MAJOR REVIEW. Pediatric Keratoplasty

Transcription

1 SURVEY OF OPHTHALMOLOGY VOLUME 54 NUMBER 2 MARCH APRIL 2009 MAJOR REVIEW Pediatric Keratoplasty M. Vanathi, MD, 1 Anita Panda, MD, FICS, FAMS, MRCOphth, 1 Sujith Vengayil, MD, 1 Zia Chaudhuri, MS, FRCS, 2 and Tanuj Dada, MD 1 1 Cornea and Refractive Surgery Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India; and 2 Pediatric Ophthalmology Services, Maulana Azad Medical College, New Delhi, India Abstract. Penetrating keratoplasty in children is a highly challenging and demanding procedure associated with a high risk of graft failure or failure of amblyopia therapy in clear grafts. Nonetheless, keratoplasty remains the surgery of choice for the management of pediatric corneal stromal opacities or edema. Allograft rejection, graft infection, corneal neovascularization, glaucoma, trauma to the anterior segment, vitreous pathology, and additional surgical interventions, especially those related to glaucoma management, are important risk factors. Successful penetrating keratoplasty in children requires careful preoperative evaluation and selection of patients follow-up by well-motivated parents, an expert corneal transplant surgeon, and a devoted pediatric ophthalmologist. (Surv Ophthalmol 54: , Ó 2009 Elsevier Inc. All rights reserved.) Key words. acquired non-traumatic opacity acquired traumatic opacity anterior segment dysgenesis congenital corneal opacity congenital glaucoma congenital hereditary endothelial dystrophy corneal transplantation endothelial rejection keratoplasty in children pediatric keratoplasty Peter s anomaly I. Introduction Congenital eye disorders, although infrequent, are important causes of childhood blindness. Visual deprivation due to corneal opacification can lead to long-term changes in the central nervous system. 161 In order to achieve optimal visual results and avoid visual-deprivation amblyopia, corneal transplantation must be performed in the early months of life. Penetrating keratoplasty in children has a higher rate of graft failure and a poorer visual prognosis than adult keratoplasty. Improved understanding of intraoperative and postoperative problems has resulted in more successful pediatric corneal grafts. Pediatric keratoplasty was performed infrequently prior to the mid 1970s 18 and was recommended only in pediatric patients with bilateral corneal involvement. 159 Technical advances, however, have now lowered the age at which keratoplasty is performed and indications have increased with improvement in surgical techniques and therapies. Special problems in corneal transplantation in children include difficult preoperative evaluation; intraoperative problems such as low scleral rigidity, increased fibrin reaction, and positive vitreous pressure; the need for frequent examinations under anesthesia for postoperative follow-up evaluations; frequent loosening of sutures necessitating replacement/early removal; increased risk of rejection and infections; and the difficulties with repeated refractive error assessments, and reversal of amblyopia. Ó 2009 by Elsevier Inc. All rights reserved /09/$--see front matter doi: /j.survophthal

2 246 Surv Ophthalmol 54 (2) March--April 2009 VANATHI ET AL Even with increased anatomic success of pediatric corneal grafts, visual rehabilitation remains a concern. In developing nations an increasing number of grafts are performed for infectious keratitis, postinfectious keratitis corneo-iridic scars, or keratomalacia. Measures to maintain clear graft and successful visual rehabilitation following keratoplastyare required to achieve a successful anatomical and functional outcome. This review of corneal grafting in infants and children evaluates the various indications, as well as factors affecting graft prognosis, technique, special problems, and outcome of pediatric keratoplasty. II. Indications Pediatric corneal opacities have been classified into three categories: 133,134 congenital, traumatic, and acquired non-traumatic. Indications for pediatric corneal transplantation (Table 1) vary widely; the proportion of keratoplasties performed for congenital indications range from %, for acquired non-traumatic conditions they range from %, and for acquired traumatic conditions they range from 6--29%. 1,31--34,95,134 Al-Ghamdi et al 5 propose a newer classification that takes into account visual prognosis in pediatric keratoplasty: A. Congenital opacities--congenital hereditary endothelial dystrophy (CHED) B. Congenital opacities--non-ched B1. Frequently associated with glaucoma B2. Infrequently associated with glaucoma TABLE 1 Indications for Pediatric Keratoplasty A. Congenital opacities: Congenital hereditary endothelial dystrophy B. Congenital opacities: Non-CHED 1. With associated glaucoma a. Congenital glaucoma b. Peter s anomaly c. Other anterior segment dysgenesis 2. Without glaucoma a. Sclerocornea b. Dermoid c. birth trauma d. Metabolic diseases e. Keloid f. Aniridia C. traumatic D. non-traumatic a. Keratoconus b. Infectious keratitis with or without perforation c. Postinfectious corneal/corneo-iridic scars d. Keratomalacia C. traumatic D. non-traumatic Developmental influences affecting anterior segment differentiation between the 6 th to 16 th week of gestation result in congenital corneal opacities. 110,162 These influences may be genetic, infectious, traumatic, toxic or a combination of these factors. The prevalence of congenital corneal opacities is approximately 3/100,000. With congenital glaucoma included this rises to 6/100, ,142 The most common primary cause of congenital corneal abnormalities in the developed nations is Peter s anomaly (40.3%), followed by sclerocornea (18.1%), dermoid (15.3%), congenital glaucoma (6.9%), microphthalmia (4.2%), birth trauma, and metabolic disease (2.8%). 110 A. CONGENITAL OPACITIES: CHED CHED presents as bilaterally symmetrical diffuse corneal opacification and edema of varying degree. 39,74,99,158 The stromal opacity is thought to result from terminal misdifferentiation of the endothelial cells. Corneal clouding in the autosomal recessive type of congenital hereditary endothelial dystrophy is present at birth or within the neonatal period. Nystagmus is often present, and there are no other signs or symptoms. The autosomal recessive form is more prevalent in countries where consanguineous marriage is frequent. 