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1.What is keratoconus?

Keratoconus is a noninflammatory ectatic disorder of the cornea that leads to variable visual impairment. The cornea becomes steepened and thinned, thereby inducing myopia and irregular astigmatism. In advanced stages the cornea assumes a conical shape, hence the term keratoconus. The condition is usually bilateral, although frequently asymmetric.

2.Who gets keratoconus?

It is difficult to estimate the incidence of keratoconus because the diagnosis is easily overlooked, especially in the early stages. The reported incidence varies between 1 and 20 per 100,000 per year with a mean prevalence of 54.4 per 100,000. Some studies report a female predominance, whereas other studies report a male predominance. There is no known racial predilection.

3.What is the cause of keratoconus?

The cause of keratoconus is unknown. The etiology is multifactorial with both genetic and environmental factors playing a role. Various biochemical abnormalities have been documented in keratoconic corneas, including reduced collagen content, decreased or altered keratin sulfate molecules, reduced total protein and increased nonproteinaceous material, and increased collagenolytic and gelatinolytic activity associated with reduced matrix metalloproteinase inhibitor levels. Several studies have shown that the enzyme and proteinase inhibitor abnormalities are most prominent in the epithelial layer of the cornea. This suggests that the basic defect in keratoconus may reside in the epithelium and its interaction with the stroma. Additional studies implicate abnormal processing of free radicals and superoxide within keratoconus corneas leading to buildup of destructive aldehydes and/ or peroxynitrites. Eye rubbing has been implicated as a cause of keratoconus. When asked, patients with keratoconus will frequently admit to excessive eye rubbing.

4.What is the relationship between contact lens wear and keratoconus?

The relationship between contact lens wear and keratoconus is controversial. Circumstantial evidence suggests that contact lens wear may lead to the development of keratoconus, especially long-term use of rigid contact lenses. Such patients tend to present at an older age and have a flatter corneal curvature than typical patients with keratoconus. In addition, the so-called contact lens-induced cones tend to be more centrally located in the cornea than the more typical cones, which are characteristically decentered inferiorly.

Contact lens warpage is diagnosed when contact lens wear induces irregular astigmatism without slit lamp features of keratoconus. Discontinuing lens wear for weeks to months eliminates the irregular astigmatism and allows the cornea to resume its normal shape, whereas in the so-called contact lens-induced keratoconus the changes are permanent and do not resolve when contact lens wear is discontinued.

Some contact lens practitioners are of the opinion that contact lenses can be used to flatten the cornea and reverse or at least retard further progression of keratoconus. However, I believe that corneal flattening induced by contact lens wear in patients with keratoconus is temporary and that the cornea ultimately reverts to its pre-contact lens shape once lens wear is discontinued.

5.Is keratoconus hereditary?

The role of heredity in keratoconus has not been clearly defined. The majority of cases occur sporadically with no familial history. However, some cases of keratoconus are transmitted within families. One study used corneal topography to diagnose subclinical cases of keratoconus. Familial transmission was documented in 7 of 12 families (58.3%) of patients with keratoconus and no known family history of corneal or ocular disease. The authors postulate autosomal dominant inheritance with incomplete penetrance as the mode of transmission. Other studies report that 6 to 25% of keratoconus patients have a positive family history, and there are numerous reports of concordance between monozygotic twins and discordance between dizygotic twins. Autorecessive inheritance has been suggested in

a few studies with high consanguinity. Numerous genetic loci have been mapped in keratoconus

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families but as of today no genetic mutations have been confirmed. It may be that there are multiple genes involved in the development of keratoconus. Genetic heterogeneity may also be involved in keratoconus wherein different gene abnormalities manifest a similar phenotype.

6.What systemic conditions are associated with keratoconus?

There is a definite relationship between atopy and keratoconus. The prevalence of atopic diseases such as asthma, eczema, atopic keratoconjunctivitis, and hay fever is higher in patients with keratoconus than in normal controls. Atopic patients are bothered by ocular itching, and excessive eye rubbing also may contribute to the development of keratoconus.

There is an association between Down syndrome and keratoconus. Approximately 5% of patients with Down syndrome manifest signs of keratoconus. The incidence of acute hydrops in keratoconus patients with Down syndrome is definitely higher than in patients without Down syndrome. As in atopic subjects, keratoconus patients with Down syndrome tend to be vigorous eye rubbers. This may explain, at least in part, the relationship with keratoconus.

Keratoconus is also associated with various connective tissue disorders, such as Ehlers-Danlos syndrome, osteogenesis imperfecta, and Marfan’s syndrome. There are conflicting reports of an association between keratoconus, mitral valve prolapse, and joint hypermobility. One study has reported an association between keratoconus and false chordae tendineae in the left ventricle. The relationship between various connective tissue diseases and keratoconus suggests a common defect in the synthesis of connective tissue.

