Corneal abnormalities in childhood

Keratoconus

Keratoconus is the most common corneal dystrophy, affecting about 1 in 375 of the general population in North Europe, although modern corneal imaging suggests that the prevalence may be as high as 1 in 45 in some ethnic groups. The disease is significantly more common in South Asian and Black populations; early onset and South Asian ethnicity are associated with rapid progression. It results in progressive corneal thinning with a conical corneal shape that can cause refractive myopia, irregular astigmatism, and corneal scarring. Rare variants are pellucid marginal degeneration, in which there is an arc of thinning close to the inferior limbus, and keratoglobus, in which there is diffuse thinning of the whole cornea. The onset of keratoconus is uncommon before the age of 10 years, but it is now identified in younger patients than previously due to the increased availability of corneal imaging equipment. The main conditions associated with keratoconus are chronic allergic eye disease, Down syndrome, and Leber congenital amaurosis – all of which may result in severe and chronic eye rubbing. Keratoconus may also be a feature of some connective tissue disorders, e.g. Ehlers–Danlos syndrome and brittle cornea syndrome, although keratoconus is rarely the presenting feature of these conditions. It is a complex genetic disease and a recent large genome-wide association study (GWAS) identified multiple genomic loci implicating dysfunction of the corneal collagen matrix and cell differentiation as disease mechanisms.

Early diagnosis and monitoring of keratoconus are important since corneal collagen cross-linking can arrest disease progression in the majority (98%) of cases. A diagnosis of keratoconus is suggested by an increase in astigmatism and a scissors reflex at refraction, but confirmation of early disease requires computerized corneal tomography ( Fig. 32.1 ). Serial computerized imaging is now the standard of care to monitor for progression, initially at 3-monthly intervals ( Table 32.1 ). Although keratoconus progression usually stops in the third to fourth decade, children should be considered at risk of progression and monitored until the corneal shape has been stable for 2 years. A characteristic of keratoconus in children and adolescents is its tendency to present with unilateral advanced disease ; acute corneal hydrops can be the presenting feature.

Complications of keratoconus are uncommon and include corneal hydrops, from an acute split in Descemet's layer ( Fig. 32.2 ). There is a sudden onset of discomfort and blur with a dense central corneal opacity from tissue swelling due to entry of aqueous into the corneal stroma. The natural history of a corneal hydrops is for gradual resolution over 3–4 months, but a residual corneal scar often reduces the vision. Secondary corneal neovascularization is a risk if there is a large hydrops adjacent to the limbus, or if there is associated severe allergic eye disease, in which case topical corticosteroid should be considered until the hydrops resolves. Secondary infection or perforation is rare, but a topical antibiotic is indicated if there is an epithelial defect. Other treatments such as hypertonic 5% saline or IOP-lowering agents are ineffective. Corneal compression sutures, or endothelial keratoplasty, have been proposed to accelerate the resolution of a hydrops, but these are not always effective and the visual outcome is unchanged. In addition, these interventions require intracameral gas injection, which carries a significant risk of iris ischemia and cataract from pupil block.

The aim of management for keratoconus is to restore functional vision. In early disease this may be achieved with glasses, but as the disease progresses glasses do not correct the irregular component of the astigmatism and contact lenses may then be required. Rigid gas-permeable contact lenses give a better level of vision than soft or soft toric contact lenses, with less risk of secondary complications (infection, corneal neovascularization), and are a suitable option once disease advances to the stage that vision in the better eye requires correction. Keratoplasty is indicated if there is advanced bilateral disease when a contact lens cannot be retained, or if there is poor vision (<6/12) even with contact lens correction. However, it is uncommon for the disease to progress to this stage in childhood. In the absence of a prior corneal hydrops, a deep anterior lamellar keratoplasty (DALK) is the treatment of choice rather than a penetrating keratoplasty because there is a lower risk of allograft rejection and a lower risk of wound dehiscence following injury.