6,115 Patients with the autosomal dominant type of endothelial dystrophy usually have clear corneas early in life, with corneal opacification being slowly progressive and nystagmus infrequent. Photophobia and epiphora, may be the first indications of the dystrophy. As the opacity develops later in the dominant type, infantile or autosomal dominant hereditary endothelial dystrophy have been considered to be more appropriate names for this variant. 64 CHED may be associated with congenital glaucoma. Deafness may accompany the autosomal dominant type. Corneal sensitivity is usually normal. On slit-lamp evaluation, Descemet s membrane is thickened and, on retroillumination, has a beaten copper appearance. Increase in thickness of Bowman s layer has also been reported. 75 Widespread edema with hyaline degeneration, superficial vascularization, scarring, and calcium deposits may occur. 99 Band keratopathy and spheroidal degeneration have also been reported in some cases of CHED. 115 The most important pathologic finding is the increased thickness of the non-banded portion of the Descemet s membrane. The autosomal dominant (AD) form of CHED has been mapped to the pericentromeric region of chromosome Mutations in the SLC4A11 gene cause autosomal recessive CHED. 65,77

3 PEDIATRIC KERATOPLASTY 247 The primary defect in patients with CHED is a degenerated and dysfunctional corneal endothelium, characterized by an increased permeability and an abnormal and accelerated Descemet s membrane secretion. 9,70 The underlying pathophysiological mechanism may be related to an abnormal endothelial barrier function, leading to secondary swelling of the stroma and epithelium. Histopathologic examination shows an absence of the endothelial cell layer with presence of a variably thick collagenous layer posterior to the anterior banded zone of Descemet s membrane. CHED is not generally thought to be associated with other ocular abnormalities. An ultrasonographic study of 20 eyes (10 patients) with CHED showed ocular enlargement similar to that occurring in uncomplicated axial myopia with an inverse relationship between the degree of enlargement and the visual acuity or visual result following penetrating keratoplasty. This suggests that infantile corneal edema sufficient to cause stimulus deprivation may result in abnormal enlargement of the globe. 143 The dystrophy may be misdiagnosed as congenital glaucoma. Birth trauma, mucopolysaccharidosis, and intrauterine infections should also be considered in the differential diagnosis. Visual acuity may be surprisingly better than the clinical appearance of the eyes, 117,131 but CHED can lead to ambylopia. Penetrating keratoplasty in congenital hereditary endothelial dystrophy is moderately successful, and graft survival and visual outcome is better in cases with delayed onset. B. CONGENITAL OPACITIES: NON-CHED The non-ched congenital corneal opacities can be subdivided into those that are frequently associated with glaucoma and those that are infrequently associated with glaucoma. 1. Frequently Associated with Glaucoma a. Congenital Glaucoma The causes of congenital corneal opacification associated with glaucoma include congenital glaucoma, Peter s anomaly with glaucoma, and CHED with glaucoma. CHED with congenital glaucoma occurs infrequently. 89,100 The combination of CHED or Peter s anomaly with congenital glaucoma 100 originates from defects in the neural crest cell contribution with abnormal neural crest cell migration, resulting in congenital glaucoma and neural crest cell differentiation, which results in CHED. 16 Histopathological evaluation reveals absence of the endothelial layer with variably thickened collagenous posterior nonbanded zone of the Descemet s membrane. Abnormalities of crest cell migration, proliferation, and differentiation contribute to disorders of the corneal stroma, endothelium, trabecular meshwork, and iris. The coexistence of different anterior segment anomalies has been termed combined mesenchymal dysgenesis. 100 Concurrent management of glaucoma and corneal opacification is sometimes required. CHED should be suspected if persistent and total corneal opacification fails to resolve after normalization of IOP. 89,106 Corneal decompensation due to congenital glaucoma is a rare indication for corneal transplantation in childhood 13,18,31,42,44,46,134,161 and usually confers a poor prognosis. Preoperative control of intraocular pressure is required before penetrating keratoplasty. Cyclodestructive procedures for control of pharmacologically resistant elevated intraocular pressure (IOP) 46 may be required to reducing the size of eyes with buphthalmos before performing keratoplasty. Mitomycin C trabeculectomy and glaucoma drainage implant surgery are other options in treatment of postkeratoplasty glaucoma. These penetrating surgeries may predispose to graft failure by disruption of blood--aqueous barriers. The simultaneous placement of glaucoma-filtering implant at the time of primary penetrating keratoplasty has been described. 15 Reports of corneal grafting for congenital glaucoma after treatment with cyclophotocoagulation 46 and glaucoma filtering implants have appeared infrequently. 5 b. Peter s Anomaly Peter s anomaly is one of the most common congenital corneal opacification encountered in corneal practice. It is bilateral in approximately 80% of the cases. This congenital malformation of the anterior segment is characterized by a central corneal opacity with corresponding defects in the posterior stroma, Descemet s membrane, and endothelium. Iris strands typically arise from the collarette and extend to the periphery of the corneal leucoma. The peripheral cornea is usually relatively clear. Peter s anomaly is associated with a wide range of congenital ocular and systemic abnormalities and commonly occurs as a sporadic disorder. A few cases have autosomal recessive and autosomal dominant inheritance. 36,110 The co-existing glaucoma can complicate the graft and visual prognosis in the management of these cases. The extent of ocular involvement varies from mild to severe. 149 Mild disease is defined by the presence of normal iris and lens. Moderate disease is defined by the presence of central iridocorneal adhesions (anterior synechiae), or other iris defects such as

