Epidemiology and Pathogenesis

The pathogenesis of keratoconus is not fully understood, although both genetic and environmental processes are likely to be involved. Keratoconus is probably not a single disorder but, rather, a phenotypic expression of several possible causes.

A hallmark of keratoconus is stromal thinning, which may be related to alterations in enzyme levels in the cornea, causing stromal degradation. This is supported by multiple studies suggesting increased levels of degradative lysosomal enzymes and decreased levels of inhibitors of proteolytic enzymes in corneal epithelium. These findings are consistent with the observation of increased collagenolytic and gelatinolytic activity in keratoconic cells.

Increased apoptosis of stromal keratocytes has been reported in keratoconus, as suggested by confocal microscopy. It is postulated that this loss of keratocytes results in a decrease in collagen and extracellular matrix production, leading to reduced stromal mass. Other investigators have suggested that abnormalities in corneal collagen and its cross-linking may be the cause of keratoconus.

Eye rubbing is strongly associated with the development of keratoconus. The mechanism by which eye rubbing contributes to keratoconus is not completely understood, but it may be related to mechanical epithelial trauma, triggering a wound-healing response that leads to keratocyte apoptosis. Other factors, such as slippage of collagen fibrils and a decrease in ground substance viscosity, may play a role. The cytokine interleukin-6 has been suggested as a mediator of eye rubbing and stromal degradation.

The prevalence of keratoconus in the general population varies in different series. A recent study that evaluated 4.4 million patients from a mandatory health insurance database found the estimated prevalence of keratoconus in the general population to be 1 out of 375 persons.

Ocular Manifestations

Manifestations of keratoconus include steepening of the cornea, especially inferiorly ( Fig. 4.18.1 ), thinning of the corneal apex, scarring at the level of Bowman’s layer, and deep stromal stress lines that clear when pressure is applied to the globe. A ring of iron deposition (Fleischer’s ring) ( Fig. 4.18.2 ) can accumulate in the epithelium at the base of the cone. Steepening of the cornea leads to clinical signs which include protrusion of the lower eyelid on downgaze (Munson’s sign), focusing of a light beam shone from temporally across the cornea in an arrowhead pattern at the nasal limbus (Rizutti’s sign), and a dark reflex in the area of the cone on observation of the cornea with the pupil dilated using a direct ophthalmoscope set on plano (Charleaux’s sign) ( Fig. 4.18.3 ). In addition, a scissoring reflex can be found on retinoscopy. In some patients who have keratoconus, especially if associated with trisomy 21 (Down syndrome), acute corneal hydrops may occur, in which an abrupt rupture of Descemet’s membrane results in acute overhydration of the cornea and accumulation of lakes of fluid within the corneal stroma. Over time, endothelial cells spread over the posterior stromal defect to lay down new Descemet’s membrane and recompensate the cornea ( Fig. 4.18.4 ).

Characteristic conical steeping of the cornea in keratoconus.

Severe Apical Thinning in a Cornea With Keratoconus.

A broader slit-beam view of the same cornea (B) reveals extensive stromal apical scarring and linear breaks in Bowman’s layer.

Charleaux’s sign in keratoconus, delineating the extent of the cone.

Massive Hydrops in Keratoconus.

Note the large tear in Descemet’s membrane.

Diagnosis

Topography and tomography are useful to confirm the diagnosis of keratoconus and, in some cases, even to make the diagnosis of subtle cases without clinical manifestations (see Fig. 4.18.3 ). Both placido disc and rotating Scheimpflug camera systems for assessing corneal curvature are reliable in distinguishing keratoconic eyes from normal eyes, although there may be differences in posterior elevation measurements between the two systems. The Rabinowitz criteria can be used for the diagnosis of keratoconus, and they include K greater than +47.20 diopters (D), inferior-versus-superior corneal dioptric asymmetry value greater than +1.40 D, KISA% greater than 60%, which is suggestive of the disease, whereas more than 100% strongly suggests keratoconus, and a pachymetry/asymmetry index of less than 105. KISA% index quantifies the topographical features seen in keratoconus. It includes the K-value, the inferior–superior dioptric asymmetry, and the AST index, which quantifies the degree of regular corneal astigmatism.

Such analyses have been used to demonstrate that keratoconus is almost always a bilateral disease, even when not evident in the fellow eye as seen under at the slit lamp.

The inheritance pattern of keratoconus is incompletely defined. In the past, it was believed that more than 90% of cases were sporadic. With the advent of videokeratography to assess family members, however, pedigrees have been analyzed. These studies show corneal changes consistent with keratoconus in some asymptomatic family members, which suggests an autosomal dominant pattern of inheritance.

Differential Diagnosis

The differential diagnosis of keratoconus includes pellucid marginal corneal degeneration, post–refractive surgery corneal ectasia, posttraumatic corneal ectasia, protrusion of the cornea after corneal thinning from ulceration, and keratoglobus.

Systemic Associations

A number of systemic and ocular disorders have been described in association with keratoconus. Conditions found to have increased odds of keratoconus include sleep apnea, asthma, and Down syndrome. Interestingly, patients with diabetes mellitus and collagen vascular disease have been found to have lower odds of keratoconus, and no association has been found between keratoconus and allergic rhinitis, mitral valve disorder, aortic aneurysm, or depression. Other systemic associations include Ehlers–Danlos, Marfan’s, Cruzon’s, and Apert’s syndromes. Ocular-associated disorders include Leber’s congenital amaurosis, retinitis pigmentosa, and retinopathy of prematurity. Fuchs’ dystrophy and posterior polymorphous dystrophy have been reported as well.

