Congenital Corneal Opacities: Diagnosis and Management

Background

The term congenital designates conditions present at birth. Congenital corneal opacities may result from genetic, developmental, traumatic, or infectious causes. They can be unilateral or bilateral and can be seen in isolation or in association with other ocular or systemic abnormalities. The prevalence of congenital corneal opacity is approximately 3per100,000 newborns, and this figure increases to 6per100,000 if congenital glaucoma is included as an underlying etiology. A recent analysis of congenital corneal opacities in New York found an incidence of 1 infant corneal transplant per 24,000 live births. Although congenital clouding of the cornea is rare, the ophthalmologist must make an accurate diagnosis to predict the natural history of the disorder, detect associated ocular and systemic abnormalities, provide genetic counseling if needed, and promptly begin appropriate medical or surgical therapy. This chapter addresses the main features and differential diagnosis of the most common causes of congenital corneal opacification ( Box 18.1 ). It also discusses an alternative classification scheme based not only on clinical appearance but also underlying genetic mutations and the likely pathophysiology of the given abnormality ( Box 18.2 ).

History and Physical Examination

Thorough evaluation of congenital corneal clouding begins with a complete history and physical examination. A detailed obstetric, birth, and family history may be helpful in identifying many diseases. With regards to an obstetric and birth history, it is important to inquire about prenatal drug and infectious exposures, including sexually transmitted infections, as well as the type of delivery and the use of assisted devices. After obtaining a complete history, examination of the newborn and the eyes must occur. A quick survey of the infant from head to toe can help to identify potentially associated systemic findings, and the use of a handheld portable slit lamp may facilitate a careful anterior segment examination. If the patient is cooperative, assessment of corneal sensation can be very helpful in narrowing the differential diagnosis. A cotton fiber can be used to touch the cornea while movement of the other lid is used as an indicator of corneal sensation. In cases where it is not possible to open the lids manually, a speculum may be used with topical anesthesia in the outpatient setting in order to provide adequate exposure for a detailed examination. Nonetheless, sometimes a thorough examination may be best accomplished by placing the patient under general anesthesia with the collaboration of a pediatric anesthesiologist, pediatric ophthalmologist, and cornea and glaucoma specialists when available ( Fig. 18.1 ). Last, examination of the patient’s parents while they are in the office may also be helpful in order to establish the diagnosis of various inherited conditions.

Components of a complete examination under anesthesia (EUA) include measurement of the intraocular pressure (IOP), corneal pachymetry, measurement of corneal diameters (both vertically and horizontally with calipers), and biomicroscopic examination of the cornea and anterior segment with and without fluorescein. Depending on the degree of corneal opacification, gonioscopy, dilated fundus examination, and retinoscopy may be attempted. During an EUA, advanced imaging modalities including A-scan ultrasound biometry (A-scan), B-scan ultrasonography (B-scan), high-frequency ultrasound biomicroscopy (UBM), and anterior segment optical coherence tomography (AS-OCT) can more easily be performed. Biomicroscopic examination must be performed with a handheld portable slit lamp, as the level of magnification and the presence of a slit beam make the slit lamp far superior to the operating microscope for corneal evaluation. Often, visualization through a cloudy cornea can be extremely limited, especially if the clouding is diffuse and dense. The view may be improved during an EUA by mechanically removing the epithelium. An EUA can also be helpful when an infectious etiology is suspected and corneal cultures are needed. In suspected unilateral conditions, the healthy eye must be thoroughly examined to look for any abnormalities, as bilateral disease can often present asymmetrically, which may give clues as to the final diagnosis.