4 248 Surv Ophthalmol 54 (2) March--April 2009 VANATHI ET AL atrophy, abnormal vasculature, or coloboma. Severe disease is defined by the presence of corneolenticular adhesion, or by the presence of corneal staphyloma with or without corneal adhesions. 167 Peter s anomaly has been associated with congenital anterior and posterior segment anomalies as well as systemic abnormalities. 165 Glaucoma is the most common of the ocular anomalies, observed in % of eyes, and is considered the most difficult to control among all the childhood glaucoma types. Peter s anomaly patients are at risk for developing glaucoma even if they present without glaucoma at the outset. Eyes presenting with glaucoma usually are found to have the lens cataractous with or without adherence to the posterior cornea. Microphthalmia occurs in % of the eyes. Iris abnormalities, chorioretinal coloboma, staphyloma, retinal dysplasia, cataract, ptosis, persistent hyperplasic primary vitreous, optic nerve hypoplasia, foveal hypoplasia, macular pigment epitheliopathy, and colobomas are sometime associated. Systemic anomalies, seen in 60% of the patients, include developmental delay, central nervous system defects, craniofacial abnormalities, microcephaly, seizure disorder, fetal alcohol syndrome, and autism. Congenital cardiac malformations, skeletal deformities, genitourinary malformations, ear defects, as well as cleft lip and palate may also be present. Histopathological evaluations 132 indicate a central absence of Bowman s membrane and iris synechia to the periphery of the central corneal leucoma. Extensive keratolenticular adhesions with retrocorneal fibrous tissue fill the central defect of endothelium and Descemet s membrane, suggesting a late anterior displacement of the normally developed lens leading to a secondary endothelial degeneration. Attenuated endothelium and abnormally composed Descemet s membrane indicates primary dysgenesis of the endothelium. Extensive defects of posterior stroma with anterior stromal disorganization and endothelial metaplasia suggest dysgenesis of both the keratocytic and endothelial mesoderm. Although a unified pathogenic mechanism is not consistently applicable, either primary or secondary dysgenesis of the corneal mesoderm may be responsible for the occurrence of Peter s anomaly. c. Other Mesenchymal Dysgenesis The terms mesenchymal dysgenesis and anterior chamber cleavage syndrome refer to a spectrum of congenital ocular disorders ranging from posterior embryotoxon in its simplest form to Peter s anomaly at its most complex. Other conditions that are included in this spectrum of congenital ocular disorders are Axenfeld anomaly, Reiger anomaly, and syndrome and posterior keratoconus. 157 All patients with the Axenfeld-Reiger (A-R) syndrome, irrespective of their ocular manifestations, share the same general features: a bilateral developmental disorder of the eyes, a frequent family history, no sex predilection, frequent systemic developmental defects, and a high incidence of associated glaucoma. The age at which A-R syndrome is diagnosed varies from birth to late childhood, most commonly early infancy or childhood. Clinical features include peripheral anterior segment anomalies and iridocorneal abnormalities with or without other associated ocular and systemic anomalies. 2. Infrequently Associated with Glaucoma a. Dermoids Dermoids are classified as choristomas, and the opacification is usually peripheral. They present as round or oval, whitish or yellowish cones protruding on the anterior surface of the eyeball. They consist of ectodermal (keratinized epithelium, hairs, sebaceous and sudoriferous glands, nerves, smooth muscles, and, less frequently, teeth) and mesodermal elements (fibrous tissue, fat, blood vessels, and cartilage) combined in different proportion. 124 Indications for surgery are astigmatism and cosmesis. Ultrasound biomicroscopy (UBM) evaluation can be helpful in determining the depth of dermoids. Most cases may require simple excision with or without amniotic membrane or only lamellar keratoplasty. b. Metabolic Causes Most metabolic causes are of autosomal recessive inheritance. The corneas are usually clear at birth, followed by progressive opacification. Corneal clouding may be a part of many metabolic disorders, including those involving amino acids, lipids, carbohydrates, purines, and so forth. Systemic mucopolysaccharidoses (MPS) are lysosomal storage disorders that affect the glycosaminoglycan catabolism. Seven types of MPS have been described, based on the enzymes affected and the clinical manifestations. Because cornea contains glycosaminoglycans, corneal clouding is a part of many of these MPS syndromes. MPS I-H (Hurler), MPS I-S (Scheie), MPS- IV (Morquio), MPS VI (Maroteaux-Lamy) and MPS VIII (Sly) are associated with variable amounts of corneal clouding. Hurler s syndrome and Scheie s syndrome share the deficiency of same enzyme (alpha-- iduronidase). The corneal clouding in the former is more diffuse and central, whereas the latter has peripheral clouding progressing centrally with age. 118 Open-angle glaucoma may occur in both. 105,130 Intelligence, stature, and lifespan are

