Pediatrics

Corneal opacity

OVERVIEW: What every practitioner needs to know Are you sure your patient has a corneal opacity? What are the typical findings for this disease?

There are five layers of the cornea that must all function properly to keep the cornea clear. The layers from anterior to posterior are corneal epithelium, the Bowman membrane, stroma, the Descemet membrane, and endothelium. Corneal opacities may be congenital or acquired and can be unilateral or bilateral. Opacification of the cornea is likely to cause decreased visual acuity, amblyopia, or blindness. Opaque and central corneal opacities are more likely to cause significant decreased visual acuity than are peripheral opacities with mild corneal haze.

Prompt referral to an ophthalmologist may help to decrease the risk of lifelong visual disability. Congenital corneal opacities are often associated with other ocular abnormalities such as cataracts and glaucoma, which may require surgical treatment. Corneal transplantation (penetrating keratoplasty) with allograft donor corneal tissue has been the procedure of choice to treat corneal opacities in the past, but the keratoprosthesis shows promise in treating pediatric corneal opacities. Blind eyes with corneal opacities that have poor cosmesis can be treated with a scleral shell that is custom made by an ocularist to cover the affected eye and improve the patients overall appearance.

The cornea is not clear but appears cloudy or white and may be affected unilaterally or bilaterally.

There is decreased vision.

There is an absent or decreased red reflex.

Increased intraocular pressure is present.

Congenital corneal opacities

Congenital corneal opacities are most commonly caused by a malformation of the anterior segment of the eye (anterior segment dysgenesis) but additional causes include congenital glaucoma (Figure 1), dermoid, trauma, infection, corneal dystrophies, and metabolic storage diseases.

Figure 1.

Congenital glaucoma.

Peter anomaly (Figure 2) and sclerocornea (Figure 3) are the most common diseases caused by anterior segment dysgenesis. Peter anomaly may be unilateral or bilateral and presents with a central white corneal opacity (leukoma) and an absent or decreased red reflex.

Figure 2.

Peter anomaly.

Figure 3.

Sclerocornea.

Peter plus syndrome is associated with systemic abnormalities including developmental delay, short stature, craniofacial, renal, cardiac, and skeletal abnormalities. Sclerocornea is a disease in which normal clear corneal tissue is replaced with vascularized opaque white sclera tissue and is often associated with abnormally flat corneal curvature (cornea plana) and microcornea (small corneal diameter). Systemic abnormalities including developmental delay, cardiac, pulmonary, and craniofacial abnormalities are rarely associated with sclerocornea.

Congenital glaucoma frequently presents with moderately hazy corneas, buphthalmos (increased corneal diameter), photophobia, blepharospasm, tearing, and increased intraocular pressure. Other less common causes of congenital corneal opacities include limbal corneal dermoids (Figure 4) , corneal trauma secondary to a forceps delivery, viral or bacterial infections (keratitis), corneal dystrophies, and metabolic storage diseases such as mucopolysaccharidoses.

Figure 4.

Limbal corneal dermoid.

Acquired corneal opacities

Corneal opacification acquired during childhood is commonly due to trauma or infection/keratitis. A corneal abrasion is the most common corneal injury and results in temporary mild corneal haze, acute onset of severe pain, tearing, conjunctival injection, and blepharospasm. A corneal abrasion is easily diagnosed by instilling fluorescein into the affected eye and shining a cobalt blue light on the eye. The area with the abrasion will stain a bright yellow from lack of corneal epithelium. The mild corneal haze associated with a corneal abrasion resolves once the corneal epithelial defect has healed.

Severe penetrating ocular injuries resulting in corneal laceration (Figure 5) require emergent surgical repair. Postoperative scar formation results in permanent corneal opacification. The visual impact of a postoperative scar depends on its location, size, and concomitant injuries to other structures within the eye. A large central postoperative scar is more likely to decrease vision than is a peripheral small scar.

Figure 5.

Corneal laceration.

Corneal infections/keratitis due to herpes simplex virus infection and bacterial keratitis secondary to improper contact lens use are often associated with corneal scarring, opacification, and permanent vision loss. Less frequent causes of acquired corneal opacification result from corneal exposure from decreased eyelid closure. Bell palsy, altered mental status in a comatose patient, and eyelid trauma with significant tissue loss can result in severe dry eye and corneal opacificaton.

