornea and iris, without touching the cornea. The tube is then inserted into the anterior chamber via the needle track using nontoothed or specially designed tube- insertion forceps, but these generally are not necessary (Figs 12A and B). The tube can be secured to the sclera by using a nonabsorbable suture, such as 9-0 prolene or nylon. The anterior chamber may need to be deepened with balanced salt solution, or viscoelastic, via the paracentesis, and Figs 11A and B: (A) Colored photograph and (B) sketch: Showing anterior chamber entry through the limbal area with a 23 gauge or a 22 the tube is checked for proper position in the anterior chamber. gauge needle to the iris plane To avoid the potential complications related to tube erosion, a rectanglular patch of preserved sclera 5 × 7 mm is sutured over the anterior chamber at a normal depth achieved by the anterior the tube at the limbus (Figs 13A and B).49 Processed pericardium chamber maintainer. (Tutoplast), donor sclera, dura and fascia lata are also available The anterior chamber is then entered with a 23 gauge or a commercially for this purpose. It is also possible to use 22 gauge needle, parallel to the iris plane/stump (Figs 11A and B). The needle creates a watertight seal, preventing leakage autologous sclera or to place the tube under a partial-thickness around the tube, and thus reducing the risk for postoperative scleral flap similar to a trabeculectomy procedure. hypotony.47 The is then sutured back to its original position The angle at which the needle enters the anterior chamber using 8-0 Vicryl sutures (Fig. 14). Once again vitrectomy status is critical, because it is important that the tube, which will pass is checked, triamcinolone acetate can be used for this purpose.

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Figs 13A and B: (A) Colored photograph and (B) sketch: A rectangular patch of preserved sclera 5 × 7 mm is sutured over the tube at the limbus

Type 96G is used in the capsular bag in cases of sector iris defects up to 90°. Iris defects between 90° and 180° could be managed by inserting two such devices. One version consists of an artificial black iris attached to a standard polymethyl- methacrylate intraocular lens. This type of iris is best used when suturing of the lens is required to secure the lens in place. An advantage of this implant is that it is very stable.

Treatment of Photophobia, Nystagmus and Strabismus Patients should be given following things: • Tinted or iris contact lenses • Tinted spectacle lenses • Tinted intraocular lenses (IOLs).

Fig. 14: Conjunctiva is sutured back to its original position using 8-0 By the above measures, reducing the amplitude and vicryl sutures and the anterior chamber is formed after hydrating frequency of nystagmus is possible. the ports In cases of strabismus, patching of the favored eye is indicated to treat amblyopia. Cycloplegic refraction should be Anterior chamber is formed after hydrating the ports. performed, and appropriate correction should be given. Subconjunctival steroids and antibiotics are injected at the Strabismus surgery may be indicated at an early age to enhance completion of the procedure in a quadrant away from the surgical binocularity. site. Treatment of Refractive Errors, Iris Abnormalities Strabismus and Amblyopia Careful refraction and complete correction must be done to Various methods have been used to overcome the disabling decrease the risk of amblyopia. Usually, the potential visual effects of iris deficiency, including surgery, colored acuity in both eyes should be symmetrical. contact lenses,34 corneal tattooing35 and implantation of artificial When the vision is unequal without structural difference, irides.36 The most commonly used prosthetic iris devices are vigorous amblyopia exercises should be performed in the worst the Morcher aniridia IOL types 67F and 67G, the aniridia ring type 50C, and the coloboma diaphragm type 96G.33 Types 67F eye. and 67G are used in traumatic or congenital aniridia either in Binocularity can be achieved if macular hypoplasia is not the ciliary sulcus, if there is adequate capsular support, or severe. trans-sclerally sutured in the absence of capsular support. Strabismus surgery is indicated at an early age. Morcher 67G aniridia IOL and type 50C is designed for Consultations endocapsular implantation in cases of traumatic or congenital aniridia. For a total reconstruction of the missing iris, two rings • Banded chromosome analysis on the patient and both have to be implanted and turned against each other to form a parents complete ring, and then an additional foldable lens is inserted.33 • Linkage analysis when large families are available.