7.What ocular conditions are associated with keratoconus?

Keratoconus has been described in association with various ocular diseases, including retinitis pigmentosa, Leber’s congenital amaurosis, vernal conjunctivitis, floppy eyelid syndrome, corneal endothelial dystrophy, and posterior polymorphous corneal dystrophy.

8.What are the symptoms of keratoconus?

The characteristic onset of keratoconus is in the late teens or early twenties, although earlier and later onset has been reported. Symptoms usually begin as blurred vision with shadowing around images. Vision becomes progressively more blurred and distorted with associated glare, halos around lights, light sensitivity, multiple images, and ocular irritation.

9.How is the diagnosis of keratoconus made?

During the early stages of keratoconus, the patient presents with myopic astigmatism, and a normal slit lamp examination. Corneal topography/tomography is helpful in documenting the presence of keratoconus even before keratometric or slit lamp findings become apparent. As the disease progresses an irregular light reflex with scissoring on retinoscopy can be appreciated through the dilated pupil. The cornea steepens and thins with irregularity of the mires on keratometry. Obvious signs of keratoconus become apparent at the slit lamp.

KEY POINTS: DIAGNOSIS OF KERATOCONUS

1. Topographic mapping of the anterior corneal surface.

2. Elevation analysis of the anterior and posterior corneal surfaces. 3. Slit lamp examination of the cornea.

4. Evaluation of the light reflex through a dilated pupil.

10.What are the topographic signs of keratoconus?

With conventional topography, the Placido rings of light are reflected off the cornea, and corneal curvature is derived from the distance between the rings and displayed as a color-coded map. Distortion of the rings is noted early on in the disease.

a.The characteristic sign of keratoconus on topography is inferior midperipheral steepening (Fig. 13-1). Numerous studies have tried to develop quantitative topographic parameters to define keratoconus. In one study, central corneal power >47.20 diopters (D) combined with steepening of the inferior cornea compared with the superior cornea of >1.20 D detected 98% of patients with keratoconus. However, it may be difficult to make a definitive diagnosis of keratoconus based on topographic findings alone. This is of particular importance in patients seeking refractive surgery because the results

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Figure 13-1.  Map showing symmetric inferior steepening.

of the surgery are poorly predictable in patients with keratoconus. Patients with apparently normal corneas may have inferior midperipheral steepening >1.20 D but normal central corneal powers in the range of 43 to 45 D. It is difficult to know whether such patients represent a forme fruste of

keratoconus and, as such, should be dissuaded from considering refractive surgery, especially LASIK because such surgery can result in cornea ectasia, in effort manifesting characteristic signs and symptoms of keratoconus. However, excimer laser photofractive keratectomy can be a viable option in select patients with borderline findings. Each case must be analyzed on an individual basis.

b.Corneal tomography units utilize scanning slit technology or a Scheimpflug-based imaging system to document corneal shape, corneal thickness measurements across the cornea, and elevation of the front and back corneal surfaces in relation to a computer-generated best-fit sphere. These instruments also present standard Placido disc color maps. The additional information, especially the corneal elevation and corneal thickness profile, is very helpful in differentiating between forme fruste or early keratoconus and nonkeratoconic corneas. Of particular note is when the thinnest area of the cornea corresponds with the area of minimal maximal elevation. Some of the units provide specialized diagnostic software to help with making the diagnosis of keratoconus. In addition, some tomography units, as well as some high-frequency ultrasound biomicroscopy machines, provide corneal epithelial thickness profiles that add to our diagnostic armamentarium. The corneal epithelium tends to be thinner over the area of corneal ectasia, which is usually decentered inferiorly with compensatory epithelial thickening centrally. However, no technology is 100% specific and 100% sensitive, requiring the surgeon’s input, especially when evaluating patients presenting for refractive surgery.

11.What are the slit lamp findings of keratoconus?

The earliest slit lamp signs of keratoconus are apical thinning and steepening, usually located inferior to the center of the pupil. As the keratoconus progresses, the thinning and ectasia become more prominent with the development of apical scarring that begins in the anterior stroma and progresses into in the deeper layers of the stroma (Figs. 13-2 to 13-5). Fine linear striae become apparent in the deep stroma just anterior to the Descemet’s membrane, usually oriented vertically or obliquely. They are thought to represent stress lines in the posterior stroma and are known as Vogt’s striae. They can be made to disappear when the intraocular pressure is transiently raised by applying external pressure to the globe. In some mild cases of keratoconus, the pressure from rigid gas-permeable contact lens wear can induce the formation of such striae, which disappear

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Figure 13-2.  Apical scarring.