Metabolic disorders such as mucopolysaccharidoses and cystinosis lead to deposition of materials within the cornea that result in opacification that is variable in severity. Vitamin A deficiency can cause severe dry eye and secondary corneal opacification.

What other disease/condition shares some of these symptoms?

Corneal opacities result in a decreased red reflex, as do cataracts, retinal detachments, and retinal tumors such as retinoblastoma. Microphthalmia (congenital small eye) is often associated with corneal leukomas and microcornea (Figure 6).

Figure 6.

Left microphthalmia with corneal opacification and esotropia.

What caused this disease to develop at this time?

Many congenital corneal opacities have an underlying genetic or metabolic cause. A complete physical examination should be conducted when the corneal opacities are diagnosed to determine if there are phenotypic findings associated with systemic conditions or syndromes that would explain the presence of congenital corneal opacities. Genetic and metabolic testing can be tailored based on physical examination findings.

Peter anomaly is a result of abnormal migration of neural crest cells during embryogenesis. This results in abnormal development of the cornea and may also affect the development of other structures within the eye, including the iris, lens, and trabecular meshwork.

Sclerocornea results in corneal opacification due to abnormal vascularized scleral tissue replacing avascular corneal tissue. Scleralization of the cornea may involve the entire cornea or just the periphery.

Congenital glaucoma results in tears of the Descemet membrane of the cornea and subsequent loss of normal fluid homeostasis, corneal stromal edema, and opacification. Congenital glaucoma has associated examination findings, including buphthalmos (increased corneal diameter), photophobia, blepharospasm, tearing, and increased intraocular pressure.

Corneal dermoids are choristomas that may contain ectodermally and mesodermally derived tissue such as keratinized epithelium, hair, muscle, and blood vessels. Corneal dermoids are slightly elevated, round, cream-colored lesions that are often located on the inferior temporal peripheral cornea.

Trauma to the cornea during delivery by forceps result in tears of the Descemet membrane similar to that seen in congenital glaucoma.

Corneal dystrophies may be autosomal dominant or recessive. Congenital hereditary endothelial dystrophy (CHED) results in the degeneration of the corneal endothelium, Descemet membrane thickening, corneal edema, and diffuse corneal haze. CHED is often associated with nystagmus, light sensitivity (photophobia), and glaucoma. The recessive form of CHED presents in early infancy, whereas the dominant form presents later. Deafness may be associated with CHED1. Posterior polymorphous corneal dystrophy results in metaplasia and overgrowth of the corneal endothelium and basement membrane.

Neonatal Infectious keratitis is rare but often occurs by maternal transmission during vaginal delivery. Herpes simplex virus ll and Neisseria gonorrhoeae are the most common infections that result in corneal opacification in a neonate.

Inherited metabolic disorders, including mucopolysaccharidoses and mucolipidoses, result in accumulation of intermediate metabolites depositing in various tissues of the body, including the cornea. Cystinosis results in crystal accumulation within the cornea, which often results in severe photophobia.

Acquired corneal opacities due to trauma or infection are a result of the healing response of the collagen fibers within the cornea. The normal cornea stroma is transparent because of the organized layers of collagen and precise balance of extracellular fluid within its matrix. Corneal injury results in scar formation with disorganized layers of collagen and loss of fluid hemostasis. Corneal exposure from improper lid closure (lagophthalmos) or decreased blink frequency in a patient with an altered mental status may result in corneal epithelium defects, infectious keratitis, and scarring.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Genetic and/or metabolic testing should be done based on physical examination findings. TORCHS (toxoplasmosis, other rare infections, rubella, cytomegalovirus,herpes, and syphilis) titers can be useful if an intrauterine infection is suspected. Viral, bacterial, or fungal cultures of the corneal ulcer in cases of infectious keratitis can help determine the causative organism and tailor antimicrobial treatment.

Would imaging studies be helpful? If so, which ones?

Neuroimaging should be done based on other systemic findings. Corneal opacities associated with microphthalmia are commonly associated with central nervous system abnormalities.

If you are able to confirm that the patient has a corneal opacity, what treatment should be initiated?

Corneal opacification can cause profound vision loss if present at an early age. Prompt consultation with an ophthalmologist will determine the treatment course. Small corneal opacities that do not involve the entire cornea can be treated pharmacologically with topical ophthalmic medications that dilate the pupil so that light can enter the eye through surrounding clear corneal tissue.