Pathology

Histopathology shows irregular epithelium and breaks in Bowman’s layer with fibrosis filling in the breaks and extending beneath the epithelium ( Fig. 4.18.5 ), and central corneal thinning. With hydrops, breaks at the level of Descemet’s membrane are seen with inward curling of the membrane, which is otherwise normal. Electron microscopy shows decreased thickness of the cornea with fewer lamellae. The collagen fibrils in the lamellae are thinned mildly, and the space between fibrils is decreased.

Keratoconus.

Breaks in Bowman’s layer, with fibrosis that extends beneath the epithelium, can be seen. The stroma shows scarring.

Treatment

Treatment consists of spectacles for myopic astigmatism and then rigid contact lenses or scleral lenses once spectacle-corrected visual acuity (SCVA) becomes inadequate. When contact lenses fail, surgical treatment is indicated. In one series, the reasons for penetrating keratoplasty were contact lens intolerance (83%), frequent contact lens displacement (8.5%), and unsatisfactory visual acuity despite good fit of contact lenses (8.5%).

Standard surgical treatment consists of deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PKP). Keratoconus accounted for 14.8% of all penetrating keratoplasty and 38.3% of all DALK carried out in the United States in 2015. At the time of keratoplasty, decreasing the donor/recipient size disparity reduces postkeratoplasty myopia. Primary advantages of DALK over PKP include increased structural integrity and reduced risk of graft rejection. Some surgical techniques, such as the big-bubble technique, have reduced surgical operating time, though it remains challenging to perform, especially for inexperienced surgeons. Bowman’s layer graft is another surgical technique in the treatment of keratoconus. It was shown to be beneficial in a small series, where reduction and stabilization of corneal ectasia were achieved in eyes with progressive, advanced keratoconus.

Intracorneal ring segments, first described for keratoconus in 2000, have been shown in several studies to be successful in reducing myopia and astigmatism and improving SCVA. The ring segments can be inserted into the stroma either via mechanical dissection or femtosecond laser assistance. Currently Intacs (Addition Technology, Sunnyvale, CA) is the only intrastromal corneal ring segment approved in the United States.

Another less invasive technique that was approved by the Food and Drug Administration (FDA) in the United States in August 2016 is combined riboflavin–ultraviolet A rays (UVA) corneal cross-linking. This procedure, first described in 1998, consists of photopolymerization of corneal stroma by combining riboflavin (photosensitizing substance) with UVA. This process increases corneal rigidity and thus reduces the likelihood of further ectasia. Cross-linking is indicated in patients with documented progressive corneal ectasia. Contraindications include corneal thickness less than 400 microns (although use of hypotonic solutions may allow swelling to greater than this level prior to treatment), prior herpetic infection, concurrent infection, severe corneal scarring, history of poor epithelial wound healing, severe ocular surface disease, and autoimmune disorders. Various protocols with different treatment and epithelium handling are under ongoing evaluation. Currently, the only FDA-approved protocol in the United States is the “epithelium off” protocol, where the cornea is treated after epithelial removal, but “transepithelial” corneal cross-linking continues to be studied and refined.

Course and Outcome

The natural course of untreated keratoconus can be unpredictable, although progressive myopia, irregular astigmatism, and corneal scarring are typical. It is widely estimated that 10%–20% of patients with keratoconus undergo keratoplasty, although a recent report found as much as a 25% reduction in the performance of keratoplasty since corneal cross-linking began to be used. Keratoplasty outcomes in terms of graft clarity and improved vision are excellent, although residual astigmatism and myopia remain problematic. Recurrence of keratoconus after keratoplasty may rarely occur, although thinning and ectasia at the inferior host–graft junction is not uncommon 15 or more years after keratoplasty. Some authors have postulated that recurrence could be related to incomplete excision of the cone at the time of surgery, unrecognized keratoconus in the corneal donor, or host cellular activity that causes changes in the donor corneal material.

In one study on the long-term outcomes of intracorneal ring segments, with 17 eyes and 5-year follow-up, Intacs placement reduced mean spherical equivalent refractive error from −5.54 ± 5.02 D to −3.02 ± 2.65 D ( P ≡ .01), reduced mean keratometry from 49.59 ± 5.10 D to 48.02 ± 4.99 D ( P ≡ .009), and improved uncorrected visual acuity in 77% of patients. Complications of Intacs include infection, corneal melt, and ring extrusion. One study showed significant postoperative problems in 30% of Intacs with thinning and ring exposure.

Results of long-term follow-up of corneal cross-linking are promising. Data from the Siena Eye Cross Study in Italy revealed a mean hyperopic shift in spherical equivalent of +2.15 D and a mean reduction in keratometry of +2.26 D on 4-year follow-up of 44 patients. Complications include temporary stromal edema, temporary or permanent corneal haze, corneal scarring, sterile infiltrates, infectious keratitis, and diffuse lamellar keratitis.

Both intracorneal ring segments and corneal cross-linking are most likely to be beneficial in patients with mild to moderate keratoconus without corneal scarring; in these patients, stabilization of keratoconus may obviate or delay the need for keratoplasty. More advanced cases typically need keratoplasty for optimal visual outcome.