Figure 13-3.  Scheimpflug-based tomography demonstrating a corneal curvature map (top left) with inferior steepening, anterior (top right) and posterior (bottom right) with inferocentral elevation posterior greater than anterior, and corneal thickness (bottom left) with thinnest area corresponding to the area of maximal elevation.

when the lens is removed. A Fleischer ring is commonly seen outlining the base of the cone. This is the result of hemosiderin pigment deposition within the deeper layers of the corneal epithelium. A Fleischer ring may only partially outline the cone but, as the ectasia progresses, tends to become a complete circle with more dense accumulation of pigmentation that is best appreciated while viewing with the cobalt blue filter on the slit lamp (Fig. 13-6). Subepithelial fibrillary lines in a concentric circular pattern have been described just inside the Fleischer ring. The source of these fibrils is unknown but has been postulated as epithelial nerve filaments. Anterior clear spaces thought to represent breaks in the Bowman’s membrane are sometimes seen within the thin portion of the conical protrusion. Prominent corneal nerves are reportedly more common in keratoconic corneas. In the more advanced stages, when the eye is rotated downward, the corneal ectasia causes protrusion of the lower lid. This is known as Munson’s sign.

CHAPTER 13  KERATOCONUS  127

A

B

C

Figure 13-4.  Belin/Ambrosio enhanced ectasia map demonstrating enhanced anterior and posterior elevation (bottom left two columns) as well as various corneal thickness profiles (right images A, B, and C) that further support the diagnosis of keratoconus.

Figure 13-5.  Apical thinning and scarring demonstrated in slit beam.

Figure 13-6.  Cobalt blue illumination demonstrating Fleischer ring outlining the extent of the cone. Arrows point to margins of the ring.

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Figure 13-7.  Acute hydrops.

12.How does keratoconus progress?

The onset of keratoconus characteristically occurs in the mid to late teens, progressing slowly for several years before stabilizing. However, delayed onset or late progression of keratoconus is not uncommon. As the disease progresses, the corneal thinning and epithelial ectasia become more prominent with increasing apical scarring. Two types of cones have been described: (1) a small round or nipple-shaped cone that tends to be more central in location and (2) an oval or sagging cone that is usually larger and displaced inferiorly, with the thinning extending close to the inferior limbus. Progression of keratoconus tends to manifest as increased thinning and protrusion, although enlargement of the cone also occurs with extension peripherally.

13.What is acute hydrops?

Acute hydrops (Fig. 13-7) occurs in the more advanced cases of keratoconus. Ruptures in the Descemet’s membrane allow aqueous to enter into the corneal stroma, resulting in marked thickening and opacification of the cornea that are usually restricted to the cone. The involved stroma becomes massively thickened with large, fluid-filled clefts, overlying epithelial edema, and bulla formation. Rarely, a fistulous tract may develop through the cornea, with resultant leakage of aqueous from the anterior chamber through the fluidfilled stroma and epithelium onto the corneal surface. The corneal edema gradually resolves over weeks

to months as endothelial cells adjacent to the rupture in the Descemet’s membrane enlarge and migrate across the defect, laying down new Descemet’s membrane. With healing, scarring tends to flatten the cornea, thereby facilitating the possibility of subsequent contact lens fitting with significant usual improvement as long as the scarring spares the visual axis. Some corneas with acute hydrops tend to develop stromal neovascularization that increases the potential risk of graft rejection if corneal transplantation ultimately becomes necessary. Acute hydrops is more common in patients with Down syndrome and vernal keratoconjunctivitis, presumably related to the repeated trauma of eye rubbing in these patients.

Most cases of acute hydrops resolve spontaneously, requiring supportive treatment with topical hyperosmotic agents such as 5% sodium chloride drops and/or ointment to promote corneal deturgescence. Some patients with acute hydrops complain of severe photophobia and benefit from

the use of topical steroids and/or cycloplegic agents. In addition, topical steroids should be instituted in patients with signs of corneal neovascularization. Recent studies have reported quicker resolution

of acute hydrops with injection of air or nonexpansile concentrations of SF6 and C3F8 into the anterior chamber to promote closure of the rupture in Descemet’s membrane. However, several injections are sometimes required and many surgeons feel the benefits do not outweigh the risks, such as cataract and pupillary block glaucoma. Once the hydrops has resolved, the resultant scarring tends to result in corneal flattening. The patient can then try to resume contact lens wear if the central cornea has not become excessively scarred. Otherwise, the only alternative is a corneal transplant.

14.What is the histopathology of keratoconus?

Most histopathologic studies of keratoconic corneas are performed on advanced cases that require lamella or penetrating keratoplasty. In addition, most patients were previous long-term contact lens wearers, which also may affect the histopathologic findings, as contact lens wearers may induce more apical scarring.

Changes have been described in every layer of the cornea. The stroma of the cone is thinner than the surrounding cornea. The apical epithelium tends to be flattened and thinned with scattered

fragmentation and dehiscence of the epithelial basement membrane. Iron noted in the epithelial cells outlining the cone corresponds to the Fleischer ring.