Amblyopia treatment will likely be necessary and requires patching or atropine penalization of the sound eye to encourage the child to use the eye with the corneal opacity. Refractive errors must be corrected with glasses and in some instances contact lenses. Acquired corneal opacifications due to infectious keratitis must be treated with aggressive topical and sometimes systemic antimicrobial agents.

Severe congenital or acquired corneal opacities may require corneal transplantation/penetrating keratoplasty (Figure 7). There is no consensus as to the optimal time to perform corneal transplantations in children and the prognosis for success of graft survival is often guarded. The use of a corneal prosthesis (keratoprosthesis) such as the Boston KPro instead of human donor corneal tissue has increased over the past few years (Figure 8). However, long-term data on success rates are not available.

Figure 7.

Corneal transplantation.

Figure 8.

Keratoprosthesis.

Glaucoma, lens, and retinal surgery is often necessary at the time of corneal transplantation due to associated ocular anomalies frequently encountered with corneal opacities. Despite surgical treatment, parents must be counseled that the prognosis for useful vision is guarded in patients who require corneal surgery.

Treatment of underlying systemic conditions or metabolic disorders should be addressed by the appropriate specialists. Crystalline keratopathy resulting from cystinosis can be treated with topical cysteamine ophthalmic drops, which are specially compounded by select pharmacies. Cysteamine drops help decrease symptoms of pain and photophobia.

Acquired corneal opacities due to penetrating trauma may require immediate surgical repair by an ophthalmologist. Lacerations of the cornea resulting in significant scar formation may cause deprivation amblyopia and irregular astigmatism. Some children can achieve excellent vision with the use of a rigid gas-permeable contact lens to correct irregular astigmatism. If the scar is in the central cornea, corneal transplantation or keratoprosthesis may be indicated. Paracentral scars may be observed.

Correction of refractive errors with glasses or contact lenses and amblyopia treatment are necessary in the majority of patients with corneal opacities, regardless of the underlying cause. Topical and sometimes systemic antimicrobial medications are instituted to treat infectious keratitis. Cultures can help guide medication selection. Infants with congenital herpesvirus or gonococcal infections require hospitalization with intravenous as well as topical ophthalmic antimicrobial medications.

Corneal exposure from lagophthalmos or decreased blink frequency must be treated with frequent administration of artificial tear ointment or solution. The eyelids may be taped closed at night or a moisture chamber may be applied if eyelid trauma precludes closing the eyelids. A surgical tarsorrhaphy to close the eyelids partially or completely may be necessary to prevent dessication of the cornea. Paralytic lagophthalmos from Bell palsy can be treated with a surgical procedure in which a gold weight is inserted within the upper eyelid to aid in eyelid closure and prevent corneal exposure.

Traumatic eyelid tissue loss may need reconstruction by an oculoplastic surgeon to facilitate proper eyelid closure and protection of the cornea.

A pediatric ophthalmologist and corneal specialist will likely need to care for the child long term to address issues such as amblyopia, refractive errors, glaucoma, and corneal transplantation if necessary. Referral to a vision rehabilitation specialist may be necessary in children with bilateral corneal opacities resulting in low vision/blindness.

What are the adverse effects associated with each treatment option?

The most common adverse effect of corneal opacities despite treatment is decreased or low vision. Amblyopia treatment and correction of refractive errors with glasses or contact lenses will likely be necessary. Corneal transplantation and keratoprosthesis have high failure rates and may require multiple surgical procedures (Figure 9) . Glaucoma is common after corneal transplantation and often requires surgery to control it. Huang et al found that corneal transplantation has a fair overall prognosis for graft survival of approximately 50% at 1 year. Glaucoma is associated with poor long-term graft survival.

Figure 9.

Failed corneal graft despite multiple procedures.

What are the possible outcomes of corneal opacity?

Treatment of corneal opacifications with surgery (corneal transplantation/keratoplasty or corneal prosthesis) requires a significant amount of time and effort on the part of the child's caregivers and ophthalmologists. Daily topical ophthalmic medications are often necessary to prevent corneal graft rejection and glaucoma. Frequent office visits or serial examinations of the eyes with the patient under anesthesia are necessary after corneal surgery if the child is unable to cooperate with ocular examinations.