In order to assess what is abnormal, one must know what is considered normal in the infant eye. Stated normals for IOP, corneal thickness, corneal diameters, and axial length in the neonate and infant are listed in Box 18.3 but reviewed in more detail here. Accurate IOP measurement is critical and should be performed either in an awake infant or early in the induction of anesthesia. General anesthesia typically lowers IOPs, which in premature infants has a mean of 10.11 ± 2.21 mm Hg. As mentioned earlier, corneal diameters should be measured with calipers in both the horizontal and vertical meridians. At birth, the corneal diameter ranges between 9.5 and 10.5 mm and increases to 11.5 mm by age 1 year. Measurements greater than 11.5 mm or marked asymmetry between the eyes should raise suspicion. Numerous studies have looked at ranges of IOP with and without anesthesia in newborns and infants. These ranges can be wide, although it is agreed that children have lower normal values than those stated for adults. ^, Several devices are available for IOP testing—including the gold standard, Goldmann applanation—as well as portable options including portable applanation (Perkins, Draeger), indentation tonometry (Schiotz, pneumotonometer, Tono-Pen), and rebound tonometers (i-Care). Another less portable option for intraocular measurement, which may be easier to perform in children than Goldmann applanation, is the noncontact tonometer (“air-puff tonometry”); but this requires awake patients who can position their chins correctly on the device. In the pediatric population, rebound tonometers such as the i-Care work well in awake patients including newborns; but they require an upright position and are prone to error. In the operating room environment, indentation tonometry or portable applanation are the most readily available and can provide more reliable measurements. One study demonstrated the pneumotonometer to be the most accurate in children whereas the TonoPen was the least. Corneal pachymetry is now easily obtained using a variety of handheld devices that utilize ultrasonic technology, including the iPac (Reichert) and Pachymate (DGH Technology, Inc.). Gonioscopy in the neonate may best be accomplished using a Koeppe lens and the operating microscope rotated to the correct angle for viewing. In the office, a Koeppe lens and the indirect ophthalmoscope with a 20-diopter (D) lens may also give an adequate view of the angle. Dilation of the pupil can sometimes expose the pupillary opening to areas of clear cornea, facilitating a view of the posterior segment despite a large corneal opacity ( Fig. 18.2 ). The direct ophthalmoscope can be used with a Koeppe lens to obtain a good view of the optic nerve and the macula. An indirect ophthalmoscope with a 14D lens can also be used to examine the disc, and with a 20 or 28D lens for the macula and peripheral retina. Retinoscopy should be done if possible, but this can be difficult through a cloudy cornea. Despite the challenges of performing a dilated examination in the presence of a corneal opacity, it is necessary to rule out concomitant causes of poor vision, including optic nerve abnormalities, macular scars, or other types of retinal pathology, including chorioretinal coloboma. If an adequate view cannot be obtained despite dilation, additional imaging modalities of the posterior segment should be employed. A-scan can determine the position of the iris and the lens as well as the axial length of the eye. B-scan provides excellent-quality imaging of the vitreous and retina and can reliably identify posterior segment abnormalities. For additional evaluation of the anterior segment, UBM and AS-OCT can be performed. UBM has been widely used for imaging the anterior segment structures of the eye with exceptional resolution ( Fig. 18.3 ). Some studies have demonstrated that UBM is capable of delineating the corneal layers except for distinguishing between the Descemet membrane and endothelium. UBM examination is not only very useful in making a clinical diagnosis but can also aid in planning prior to penetrating keratoplasty. UBM can readily detect iridocorneal and keratolenticular adhesions as well other ocular abnormalities such as aniridia, congenital, aphakia, and abnormalities posterior to the iris, including ciliary body masses or irregularities. Awareness of these types of anterior segment abnormalities can aid surgical planning and reduce surgical complications. AS-OCT, once limited to the outpatient setting, can now also be performed intraoperatively with the advent of handheld OCT devices. This technology, similar to UBM, can identify the presence of iridocorneal adhesions, keratolenticular adhesions, and features of anterior staphyloma. It can also perform biometry and measure the depth of the anterior chamber as well as the thickness of the cornea. Advantages over the UBM include that it is a noncontact device, has quick image acquisition times, and uses infrared technology, which is helpful in photophobic patients. Disadvantages, however, include a limited ability to image structures posterior to the iris and its shallower depth of penetration.

With these examination considerations in mind, one can then refer to the STUMPED mnemonic developed by Waring and colleagues to reach a possible diagnosis (see Box 18.1 ). Although this mnemonic can serve as a useful framework for creating a differential diagnosis, it does not differentiate between disease entities with similar phenotypes and different underlying etiologies. Thus we propose a new approach to the classification of neonatal corneal opacities (see Box 18.2 ).

Sclerocornea ( S TUMPED)

Sclerocornea is a primary anomaly that involves scleralization of usually the peripheral part of the cornea occurs ( Fig. 18.4 ). Occasionally, sclerocornea involves the entire cornea ( Fig. 18.5 ). It may be an isolated finding or present in conjunction with other ocular defects. It generally appears sporadically but can also be autosomal dominant. The embryogenesis and genetics of sclerocornea are discussed in more detail in discussed in more detail in later chapters of this book. Sclerocornea is nonprogressive and usually bilateral, though commonly asymmetric (see Fig. 18.1 ). The opacification of the cornea is smooth, white, and vascular. Clinically, it appears to be an extension of the sclera into the cornea without limbal landmarks; typically it is greater peripherally than centrally. The vessels are fine continuations of conjunctival vessels, but deep vascularization can sometimes occur. Waring and Rodrigues have classified sclerocornea into the following four groups ^, :