Journal of Current Glaucoma Practice, May-August 2011;5(2):1-13 11 Dewang Angmo et al

Genetic Counseling 18. Callahan A. Aniridia with ectopia lentis and secondary glaucoma: Genetic, pathologic and surgical considerations. Am J • All patients with aniridia should be referred for genetic Ophthalmol 1949;32:28-39. counseling. A full family history should be sought, with 19. David R, MacBeath L, Jenkins T. Aniridia associated with specific attention to ocular abnormalities, low vision, microcornea and subluxated lenses. Br J Ophthalmol genitourinary abnormalities, Wilms’ tumor and mental 1978;62:118-21. retardation 20. Ginsbwg J Buvc KE Cuesta MC. Aplasia of the optic nerve with aniridia. Ann Ophthalmol 1980;12:433-39. • A full physical examination should be performed 21. Blue JB. Bilateral aniridia. Am J Ophthalmol 5t 1922;483. concentrating on the genitourinary system. Imaging of the 22. Arroyave CP, Scott IU, Gedde SJ, Parrish RK 2nd, Feuer WJ. abdomen and brain, preferably MRI, is indicated Use of glaucoma drainage devices in the management of • Chromosome analysis of the patient and family and genetic glaucoma associated with aniridia. Am J Ophthalmol Feb analysis of the PAX6 gene should be performed 2003;135(2):155-59. 23. Lopez-Garcia JS, Rivas L, Garcia-Lozano I. Moderate limbal • Parents and close relatives should have a careful ocular deficiency in patients with congenital aniridia treated with examination performed amniotic membrane transplantation. Arch Soc Esp Ophthalmol. • Fluorescein angiography of the iris and may reveal Sep 2005;80(9):517-23. subtle abnormalities not found clinically, e.g. abnormalities 24. Walton DS. Aniridic glaucoma: The results of gonio-surgery to of the iris collarette and foveal avascular zone. prevent and treat this problem. Tr Am Ophth Soc 1986;50-70. 25. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Tr Am Ophth REFERENCES Soc 1974;72:207-29. 1. Nelson Lb, Spaeth Gl, Nowinski Ts, Margo Ce, Jackson L. 26. Okamoto F, Nakano S, Okamoto C, Hommura S, Oshika T. Aniridia: A review. Surv Ophthalmol 1984;28:621-42. Ultrasound biomicroscopic findings in aniridia. Am J 2. Shaw MW, Falls HF, Neel JV. Congenital aniridia. Am J Hum Ophthalmol 2004;137:858-62. Genet 1960;12:389-415. 27. Wiggins RE, Tomey KF. The results of glaucoma surgery in 3. Duke-Elder S. Normal and abnormal development: Congenital aniridia. Arch Ophthalmol 1992;110:503-05. deformities. System of . St Louis: CV Mosby 28. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and 1963;3:566. complications of mitomycin-C–augmented trabeculectomy in 4. Gillespie FD. Aniridia, , and oligophrenia. Arch refractory developmental glaucoma. Ophthalmic Surg Laser Ophthalmol 1965;13:338-41. 1999;30:473-80. 5. Falls HF. 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Variable expressivity keratopathy with keratolimbal allograft: A limbal stem cell in autosomal dominant aniridia by clinical electrophysiologlcal transplantation technique. Ophthalmology Jan 2003;110(1): and angiographic criteria. Am J Ophthalmol 1980;89:531-39. 125-30. 10. Pagon RA. Ocular coloboma. Surg Ophthalmol 1981;25: 33. Mavrikakis I, Mavrikakis E, Syam PP, Bell J, Casey JH, Casswell 223-36. AG, Brittain GP, Liu C. Surgical management of iris defects 11. Barkan O. Goniotomy for glaucoma associated with aniridia. with prosthetic iris devices. Eye 2005;19:205-09. Arch Ophthalmol 1953;49:l-5. 34. Burger DS, London R. Soft opaque contact lenses in binocular 12. Callahan A. Aniridia with ectopia lentis and secondary glaucoma: vision problems. J Am Optom Assoc 1993;64:176-80. Genetic, pathologic and surgical considerations. Am J 35. Burris TE, Holmes-Higgin DK, Silvestrini TA. Lamellar Ophthalmol 1949;32:28-39. intrastromal corneal tattoo for treating iris defects (artificial iris). 13. Elsas FJ, Maumenee IH, Kenyon KR, et al. Familial aniridia Cornea 1998;17:169-73. with preserved ocular function. Am J Ophthalmol 1977;83: 36. Thompson CG, Fawzy K, Bryce IG, Noble BA. Implantation of 718-24. a black diaphragm intraocular lens for traumatic aniridia. J 14. Grant WM. Walton DS. Progressive changes in the angle in Cataract Refract Surg 1999;25:808-13. congenital aniridia with development of glaucoma. Am J 37. Wagle NS, Freedman SF, Buckley EG, et al. Long-term outcome Ophthalmol 1974;18:842-47. of cyclocryotherapy for refractory pediatric glaucoma. 15. Lewallen WM. Aniridia and related iris defects. Arch Ophthalmology 1998;105:1921-27. Ophthalmol 1958;59:831-39. 38. Wallace DK, Plager DA, Snyder SK, et al. Surgical results of 16. Shaffer RN, Cohen JS. Visual reduction in aniridia. J Ped secondary glaucomas in childhood. 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