5 PEDIATRIC KERATOPLASTY 249 increased in Scheie s syndrome compared to Hurler s syndrome. Pigmentary retinopathy and optic atrophy are complicate the visual prognosis in these syndromes. 43 Morquio syndrome and Maroteaux-Lamy syndrome presents with marked dwarfism, chest wall deformities, cardiovascular abnormalities, and corneal clouding. There is diffuse ground glass corneal stromal opacification in Morquio syndrome 155 and is of varying severity in Maroteaux-Lamy syndrome. The more recently described MPS VIII (Sly syndrome) also has corneal clouding (mild to severe), papilledema, and retinal pigmentary degeneration. 43 c. Sclerocornea Sclerocornea is a primary, nonprogressive anomaly in which scleralization of part or all of the cornea occurs. In the peripheral type of sclerocornea, the affected area is vascularized with peripheral arcades of superficial scleral vessels. The corneas in sclerocornea may be smaller in diameter with diffuse anterior stromal opacification and may be associated focal nebular densities and extensive superficial vascularization. Sclerocornea can present either as a primary anomaly or in association with cornea plana 17,40,72 and has been reported to occur in isolation or with associated ocular and systemic anomalies. 48,55,60,81,88,113,116,138 Histopathologically, vascularized collagenous tissue occupies the anterior one-fourth of the corneal stroma, with bundles of collagen fibrils nm in diameter. Descemet s membrane shows abnormal anterior lamination. 102 The results of keratoplasty in sclerocornea have not been encouraging. 37,52,163,172 Frucht-Pery 45 observed reduced nystagmus excursions and attainment of reading vision in two children with bilateral sclerocornea after unilateral corneal transplants at the ages of 4.5 and 16 years, respectively. d. Birth Trauma Birth trauma caused by forceps blade placement across the orbit and globe during delivery can result in blunt trauma and rupture of Descemet s membrane. Descemet s tears in birth trauma are usually central and unilateral in a vertical or oblique pattern. Diffuse stromal and epithelial edema due to birth trauma usually clears within weeks or months. The residual high astigmatism necessitates penetrating keratoplasty when contact lens wear is not possible. 11 e. Corneal Keloid Congenital corneal keloids are a rare entity that present as white glistening benign protuberant masses, appearing as single, solitary nodules or involving the entire corneal stroma. Keloids occur more frequently in males than females. Congenital keloids usually occur in the presence of other ocular anomalies, 150 including peripheral iridocorneal adhesions, anterior segment mesenchymal dysgenesis, aniridia, and cataract with subluxated lenses. Corneal keloids also have been described in children with Lowe s syndrome, Rubinstein Taybi syndrome, and fibrodysplasia ossificans progressive. Corneal keloid may mimic a limbal dermoid. Congenital keloids have been attributed to undifferentiated hyperplasia of opaque corneal and scleral tissue. Corneal keloid in Lowe s syndrome is major cause of visual disability in children over the age of 6 or 7 years in whom glaucoma and cataract have treated surgically. In cases of Lowe s syndrome, it has been suggested that amino acids filter into the cornea from abnormal vessels or that substances from within the anterior chamber go through a defective endothelium. Histopathologically, keloids are characterized by a haphazard arrangement of fibroblasts, collagen bundles, and blood vessels. f. Aniridia Absence of iris tissue is the sentinel finding, but additional ocular structures are often affected. Mutations of the Pax 6 gene have been identified also in families affected by aniridia. Corneal lesions in aniridia include peripheral pannus and epithelial abnormalities that may advance centrally, resulting in the need for penetrating keratoplasty. 79 Aniridic keratopathy remains a significant cause for visual loss. Poor vision in aniridic eyes may be the result of macular hypoplasia, nystagmus, amblyopia, cataracts, glaucoma, and corneal disease, termed aniridic keratopathy. Congenital aniridia rarely requires keratoplasty at an early age except when associated with significant opacification or with glaucoma leading to corneal decompensation. Penetrating keratoplasty alone is not adequate treatment for severe stromal scarring in aniridia, as it does not treat the underlying epithelial disease, which requries limbal stem cell transplantation. 57,76,82,139 g. Posterior Polymorphous Dystrophy (PPMD) PPMD 56 is autosomal dominant in inheritance with high penetrance. It is a bilateral disease, but may be asymmetrical. Although it typically occurs in the second or third decade of life, it may also be congenital or develop early in life. It may be seen in Alport syndrome. The corneal lesions in PPMD are the level of the Descemet s membrane and endothelium and may be vesicle-like, bands, or diffuse opacities. The vesicular lesions that are the hallmark

6 250 Surv Ophthalmol 54 (2) March--April 2009 VANATHI ET AL of PPMD are seen as a transparent cyst with a surrounding gray halo at the level of the Descemet s membrane and the endothelium, appearing in the entire cornea or as isolated lesions. Sinous brad bands and gray thickened Descemet s membrane may be seen. Endothelial guttae can also be seen in PPMD. These may produce corneal edema ranging from severe stromal edema to bullous keratopathy. Peripheral anterior synechia, raised intraocular pressure, corectopia, calcific band keratopathy, hydroxyapatite deposition in the corneal stroma, and posterior keratoconus occur in PPMD. PPMD may be confused with iridocorneal endothelial syndrome (ICE), but the sporadic nature and unilateral involvement distinguishes ICE. The characteristic pathologic changes in PPMD are the appearance of epithelial like cells on the posterior corneal surface. C. ACQUIRED TRAUMATIC Penetrating injuries remain an important cause of acquired corneal scarring in the pediatric age group. 159 traumatic corneal scars are the indication for 8--26% of penetrating keratoplasties in children. 5,20,32,33,95 The most important issue to be considered in the timing of keratoplasty for penetrating trauma is the threat of amblyopia. D. ACQUIRED NON-TRAUMATIC One of the most common causes of acquired corneal scarring in children under the age of 6 years is Herpes simplex keratitis. 159 In developing nations, other infectious keratitides remain the main indications for pediatric keratoplasty. 1,32,123, Penetrating keratoplasty for post keratomalacia corneal melts are also common. 21,126,148 Keratomalacia from vitamin A deficiency as an important cause of preventable corneal opacification has a reported incidence varying between 8% and 27.3% 71,108,109,128 and remains a major cause of pediatric ocular morbidity and severe visual impairment in developing countries. 108,109,127 Ocular surface changes include xerosis, keratinised plaques, stromal punched out ulcers, and focal or diffuse stromal melting. 127 Malnutrition, systemic diseases, and lack of immunization predispose to keratomalacia. Acute corneal melting results from the ocular pathological changes in severe vitamin A deficiency. 