Corneal graft failure is most commonly caused by rejection, but graft survival is also adversely affected by glaucoma, infectious keratitis, keratoplasty performed before the age of 6 months, concomitant lensectomy, and vitrectomy at the time of keratoplasty. The reported percentages of graft rejection in pediatric keratroplasty vary between 22% and 43.4%.

Graft survival in the pediatric patient is low and has been reported to be 52% at 6 months, dropping to 22% at 2 years in a study by Rao et al. Multiple surgical procedures are often necessary to treat a failed graft, secondary cataract formation, glaucoma, and secondary membrane formation after keratoprosthesis surgery.

Severe infections after corneal surgery due to endogenous endophthalmitis can result in loss of the eye (Figure 10). Despite aggressive surgical treatment, the visual prognosis for most corneal opacities is poor.

Figure 10.

Corneal graft with glaucoma tube shunt-related endophthalmitis.

Nonsurgical treatment of congenital corneal opacities may be the best option in patients who have unilateral corneal opacities or socioeconomic situations that preclude compliance with postoperative care. Patients who are monocular (have useful vision in one eye) should wear eye protection at all times to prevent injuries to the sound eye.

What causes this disease and how frequent is it?

Congenital corneal opacities occur in 3/100,000 births. The most common primary cause of congenital corneal abnormalities in developed nations is Peter anomaly (40.3%), followed by sclerocornea (18.1%), dermoid (15.3%), congenital glaucoma (6.9%), microphthalmia (4.2%), and birth trauma and metabolic disease (2.8%) in a study by Rezende et al.

Peter anomaly may be sporadic, caused by teratogens, chromosomal abnormalities, or gene mutations. The most common gene mutations include PAX6, PITX2,CYP1B1 and FOXC1. The corneal opacity is due to abnormalities of mesenchymal migration beginning in the sixth week of gestation. Abnormalities are noted within the posterior corneal stroma, Descemet membrane, and endothelium. Adhesions between the iris, lens, and cornea are common.

Peter anomaly is commonly associated with microphthalmia. Primary congenital glaucoma usually results from mutations in the CYP1B1 gene located on chromosome 2p22.2. Glaucoma causes high intraocular pressure, resulting in corneal edema, corneal endothelial scarring, and opacification. Histopathologic abnormalities are often noted within the drainage angle of the eye called the trabecular meshwork. Imbalance of aqueous fluid production and drainage through the trabecular meshwork results in elevated intraocular pressure, breaks in Descemet membrane, and subsequent stromal edema and opacification.

Corneal dystrophies may be autosomal dominant or recessive, have been mapped to chromosome 20 and 22; mutations of SLC4A11, VSX1 and COL8A2 genes have been identified. The autosomal dominant form of congenital hereditary endothelial dystrophy is called CHED1, and the autosomal recessive form is referred to as CHED2. CHED1 and CHED2 map to distinct regions of chromosome 20.

CHED1 is caused by a mutation on chromosome 20p11.2-q11.22 and CHED2 is caused by mutation in the SLC4A11 gene and encodes a sodium borate cotransporter, on chromosome 20p13-p12. Posterior polymorphous corneal dystrophy-1 is caused by heterozygous mutation in the VSX1 gene on chromosome 20p. Endothelial dysfunction ultimately results in stromal edema and opacification.

Sclerocornea has been mapped to a mutation of the FOXE3 gene.

Corneal dermoids may be associated with oculoauriculovertebral spectrum or Goldenhar syndrome, but central corneal dermoids have been reported as a nonsyndromic ocular abnormality.

Acquired corneal opacification after trauma or infection is a result of disorganization of collagen fibers within the corneal stroma. The corneal stroma is composed of keratocytes and an extracellular matrix composed of collagen fibrils that form lamellae, which minimizes light scatter to appear transparent. Disorganization of the collagen fibers within the corneal stroma as part of the healing response results in opacification of the cornea.

How do these pathogens/genes/exposures cause the disease?

Abnormal development of the five layers of the cornea during embryogenesis seen in diseases such as Peter anomaly or sclerocornea results in opacification of the cornea. Increased intraocular pressure seen in congenital glaucoma results in dysfunction of corneal endothelial cells responsible for maintaining stromal fluid hemostasis and resultant stromal edema and scarring. Corneal scarring of any cause, whether it is congenital or acquired, results in opacification. The opacification at a microscopic level is due to disorganization of collagen lamellae within the corneal stroma.