Corneal collagen cross-linking (CXL) is the only intervention that has been demonstrated to arrest the progression of keratoconus. The preferred technique (see Chapter 33 ) is to remove the corneal epithelium to allow penetration of topical riboflavin into the corneal stroma, followed by irradiation with ultraviolet B (UVB). This can normally be performed in children with topical anesthesia, although mild sedation may be required. A controlled clinical trial has confirmed that treatment is effective in children. Effective postoperative pain management is essential, but temporary therapeutic soft contact lenses are not recommended because of the risk of infection. Any associated allergic eye disease must be fully controlled before treatment. Although transepithelial CXL is being developed, which would avoid epithelial debridement with the associated pain, the efficacy compared to standard treatment has not yet been demonstrated. Because of the risk of complications, it is usual to confirm progression with serial tomography before treatment is offered. It is not known whether repeat CXL treatment is safe. Potential complications of CXL include microbial infection and corneal scar.

Brittle cornea syndrome

Brittle cornea syndrome (BCS) is a rare autosomal recessive condition characterized by blue sclera and extreme thinning of the cornea. There is a risk of corneal rupture after minor trauma, which may be the first manifestation of disease ( Fig. 32.3 ). BCS is caused by biallelic mutations in either the ZNF469 gene (BCS1) or the PRMD5 gene (BCS2), but the corneal phenotypes are similar. ZNF469 is a transcription factor that plays an important role in normal anterior segment development and corneal thickness. Similarly, PRDM5 has an important role in the development and maintenance of the extracellular matrix. BCS is a generalized connective tissue disorder with associated joint hypermobility, scoliosis, deafness, and hyperelasticity of the skin. Affected individuals should restrict physical activity and wear protective acrylic glasses at all times to reduce the risk of accidental traumatic eye rupture. Scleral lenses may be an alternative in older patients. Extreme secondary central corneal ectasia (similar to keratoconus) can occur, and in these individuals the option of a limbal-sparing onlay corneo-scleral transplant to structurally support the cornea should be considered.

Blue sclera

Blue-tinged sclera is the result of scleral translucency or thin sclera with choroidal show-through. It may be present in normal children, particularly if there is high myopia. Blue sclera is associated with a wide range of skin and musculoskeletal abnormalities, but it is most frequently seen in association with pseudoxanthoma elasticum, osteogenesis imperfecta, Ehlers–Danlos syndrome, Marfan syndrome, alkaptonuria, or hypophosphatasia syndrome. Early referral to a pediatrician for systemic review is essential.

Increased diameter

Buphthalmos

This is enlargement of the cornea resulting from the raised intraocular pressure of primary congenital glaucoma (see Chapter 36 ). Increased corneal diameter is also a feature of X-linked megalocornea. Forceps injury can cause unilateral corneal edema from birth, although the cornea is not enlarged. The edema will usually resolve leaving characteristic oblique splits in Descemet's layer ( Fig. 32.4 ), with oblique astigmatism. There is a high risk of secondary amblyopia.

X-linked megalocornea (MGC1)

X-linked megalocornea (MGC1) is a congenital bilateral enlargement of the cornea, characterized by a horizontal white-to-white diameter of ≥13 mm (typically 14–16 mm) when measured after the age of 2 years. The corneas are clear but there is generalized reduced corneal thickness (470–500 µm), an abnormally deep anterior chamber (4–6 mm), and trabeculodysgenesis but without raised intraocular pressure (IOP) ( Fig. 32.5 ). This is one of the rare situations in which the trabecular meshwork can be viewed directly without the use of a gonioscopic mirror or lens. Affected individuals have normal vision. The corneal morphology is static but other secondary degenerative features develop with age (>40 years), including corneal arcus, mosaic stromal corneal degeneration (shagreen), iris atrophy, lens dislocation and cataract. Despite a striking focal loss of myelination of white matter on magnetic resonance imaging (MRI) there is no cognitive deficiency. The genetic cause of MGC1 are hemizygous mutations in CHRDL1 . Female carriers are unaffected . CHRDL1 encodes chordin-like protein 1, an antagonist of bone morphogenetic protein 4 (BMP4), which plays a role in anterior segment development. CHRDL1 normally antagonizes the function of BMP4, and in its absence unregulated growth of the anterior eye occurs during development.