128 non-traumatic corneal opacities were the major indication (71.32%) for pediatric keratoplasty in a tertiary care center in north India, 32 which is in contrast to series from the western world. Infectious keratitis (72.6%) and keratomalacia (27.36%) constituted the major causes for keratoplasty. Fever, diarrhea, and malnutrition were the commonly associated systemic presentations in the acquired non-traumatic group in this large retrospective series. Poverty and low socioeconomic status prevalent in developing nations predispose those individuals to corneal infection and malnutrition. 32,122,146,148 Keratomalacia in children is hastened by protein-caloric malnutrition precipitated by childhood communicable diseases such as measles. 129 III. Technique Pediatric keratoplasty was considered previously to be contraindicated because of its technical challenges due to a low scleral rigidity and forward displacement of lens--iris diaphragm. 13,47,103,115 Although pediatric keratoplasty is now considered to be a safe and effective procedure, specific problems do exist in the management of children who undergo corneal transplantation. A. PREOPERATIVE EVALUATION AND DECISION- MAKING An examination under anesthesia (EUA), including A and B scans, is usually done prior to penetrating keratoplasty. A portable hand-held slitlamp evaluation immediately preoperatively can eliminate the need for another EUA. In cases with posterior segment pathology, electrophysiological tests, such as visual evoked responses and electroretinography, can help decide on the need to proceed with surgery. The decision of surgery at an earlier age will depend on the laterality of the corneal condition and its severity, the risks of general anesthesia for initial surgery and for repeated postoperative EUAs, and the associated systemic abnormalities and metabolic conditions. The commitment of parents to the long-term care of the child after surgery plays a crucial role. Hence, proper counseling for the social, economic, and psychological demands on them following surgery is vital for a successive outcome in pediatric keratoplasty. Early penetrating keratoplasty for congenital corneal opacity may prevent deprivation amblyopia. However the increased risk of failure, especially in neonatal and infant eyes, requires careful case selection. Younger age at the time of surgery appears to increase the risk of failure due to difficulties with intra- and postoperative management. The decision regarding surgery in CHED cases is difficult. Although the cornea appears hazy and no

7 PEDIATRIC KERATOPLASTY 251 red reflex is seen, these patients seem to see much better than would be predicted. If the patient has good fixation and the eyes are orthophoric, surgery may be delayed. However, if fixation is lost and nystagmus develops, penetrating keratoplasty should be performed promptly. When the child presents with nystagmus, some recommend performing keratoplasty in one eye with the hope of achieving better visual acuity. 115 In cases of Peter s anomaly, the extent of ocular involvement is to be graded preoperatively. The association of central nervous system abnormalities with in Peter s anomaly, should prompt the treating ophthalmologist to look for signs of central nervous system problems (developmental delay, structural defects, seizure disorders, fetal alcohol syndrome) as these increase the difficulty of caring for the child. A pediatric neurological examination and neuroimaging may be required in such cases. The important issue considered in keratoplasty for traumatic corneal scarring is the threat of amblyopia. It has been recommended not to delay keratoplasty for penetrating trauma in children once the decision is made to perform the surgery. 34 The optimal timing and sequence of penetrating keratoplasty and glaucoma drainage implant surgery in refractory congenital glaucoma patients who require corneal and glaucoma surgery is still unclear. 8 The decision to perform regrafts is made in the light of factors such as age, risk of glaucoma, and risk of amblyopia. When graft failure occurs, regrafting is required to visually rehabilitate the child. The causes of the corneal graft failure influence the outcome of the regraft. When the risk of surgical complications and glaucoma outweigh the benefits of the surgery, it is wise to avoid regrafting. Lamellar keratoplasty should be considered in order to obtain desired results in conditions such as superficial scars or limbal dermoid because of the significantly lower risk of rejection and avoidance of intraocular surgery. Tectonic patch grafts, 148,152 rotational keratoplasty, 84,90 and optical iridectomy may also be considered in selective cases of pediatric corneal opacification as an effective alternative management option to keratoplasty. B. ANESTHESIA When performing pediatric keratoplasty, it is desirable to have an anesthesiologist with experience in pediatric anesthesia. It is imperative to be able to maintain the optimal depth of anesthesia throughout the entire procedure. Use of a nonpolarizing muscle relaxant with a peripheral nerve stimulator can help eliminate the risk of movement and contraction of the extraocular muscles. 47 Hyperventilation of the patient can help reduce intraocular pressure. 7 A slightly higher positioning of the head aids in lowering positive pressure. C. PREPARATION OF GLOBE Increased positive pressure during surgery is a major problem in pediatric keratoplasty. After anesthesia is induced, 20% intravenous mannitol ( g/kg body weight over a period of minutes) and/or digital massage aid in achieving optimal ocular hypotony during surgery. Some surgeons prefer to use preoperative Honan balloon and intravenous mannitol to reduce positive vitreous pressure and the possible risk of anterior displacement of the lens--iris diaphragm. Preoperative mydriatics or miotics may be used depending on the procedure. The surgical table should contain all instruments necessary to deal with an unexpected lens loss in the even of raised positive pressure. The surgeon should ensure that the donor button has been punched and is ready before anterior chamber entry. A lid speculum with or without Flieringa ring is used. Care should be taken to ensure that the speculum, surgeon, and assistant do not apply pressure on the globe. A lateral canthotomy may be considered. As pediatric eyes have an increased scleral elasticity and decreased scleral rigidity, the use of a Flieringa ring provides scleral support for the immature and lax infant tissue, thereby preventing collapse of sclera after host trephination. The Flieringa ring must be sutured with care in infants because the needle can penetrate the thin sclera of pediatric eyes and cause retinal tears. In addition, unequal placement of the fixation sutures can result in irregularity of the graft recipient bed and considerable astigmatism. D. TREPHINATION The recipient cornea is trephined to % depth by using disposable suction trephines. Corneal trephination is technically demanding in younger patients because of the increased elasticity of infant tissue. 