What complications might you expect from the disease or treatment of the disease?

Low vision, blindness, amblyopia, and strabismus are common complications associated with corneal opacities. Low vision may occur even if corneal opacities are treated surgically with a corneal transplant or keratoprosthesis. Secondary glaucoma after corneal surgery commonly requires additional surgery but often results in blindness despite treatment.

Other complications after corneal surgery include irregular astigmatism, cataract formation, retinal detachment, and membrane formation posterior to the corneal prosthesis.

Low vision in a child frequently causes strabismus (misalignment of the eyes). Esotropia (crossed eyes) or exotropia (wall eyed) commonly affect an eye with low vision. Strabismus surgery to improve ocular alignment may be necessary.

A unilateral failed corneal graft or poorly sighted eye after trauma is likely to have a poor cosmetic appearance. An unsightly appearance to an eye can be treated with a scleral shell custom made by an ocularist or with cosmetic contact lenses (Figure 11 and Figure 12). Corneal graft rejection and glaucoma may result in a blind painful eye that may require enucleation (removal of the eye).

Figure 11.

Poor cosmesis due to microphthalmia/corneal opacity before scleral shell application.

Figure 12.

After scleral shell to improve cosmesis of microphthalmic eye with corneal opacity.

Are additional laboratory studies available; even some that are not widely available?

Gene sequencing should be based on the phenotypic ocular and systemic findings.

How can corneal opacity be prevented?

Corneal opacities resulting from congenital infection may be prevented by treating the mother before delivery or by performing a cesarean section instead of using forceps, which may traumatize the cornea. Injury prevention with goggles during sports may prevent traumatic corneal injuries. Genetic counseling is necessary for families with known diseases so that they can make informed decisions regarding family planning.

What is the evidence?

The studies evaluating penetrating keratoplasty and keratoprosthesis listed below evaluate the pediatric population. Studies that evaluated corneal transplantation and keratoprosthesis in adults were not reviewed. Publications regarding corneal opacities and corneal surgery in children are generally limited by small numbers of study patients.

Huang, C, O'Hara, M, Mannis, MJ. "Primary pediatric keratoplasty: indications and outcomes". Cornea. vol. 28. 2009. pp. 1003-8.

(A good study examining children and how they respond to treatment of corneal opacities.)

Aasuri, MK, Garg, P, Gokhle, N. " Penetrating keratoplasty in children". Cornea. vol. 19. 2000. pp. 140-4.

(Another good study examining the management of corneal opacities in children.)

Rao, KV, Fernandes, M, Gangopadhyay, N. "Outcome of penetrating keratoplasty for Peters anomaly". Cornea. vol. 27. 2008. pp. 749-53.

(Describes the response to treatment of the most common cause of congenital corneal opacity, Peter anomaly.)

Rezende, RA, Uchoa, UB, Uchoa, R. "Congenital corneal opacities in a cornea referral practice". Cornea. vol. 3. 2004. pp. 565-70.

(A good review of congenital corneal opacities.).

Ciralsky, J, Colby, K. "Congenital corneal opacities: a review with a focus on genetics". Semin Ophthalmol. vol. 22. 2007. pp. 241-6.

(A good review of the role of genetics in corneal opacities.)

Aquavella, JV. "Pediatric keratoprosthesis: a new surgical approach". Ann Ophthalmol (Skokie).. vol. 40. 2008. pp. 64-7.

(Describes a new surgical procedure used to treat corneal opacities in children.)

Ongoing controversies regarding etiology, diagnosis, treatment

Surgical treatment of unilateral congenital corneal opacities remains controversial. Some specialists believe that a unilateral corneal opacity present from birth should be treated conservatively with amblyopia management because of the high risk for graft failure and glaucoma with surgical intervention.

There is no clear consensus as to which surgical procedure, penetrating keratoplasty (corneal graft) versus keratoprosthesis, may help decrease the risk of surgical failure in a child. There is no agreement among ophthalmologists as to when the optimal time is to perform corneal surgery in a child with a congenital corneal opacity. Surgery performed at an early age may decrease the severity of deprivation amblyopia but increases the risk of graft failure and need for additional surgery.

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