Among the most characteristic histologic changes of keratoconus are breaks in Bowman’s membrane that are sometimes filled in with epithelium and/or stromal collagen. Ultimately, the anterior corneal stroma may become replaced with irregularly arranged connective tissue.

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18.What are the surgical options for treating keratoconus?

Surgical intervention is reserved for patients with keratoconus who cannot be successfully fit with contact lenses or who fail to obtain satisfactory vision with contact lenses. Atopic patients with keratoconus tend to require surgery much more frequently than nonallergic patients because the allergic diathesis tends to interfere with contact lens tolerance.

•Penetrating keratoplasty (full-thickness corneal transplantation) is the most common surgical technique used to rehabilitate patients with keratoconus. The surgical procedure requires excision of the entire cone, frequently determined by the outline of the Fleischer ring using a manual trephine or femtosecond laser. The donor tissue is cut the same size or slightly larger to obtain good wound apposition with sutures, most commonly 10-0 nylon, utilizing various interrupted running or combined suturing techniques. If the cone extends close to the limbus (usually inferiorly), a large corneal graft is needed. Usually the grafted tissue is centered on the pupil, but when the cone is eccentric, an eccentric graft is used to encompass the entire cone, taking care to leave the optical zone free of sutures. Increasing graft size with proximity to the limbal blood vessel reduces the “immune privilege” of the usually avascular cornea, thereby increasing the risk of immunologic reaction.

•Lamellar (partial thickness) keratoplasty has become increasingly popular for the treatment of keratoconus. A lamellar graft has the advantage of being an extraocular procedure that avoids the risk of intraoperative positive pressure wherein intraocular contents can be expelled through the trephined opening in the cornea made during penetrating keratoplasty. It also eliminates the risk of endothelial rejection while increasing the donor pool because it does not require a healthy corneal donor endothelium, which is discarded at the time of surgery.

A lamellar procedure is more demanding technically than a full-thickness procedure. It involves replacing as much of the corneal stroma as possible while leaving behind the patient’s own endothelial layer and Descemet’s membrane. The resultant visual acuity is similar to that from a penetrating keratoplasty when no stroma is left behind. This is best accomplished in deep anterior lamellar keratoplasty (DALK) with the Anwar “Big Bubble” technique. Air is used to cleanly separate Descemet’s membrane from the overlying stroma. When some recipient stoma remains during manual lamellar dissection, the resultant interface usually causes some degradation of the usual image, which can limit the visual recovery.

•Intracorneal rings are polymethylmethacrylate ring segments of varying thickness and configuration inserted into the midperipheral corneal stroma. They are useful in treating mild keratoconus in patients who are contact lens intolerant. The therapeutic rationale is to support the ectatic area of the cornea, thereby reducing corneal steepening and regularizing the astigmatism associated with keratoconus, with improvement in both uncorrected and best spectacle-corrected visual acuity.

However, they do not slow or prevent progression of corneal ectasia. In the United States, Intacs (Addition Technology) are the only ring segments that are FDA approved.

•Epikeratophakia is a type of onlay lamellar procedure using a freeze-dried donor cornea that is sewn on top of a deepithelialized host cornea. The purpose is to flatten the cornea with the hope of offering improved spectacle-corrected visual acuity and/or better contact lens fitting. After initial enthusiasm in the late 1980s, the procedure has been abandoned by most surgeons because of complications and poor visual results. However, in select cases in which a full-thickness corneal transplant is contraindicated, such as patients with Down syndrome who may aggressively

rub their eyes and dehisce a full-thickness wound or patients at high risk for immune rejection (e.g., multiple graft failures in the other eye), lamellar grafts or epikeratophakia are worthy of consideration.

•Thermokeratoplasty is a technique in which heating the cornea from 90° C to 120° C causes shrinkage of corneal collagen fibers with resulting flattening of the cornea. This procedure has been abandoned for the most part because of unpredictable results, induced scarring, and the potential for recurrent corneal erosions because of damage to the epithelial basement membrane complex. However, when the apex of the cone spares the visual axis, thermokeratoplasty may be used to flatten the cornea, thereby allowing more favorable spectacle-corrected visual acuity and/ or contact lens fitting. In addition, thermokeratoplasty may be helpful in promoting resolution of acute hydrops.

Additionally, some patients with keratoconus develop an elevated subepithelial scar at the apex of the cone as the result of chronic apical irritation from contact lens wear. Corneal epithelial breakdown may develop over the scar, thereby interfering with contact lens wear. These scars can be removed or smoothed out manually with a blade or with the excimer laser, thereby allowing resumption of contact lens wear and sparing the patient an otherwise needed corneal transplant.

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