18,116 Anterior chamber entry is made with an MVR blade through the incision, and the chamber is filled with viscoelastic to protect the lens and iris from injury. The incision is then completed with scissors. The donor cornea is punched out from the endothelial side, and a graft host disparity of mm is used by most corneal surgeons. Rapid formation of peripheral anterior synechias (PAS) and difficulty reforming the chamber are also important problems faced while

8 252 Surv Ophthalmol 54 (2) March--April 2009 VANATHI ET AL performing pediatric keratoplasty. The use of 100 U/ml of heparin solution to irrigate the anterior chamber to prevent fibrin formation and subsequent synechia is preferred by some. The injection of sodium hyaluronate into the angle after anterior chamber is entered may decrease the risk of PAS formation and secondary glaucoma. Performing several peripheral iridectomies has been found to be important in preventing synechia formation. Hemorrhage in the anterior chamber should be controlled and clots removed as fibrin remaining can lead to formation of posterior synechia and PAS formation. Although would closure is faster with a running suture, interrupted single sutures for keratoplasties is usually preferred in children as they allow for an earlier suture removal to avoid suturerelated problems. Oversized corneal grafts (1 mm) have been used in keratoplasty in an attempt to increase the morphologic success of corneal grafting in children. 147 In a prospective, nonrandomized clinical trial, 40 pediatric patients with unilateral or bilateral corneal opacification of congenital or acquired origin (post infectious keratitis corneal opacification, 25%; traumatic corneal scars, 20%; sclerocornea, 20%) underwent corneal grafting surgery with donor corneal buttons oversized by 1 mm. At the end of 1 year, 85% of grafts remained clear, providing an adequate anterior chamber depth ( mm in the congenital group and mm in the acquired group). Although the authors concluded that oversizing donor corneal buttons achieves adequate anterior chamber depth in pediatric cases and can help prevent postkeratoplasty glaucoma, a longer follow-up will be required to confirm these conclusions. Larger grafts have been used in patients with keratoconus and buphthalmos. 31,140 Failed regrafts in congenital glaucoma have been found to be associated with smaller diameter of the graft. Transplanted endothelial cells migrate over graft--host junction to the recipient rim; the fewer number of transplanted endothelial cells in small-sized grafts migrating over to the relatively larger sized recipient rim in buphthalmos has been thought to be responsible for graft failure. Toker et al 140 therefore recommend adjusting the graft size in each eye before surgery. Surgery in buphthalmic eyes can be complicated as the corneas are thinner. E. CONCOMITANT PROCEDURES Loss of crystalline lens and vitreous at the time of transplantation may occur despite rigorous preventive measures. When the posterior capsule is intact, a thorough aspiration of cortical remains is required. If vitreous prolapse occurs, anterior vitrectomy with an automated vitreous cutter must be performed. Any vitreous strands adherent to the wound or iris are removed to prevent vitreous adhesive syndromes and PAS formation. Planned additional procedures, such as lens extraction, IOL implantation, synechiolysis, and anterior vitrectomy may be performed as required. Performance of an additional surgical procedure at the time keratoplasty is strongly associated with decreased graft survival rate. 1,8,31 Among the variables analyzed, corneal ulceration, vitrectomy-lensectomy, persistent inflammation, posterior segment anomalies, regrafts, and postoperative complications have been found to be associated with poor visual outcome and allograft survival. 33,34 F. SIMULTANEOUS KERATOPLASTY WITH GLAUCOMA FILTERING DEVICE IMPLANTATION Upon completion of the keratoplasty, a limbalbased conjunctival flap is created in the superotemporal quadrant. The plate of the primed drainage device is sutured to the sclera with 8.0 non-absorbable sutures, mm posterior to the limbus. The tube is cut to an appropriate length with an anterior bevel and inserted into the anterior chamber through a 23-gauge needle track and is covered by a donor scleral patch. In patients younger than 6 months with anteroposterior diameter less than 22 mm, a pediatric-sized implant is preferred. 7 When cyclocryotherapy is necessary in cases of refractory glaucoma requiring penetrating keratoplasty, it is typically performed in two or three quadrants with two to four spots in each quadrant. Problems in pediatric keratoplasty can be subdivided into those arising in the preoperative, intraoperative, and postoperative periods. 18 Preoperative problems 1. Complete preoperative evaluation of the corneal pathology is usually not possible. 2. Need for specialized investigations such as ultrabiomicroscopic examination. 3. IOP evaluation usually not accurate in opaque corneas. 4. Patient should be evaluated for systemic associations in cases of congenital corneal opacities. Intraoperative problems 1. Small size of the palpebral fissure reduces the working space available for manipulations. 2. Excessive lowering of the intraocular pressure is to be avoided as severe hypotony prevents optimal trephination of the recipient cornea.