• Isolated peripheral sclerocornea

• Sclerocornea plana

• Sclerocornea associated with cleavage anomalies of the anterior chamber

• Total sclerocornea

Isolated peripheral sclerocornea is diagnosed when there is an abrupt change from sclera-like tissue to clear cornea without other ocular abnormalities (see Fig. 18.4 ). Sclerocornea plana is diagnosed in the setting of a flat cornea with a keratometry readings of less than 38D and associated high hyperopia. The anterior chamber is usually shallow, but glaucoma is uncommon. Pseudoptosis can be seen because the flat cornea supports the upper lid poorly. Sharkey et al. reported an association with epidermolysis bullosa dystrophica. Reduced corneal sensitivity has also been reported. Sclerocornea associated with anterior chamber cleavage anomalies is diagnosed when sclerocornea is seen in the setting of other anterior segment anomalies, particularly Peters anomaly, characterized by paracentral iridocorneal or keratolenticular adhesions. Total sclerocornea is the most common form of sclerocornea causing congenital corneal opacity (see Fig. 18.5 ). The cornea is totally opaque and vascularized, but the central cornea is not as densely opacified as the peripheral cornea. The opacification generally affects the full-thickness of the stroma and thereby significantly limits visualization of the endothelium, pupil, and anterior chamber structures. Patients with sclerocornea sometimes exhibit systemic abnormalities including developmental delay and anomalies of the skin, face, ears, cerebellum, and testes. A list of ocular and systemic abnormalities associated with sclerocornea can be found in discussed in more detail in later chapters of this book. Histopathologically, the corneal stroma in sclerocornea resembles sclera. Precisely arranged corneal stromal lamellae are absent, and stromal vascularization is often present ( Fig. 18.6 ). Electron microscopy has also shown that the collagen fibrils of the corneal stroma are arranged irregularly and are variable in caliber. Most notably, their diameter is often markedly increased (up to 1500 Å), resembling the diameter of scleral fibrils ( Box 18.4 ). UBM and AS-OCT can assist in making the diagnosis of the sclerocornea ( Fig. 18.7 ) and facilitate surgical planning. ^,

The differential diagnosis of sclerocornea includes arcus juvenilis, interstitial keratitis, Peters anomaly, and microcornea, but it can be narrowed by history, clinical examination, the presence of ocular and systemic associations, and observation of the patient over time ( Table 18.1 ). Management is similar to that of other congenital corneal opacities. If the disorder is unilateral and the other eye has good visual acuity, the decision to operate becomes more difficult; in such a case surgery should be performed only if other ocular structures in the affected eye are relatively normal. If the condition affects the central corneas bilaterally, causing significant visual impairment, penetrating keratoplasty should be considered in an attempt to provide useful vision. As mentioned previously, additional imaging modalities should be considered to assess for concomitant ocular abnormalities prior to surgery in an effort to reduce the risk of surgical complications. Unfortunately, the prognosis for a clear graft is poor and is usually worse than in Peters anomaly. However, rates of success have improved in recent years with the use of topical cyclosporine.

Tears in the Endothelium and Descemet Membrane (S T UMPED)

Tears visualized in the Descemet membrane in the neonate are typically associated with one of two primary disorders: congenital glaucoma, classically diagnosed in the setting of horizontal breaks in the Descemet membrane, and forceps trauma, seen with vertical breaks in the Descemet membrane.

Congenital Glaucoma

Congenital glaucoma is the most important disease in the differential diagnosis of congenital corneal clouding because early diagnosis may allow adequate treatment and preservation of vision whereas delayed diagnosis can result in irreversible visual loss. All infants with unilateral or bilateral cloudy corneas must be evaluated carefully for glaucoma. Primary congenital glaucoma is usually sporadic but may be inherited as an autosomal recessive trait. The first symptoms of primary congenital glaucoma are epiphora, photophobia, and blepharospasm resulting from epithelial edema due to the elevated IOP. Early signs are corneal clouding and elevated IOP; late signs include corneal enlargement, increased axial length, and optic nerve cupping. Because the corneas and sclerae of infants and children are more elastic and distensible than those of adults, prolonged periods of increased IOP cause enlargement of the globe, or buphthalmos. The buphthalmic eye has a diameter greater than that of the normal infant cornea (see Box 18.2 ). Buphthalmos is generally not present in the immediate postpartum period; however, by 6 months of age, approximately 75% of affected infants will demonstrate corneal enlargement. ^, Other theories for buphthalmos include the thinner Descemet membrane in infants (3–4 μm) compared with that of the adult (10–12 μm), which corresponds to less protection of the cornea in the setting of elevated IOP. Additionally, as the eye enlarges and the cornea stretches, the resultant tension on the Descemet membrane causes it to break, leading to a disruption in the endothelial barrier and subsequent access of aqueous to the corneal stroma and epithelium; this manifests as corneal edema and clouding. Tears in the Descemet membrane can be single or multiple and generally appear as elliptical, glassy, parallel ridges on the posterior cornea, either peripherally or across the visual axis. These breaks, also known as Haab striae, have a random distribution, but are most commonly horizontal or concentric to the limbus ( Fig. 18.8 ), in contrast to the oblique and vertical orientation of the breaks in the Descemet membrane seen in birth trauma ( Fig. 18.9 ).