MGC1 is almost always a benign condition that is not associated with juvenile glaucoma. It is important to distinguish MGC1 from primary congenital glaucoma (PCG) during infancy to avoid unnecessary investigation. Infants with suspected MGC1 should have genetic screening for changes in the CHRDL1 gene. In the absence of genetic testing the deep anterior chamber in MGC1 and the low ratio of anterior chamber depth to axial length on B-scan ultrasonography is a reliable indicator.

Megalocornea is also a feature of megalocornea–mental retardation (MMR; Neuhäuser syndrome). The condition is rare and associated with neurological symptoms including mental retardation, hypotonia, and seizures. Syndromic facial features include a prominent forehead, broad nasal root, epicanthus, large low-set ears, long upper lip, and anteverted nostrils. The genetic cause of MMR syndrome is currently unknown.

Microcornea

Microcornea is a corneal horizontal diameter of ≤9 mm at birth. It may be unilateral or bilateral and may be an isolated finding or associated with dysmorphism, microphthalmos or nanophthalmos ( Fig. 32.6 ). It may be associated with posterior polar cataract (microcornea–cataract syndrome with mutations of the ABCA3 gene identified in Chinese patients), coloboma, sclerocornea, cornea plana, Peters anomaly, or oculocerebrofacial syndrome. B-scan ultrasonography is essential for a full assessment. The cornea can be clear with a normal thickness, but is more usually flat with low keratometry values and a resultant hyperopia, with a risk of secondary glaucoma. When microcornea is an isolated finding, there is a good visual prognosis with correction of refractive error, but other ocular or systemic associations often reduce the vision.

Superficial keratopathy

This may be a focal, linear, or vortex pattern. The causes of focal superficial lesions include punctate epitheliopathy from dry eye disease, Thygesson superficial keratopathy ( Fig. 32.8 ), staphylococcal hypersensitivity spots, adenoviral keratoconjunctivitis, and rarely Meesmann corneal dystrophy. Linear epithelial lesions include dendritic ulceration (herpes simplex) or mucous plaque keratopathy (herpes zoster). A very rare linear kerotopathy associated with tyrosinemia type II is also described as pseudodendritic, although this is not normally the presenting feature of this disease. Tyrosinemia type II ( Fig. 32.9 ) is autosomal recessive and due to mutations of the TAT gene encoding tyrosine aminotransferase. There is bilateral keratitis with intense photophobia and associated painful palmar and plantar lesions (palmoplantar keratoderma), mental retardation, and raised serum tyrosine. It is treatable with a low-tyrosine and low-phenylalanine diet.

Vortex keratopathy is a normal physiologic appearance during epithelial wound healing, but in the absence of a prior epithelial defect it can be a feature of chronic drug ingestion (e.g. amiodarone) ( Fig. 32.10 ). It is also a feature of Fabry disease, an X-linked recessive lipidosis caused by a mutation of the GLA gene encoding α-galactosidase-A, with deposition of glycosphingolipid in the cytoplasm of the epithelial cells. There may also be conjunctival and retinal vascular tortuosity and spoke-shaped cataract.

Thygeson superficial punctate keratitis

This has been reported in children as young as 2 years. Symptoms include photophobia, discomfort, and blurred vision. Coarse elevated epithelial lesions (1 to 50) with minimal stromal reaction and an absence of peripheral corneal vascularization, conjunctivitis or upper tarsal conjunctival inflammation are characteristic (see Fig. 32.8 ). The cause is a presumed immune response against an, as yet, unidentified pathogen (possibly viral). Initial treatment is with topical lubricants. Low-dose topical steroid (e.g. fluromethalone 0.1% once daily or less) is effective but may prolong the course of the disease. Cyclosporine 1% drops are also effective. Daily-wear therapeutic contact lenses may be an option to control the chronic irritation in older children. The lesions recur after epithelial debridement. Despite a potentially protracted course lasting several years, the visual prognosis is excellent.