9 PEDIATRIC KERATOPLASTY Caution is to be exercised while performing the scleral fixation due to the higher risk of perforation as the sclera is thinner in pediatric eyes. 4. Use of Flieringa rings with unequal placement of fixation sutures may also result in increased distortion resulting in difficulty while suturing. 5. Need for performing associated procedures such as lensectomy, anterior vitrectomy, glaucoma procedures, and so on, is high. 6. Increased positive pressure of vitreous with forward shift of lens--iris diaphragm due to the low scleral rigidity and increased elasticity of pediatric eyes. 7. Increased difficulty in suturing and cheese wiring due to the thin peripheral corneal tissue in certain cases. G. PEDIATRIC KERATOPROSTHESIS Use of keratoprosthesis to treat pediatric corneal opacity 11,25,114 offers an alternative treatment option for those eyes with poor prognosis for graft survival. A retrospective review of 22 eyes of 17 pediatric patients with a history of corneal opacification due to primary congenital disease and/or previous failed keratoplasty treated with keratoprosthesis surgery by Aquavella et al 11 explores the option of keratoprosthesis in pediatric patients. Over a mean follow-up of 9.7 months (range months), all 21 Boston keratoprostheses were retained without dislocation or extrusion. In the two cases with AlphaCor implants, the keratoprosthesis was not retained (spontaneous extrusion in one case and traumatic dislocation in the other) and had to be replaced with a Boston keratoprosthesis. The visual axis remained clear in all cases, with five eyes having undergone retroprosthetic membranes removal. Reoperation for management of concurrent glaucoma (three eyes) or retinopathy (two eyes) was sometimes required. Although the authors 11 conclude that the Boston keratoprosthesis implantation helps to restore a clear visual axis without extrusion or rejection and may be an appropriate alternative for the management of pediatric corneal opacity, keratoprosthesis in pediatric cases should be considered only as the last resort. Keratoprosthesis may offer the possibility of rapid visual rehabilitation due to high optical quality, which enables early amblyopia treatment. H. EPIKERATOPLASTY Epikeratoplasty has been performed to provide refractive correction of pediatric aphakia. Epikeratoplasty in children is more successful if risk factors, such as younger patient age, microcornea, corneal endothelial cell dysfunction, mental retardation, and combined cataract surgery, are avoided. 28 Complications such as residual refractive error, epithelial defect, interface opacities, graft vascularization and graft infection, graft necrosis, graft haziness or opacification, and graft dehiscence have made this procedure less desirable. IV. Postoperative Management Postoperative management of pediatric corneal grafts demands dedicated follow-up evaluations under anesthesia, monitoring of postoperative medications for frequency alterations, appropriate management of sutures, close watch for rejection, frequent correction of refractive errors, initiation of amblyopia therapy, and ensuring compliance to long-term amblyopia therapy. Hence, the need to emphasize on the biphasic approach of 1) maintaining a clear graft, and 2) reversing amblyopia, is of paramount importance in the postoperative management. A. IMMEDIATE POSTOPERATIVE MANAGEMENT Postoperative treatment regimen involves topical corticosteroid along with antibiotics and lubricants. Topical steroids are given more frequently in the initial postoperative period and gradually tapered and changed to less potent steroids such as fluoromethalone in 3--6 months. Topical CsA 2% when used in pediatric keratoplasty can help reduce frequency and duration of postoperative topical steroids. EUAs in the early postoperative period are important in order to assess the graft status, assess intraocular pressure, and initiate prompt treatment, if required. B. SUTURE REMOVAL Loosening of sutures or vascularization requires an urgent EUA. Frequent EUAs during the first 2 months after pediatric keratroplasty in children less than 6 months of age is mandatory until all sutures are removed and at monthly intervals for 6 months and less frequently thereafter. Frequent EUAs are also required to detect problems such as glaucoma and retinal detachment. All sutures are usually removed within 3 months in children younger than 8 years and by 6 months in older children. Different centers follow their own set routines for suture removal in pediatric keratoplasty. An increased frequency of topical steroid and antibiotics is required for a week after suture removal. Suture loosening and graft rejection can occur insidiously in young children who cannot

10 254 Surv Ophthalmol 54 (2) March--April 2009 VANATHI ET AL communicate discomfort and vision changes. Graft rejection is thought to occur more quickly in children due to an amplified wound healing response. 24 C. REFRACTIVE CORRECTION Refraction is done after suture removal for optical correction, and amblyopia therapy is initiated as soon as possible. In cases of potential risk of dense amblyopia, early refractive correction may be provisionally prescribed with frequent changes as required in an attempt to increase the efficacy of amblyopia therapy. Early refractive rehabilitation by spectacle correction or contact lenses to correct residual astigmatism and contact lenses or intraocular lens implants for aphakia are required. D. AMBLYOPIA MANAGEMENT The neurological basis of amblyopia is related to the concept of cortical competition. Visual cortical cells are potentially connected to both the eyes equally, provided both eyes are functioning. 49,59,135,153 If one eye predominates, these cortical cells are stolen by the dominating side. The dominance of one eye over the other is usually a result of better visual acuity in that eye, especially if primary strabismus is not present. It is postulated that strabismic amblyopia is initiated as a maladaptive differentiation in the ocular dominance columns, whereas the non-strabismic amblyopias (anisometropic and the deprivation amblyopias) may be initiated from the malfunctioning of the ganglion cell population of the amblyopic eye. 41,69,135 Thus the non-strabismic amblyopias are caused by optical degradation of one retinal image while in strabismic amblyopias both retinal images are initially clear. The total clinical picture is confusing because of secondary changes in other parts of the central nervous system that occurs subsequently. The manifest features can be due to a slower, more enduring type of change (pooling, loss, and re-wiring of the neurons) as well as a more transient, adaptive type of response (such as suppression of diplopia). Thus, mechanisms leading to amblyopia have been divided into two basic types, those causing form deprivation and those resulting in abnormal binocular interaction. 86,120,135,136,153,154 It is of importance to realize that the process of visual maturation and development of amblyopia becomes especially significant in the early period of visual development, also called the critical period, when neural plasticity makes the visual system vulnerable. This may last is up to 7--8 years in humans. 69,135,153,154 Once this period is over amblyopia cannot occur. This is the time when amblyopia therapy is maximally effective as the immature visual system can be modulated. 41,49,69,135,153,154 As the visual deprivation in amblyopia is more related to the competitive interaction between both the eyes rather than disuse in most cases, results of treatment are better if started within the critical period as this is the time when changes in the lateral geniculate body and the visual cortex are partially or completely reversible. 135,153 The key for the management of amblyopia is equalization of visual acuity in both the eyes so that they can function together. The modalities include a high degree of suspicion of the condition, early detection, observation of associated abnormal eye movements in the form of roving eye movements, nystagmus, abnormal head postures, and so forth, removal of any media opacity, correction of refractive errors, and providing the worse eye a competitive advantage over the better eye by occluding the better eye, either physically with a patch or with the help of cycloplegic drugs. Strict vigilance and monitoring of therapy is important. Aggressive amblyopia management is mandatory for good visual outcomes in pediatric patients undergoing keratoplasty. 29,33,34,135,153,171 Occlusion of the better eye by direct patching forms the mainstay of the treatment for amblyopia. A patch applied over the skin is preferred to a patch over the spectacles as the child can easily take off the spectacles or look outside through the sides of the occluded spectacle. The principle of this therapy is to provide a competitive advantage to the worse eye, which will eliminate the components of abnormal binocular interaction and the inhibitory influences of the better eye on the receptive fields of the worse eye. Occlusion should be started as soon as possible. The family should be educated to recognize the fixating eye and guide the patient toward free alternation. 19,85,101,104,111,112 E. REGRAFTS Repeat penetrating keratoplasty is quite often required in pediatric eyes as there is high chance of failure of the primary graft. The graft survival rate is lower in eyes undergoing multiple regrafts. 151 Regrafts in congenital glaucoma tend to fail earlier than primary grafts. 2,140 In the heterogenous group studied by Dana et al, 33 20% of eyes had undergone regrafting at a mean of 17 months after the first surgery, of which 22% had a second regraft at a mean of 62 months after the original procedure. Anatomical success of the grafts dropped from 78% in the eyes that had one graft, to 19% in those eyes that had two grafts, and to nil in those eyes that had three grafts.