The management of congenital glaucoma is surgical, although topical antihypertensive drops can be employed as a temporizing measure. Procedures should be performed by a glaucoma specialist or a pediatric ophthalmologist experienced in the surgical management of congenital glaucoma. In general, if the view through the cornea allows for direct visualization of the angle, a goniotomy is the procedure of choice. If, however, the cornea is very cloudy, limiting a clear view of the anterior segment structures, a trabeculotomy is the preferred approach. If these procedures fail, trabeculectomy or aqueous shunt implantation may be considered.

Birth Trauma

Injury to the cornea at birth occurs from accidental placement of the forceps blade across the globe and orbit during delivery, causing acute elevation of IOP with globe distention and subsequent rupture of the Descemet membrane. ^, Other soft tissue injuries, such as unilateral periorbital edema and ecchymoses, may also occur. Left eyes seem to be affected more commonly than right eyes because neonates usually present in the left-occiput-anterior position. Descemet tears in birth trauma are usually unilateral, central, and, in contrast to congenital glaucoma, occur in a vertical or oblique pattern ( Table 18.2 and see Fig. 18.9 ), presumably because the tip of the forceps has slipped over the rim of the orbit and compressed the globe vertically. Consequently birth trauma produces diffuse stromal and epithelial edema in the immediate postpartum period (see Table 18.2 ). If the damage is not too severe, the corneal edema usually clears within weeks to months. The young endothelium resurfaces the posterior cornea and synthesizes a new thick basement membrane that accentuates the edges of the tear and fills in the area of dehiscence. Once the corneal edema has disappeared, the edges of the break appear as rounded glassy ridges that protrude from the posterior cornea and light up strikingly in retroillumination (see Fig. 18.9B ). Although the cornea remains clear, high residual corneal astigmatism, which may range from 4 to 9D, requires urgent correction and amblyopia treatment. The steep meridian of the astigmatism typically parallels the orientation of the Descemet ruptures. Once the corneal edema has resolved, refraction for glasses or contact lenses should be performed as soon as possible. Early fitting with rigid gas-permeable lenses has been reported to successfully prevent amblyopia secondary to severe astigmatism and anisometropia ( Fig. 18.10 ). However, patching or atropine therapy are typically necessary to treat underlying amblyopia in conjunction with correction of the refractive error. The corneal specialist should work closely with a pediatric ophthalmologist to manage amblyopia effectively. Later in life, the previously stressed endothelium may decompensate, with resulting corneal edema that requires penetrating keratoplasty or endothelial surgery to restore vision. ^,

TABLE 18.2

Distinguishing Features of Birth Trauma and Congenital Glaucoma

Birth Trauma	Congenital Glaucoma
Normal IOP	High IOP
Normal corneal diameter	Large corneal diameter with buphthalmos (may return to normal with IOP lowering)
Corneal edema immediately postpartum	Corneal edema weeks or months after birth
Corneal edema clears after weeks to months	Corneal edema clears after IOP lowering
Vertical or oblique tears in Descemet membrane	Horizontal or concentric tears in Descemet membrane
Higher incidence in left eyes, often with other associated soft tissue injuries	Equal incidence between right and left eyes
No photophobia	Photophobia present

IOP , Intraocular pressure.

A second type of trauma that can cause corneal opacity occurs in amniotic band syndrome. A portion of the amniotic band may stretch across the face in utero, often causing a cleft lip, which is sometimes associated with microphthalmia and a cloudy cornea, possibly secondary to direct corneal trauma as opposed to tears in the Descemet membrane.

Corneal Ulcers and Inflammation (ST U MPED)

Congenital opacities caused by corneal ulcers are rarely present at birth. But when a fluorescein-staining epithelial defect does occur in a neonate, the ophthalmologist should consider infectious and neurotrophic etiologies. This section begins with the infectious agents that are transmitted in utero from mother to fetus and cause congenital corneal opacification at birth without epithelial defects. Then, the discussion goes on to cover the common infectious agents transmitted in the perinatal period that can cause corneal pathology with or without epithelial defects. Last, hereditary causes of neurotrophic keratitis that cause corneal inflammation, sterile ulcers, and subsequent opacification are considered.