Corneal deposits and crystals

Corneal deposits occur in several conditions; some indicate localized disease, but some have important systemic associations. Corneal deposits are of different types: (1) lipid (e.g. Schnyder corneal dystrophy), Tangier disease (lecithin–cholesterol acyltransferase deficiency [LCAT]); (2) protein (cystinosis, monoclonal gammopathy); (3) mucopolysaccharide, including Hurler, Scheie, and Hurler–Scheie syndromes (MPS I), Morquio syndrome (MPS IV), and Maroteaux–Lamy syndrome (MPS VI) ( Fig. 32.11 ); (4) bacteria and bacterial biofilm (infectious crystalline keratopathy); (5) mineral deposits (band-shaped degeneration of calcium, calcareous degeneration, hyperuricemia, iron, copper, silver, lead, gold); (6) drug (topical ciprofloxacin, chlorpromazine, chloroquine). In the majority of cases a history of drug therapy, or associated systemic or ocular pathology, will help guide the diagnosis. Biopsy is very rarely indicated for diagnosis.

Cystinosis

Cystinosis is a rare (1:175,000) autosomal recessive lysosomal storage disease caused by a failure to transport the amino acid cysteine out of the lysosomes. Cystine (a dimer of two cysteine molecules) accumulates with intracellular crystal formation in all tissues including the eye. In addition to corneal crystals, retinal depigmentation also appears by 3–7 years of age, progressing to legal blindness in 15% of cases. Abnormalities of the anterior chamber angle from crystal deposition in the trabecular meshwork can lead to secondary glaucoma. Excess cystine can be detected by measuring serum levels of cystine-binding protein, which can be used to confirm a clinical diagnosis. Genetic confirmation is by detection of mutations of the CTNS gene that encodes cystinosin, which is the lysosomal membrane transport protein for cystine. Cystinosis is classified in three forms according to age of onset and severity: the most common (95%) is infantile nephropathic cystinosis which manifests at 6–12 months. There is renal proximal tubular dysfunction (renal Fanconi syndrome) that untreated leads to growth retardation and end-stage renal disease by age 10 years. The juvenile form (5%) has an onset at 12–15 years present with proteinuria but does not have such severe renal impairment or growth retardation. Finally, an adult onset form develops corneal crystal but without renal or growth impairment ( Fig. 32.12 ).

Patients in all subtypes may be severely photophobic, although the visual acuity may be preserved in reduced light. The corneal appearance is of myriads of needle-shaped, highly refractile crystals, initially concentrated in the anterior periphery, but with spread to involve all layers of the cornea including the endothelium. They are easily identified at the slit-lamp. Secondary corneal changes include superficial punctate keratopathy, recurrent corneal epithelial erosion, filamentary keratitis, and band-shaped keratopathy.

Lifelong systemic cysteamine is the treatment of choice for nephropathic disease. This breaks down cystine into smaller products that can traverse the lysosome membrane. Early treatment can protect tubular function and minimize any retinopathy, but management of the renal impairment and growth retardation is usually also necessary. Oral treatment does not reduce corneal crystal accumulation, probably due to inadequate tissue concentration, but topical cysteamine is safe and effective. The recommended dose is 0.44% cysteamine hydrochloride solution used 10–12 times per day.

Schnyder corneal dystrophy is described below. The corneal crystals of Bietti retinopathy are tiny, peripheral, and do not affect vision.

Secondary lipid deposition

The deposition of lipid in the cornea is normally preceded by corneal neovascularization (e.g. following recurrent stromal herpes simplex virus [HSV] keratitis or vernal keratoconjunctivitis), but may also develop in an arc (pseudogerontoxon) central to an area of recurrent conjunctival or episcleral inflammation at the limbus (e.g. limbal vernal keratoconjunctivitis) ( Fig. 32.13 ). It may also develop as a complication of congenital vascularization (e.g. limbal dermoid) or as a late association with aniridic keratopathy.

Corneal arcus

Phospholipids, low-density lipoproteins, and triglycerides are deposited in the stroma and the peripheral cornea in the absence of an epithelial defect ( Fig. 32.14 ). When this appears in children, familial hypercholesterolemia (Fredrickson type II) and hyperlipoproteinemia (type III) should be excluded.

Diffuse lipid infiltration and opacity can occur in other systemic diseases of lipid metabolism such as lecithin–cholesterol acyltransferase (LCAT) deficiency and Tangier disease.