11 PEDIATRIC KERATOPLASTY 255 Parmley et al 94 also had a high rate of regrafts in 26 grafts on 16 eyes in 10 patients of which six eyes that were grafted two or more times over a mean follow-up of 30 months. Of the six eyes that were regrafted, only one child obtained ambulatory vision. 4 Apart from the eight primary keratoplasties, three repeat keratoplasties were required in the series of Peter s anomaly described by Althaus and Sundmacher. 10 The Kaplain-Meier survival curve showed a highly significant difference in the likelihood of maintaining a clear graft with initial grafts compared with second, third, and fourth grafts in the large series by Yang et al. 167 Thirty-six percent of first grafts maintained long-term clarity compared with just 6% of second grafts. The probability of second or subsequent grafts surviving for 3 years was less than 10%. Ten out of 26 transplants in the series of Comer et al 29 were regrafts, of which seven subsequently failed. Of 58 eyes (the majority of which had Peter s anomaly or sclerocornea) 23 eyes required regrafting between 2 weeks and 110 months postoperatively. 44 The probability of maintaining a clear graft, calculated by survival analysis, was 75% (SE, 6%) at 1 year and 58% (7%) at 2 years. Rejection reversals tend to be more successful in the primary grafts compared to that in regrafts. 68 The increased need for regrafting, besides the high incidence of complications in pediatric corneal transplantation, calls for a cautious approach to decision-making before attempting surgical intervention. Repeat grafts may still be indicated in infants or children in the amblyogenic age group as even if the regraft survives for only 1 year, this will enhance the visual development of the child and reduce the risk of amblyopia. 47 V. Complications corneal scars, later corneal decompensation in older children, and phakic eyes have the best prognosis. Corneal perforations, active inflammation or infection, and infants with multiple ocular anomalies have the poorest prognosis. Children undergoing combined procedures have been found to have a less favorable result than those undergoing a single- or two-staged procedure. 31 Complications such as cataract development, secondary glaucoma, epithelial defects, band keratopathy, retinal detachment, wound leakage, retrocorneal membrane, and microbial keratitis make the postoperative course complex often necessitating regrafting. 44 Preoperative vascularization of the cornea, persistent epithelial defects, and performance of lensectomy-vitrectomy were factors most highly correlated with poor graft survival. 134 Postoperative shallowing of the anterior chamber and the occurrence of anterior synechiae leading to secondary glaucoma are other causes of graft failure in the pediatric age group. 147 Other factors limiting visual outcome include glaucoma, hemorrhage, and retinal complications. 18 A. GRAFT REJECTION Pediatric corneal transplantation has an increased rejection rate because of the more active immune system in younger patients. 9 Endothelial immune rejection 165 leading to graft failure is one of the main causes for graft failure. Well-established graft rejection in children is usually irreversible. 18 Increased risk of allograft rejection after bilateral keratoplasty is controversial. 9,12,38 Early intervention may be considered in both eyes in an attempt to provide useful vision and avoid irreversible amblyopia. In infants with an amplified inflammatory response, graft rejection can occur rapidly and be less responsive to treatment. Early symptoms of graft rejection, such as reduced visual acuity and ocular discomfort, cannot be communicated, resulting in a delay in the diagnosis and treatment and, hence, a higher degree of graft failure. The reported percentages of graft rejection in pediatric keratroplasty vary between 22% 146 and 43.4%. 1,62 Graft rejection was the cause for all graft failures in series of pediatric keratoplasty in CHED reported by Javadi et al 62 in which rejection had occurred in 10 eyes (43.4%), of which endothelial rejection accounted for 30.4% of eyes. Yang et al observed graft rejection to be the most frequent cause for graft failure in their series (25%), with 48% of the rejection episodes involving the first graft. 167 Rejection was reversible in only 28% of episodes, showing a much lower reversal rate in pediatric grafts compared to that of % in adult grafts. 9 In the series by Comer et al, 29 53% of the rejection episodes were not reversible and resulted in failure. Vajpayee et al 146 also noted rejection in 22.5% of cases with 55% of them not being reversible, and all of these children had reported late for management. Seventeen of 19 grafts with rejection failed in the series reported by Cowden. 31 Stulting et al 134 reported 11% of graft failures to be related to allograft rejections; whereas more than 50% of the graft failures in the series by Dana et al 33 were attributed to graft rejection. Although graft rejection was the primary cause for graft failure in their series, Dana et al 35 conclude that rejection is not a significant predictor of failure as most of their rejection episodes were successfully treated.