Keratoconus

INTRODUCTION — Keratoconus is a noninflammatory disorder of the cornea of unknown etiology. It is characterized by progressive thinning and cone-shaped protrusion of the cornea leading to visual impairment (picture 1). Patients may present with blurry vision or a sudden decrease in visual acuity. Corrective lenses may be difficult to fit and require frequent changes due to progressive myopia and irregular astigmatism. Visual impairment can be managed initially with corrective lenses but may require corneal cross-linking to prevent disease progression or penetrating keratoplasty in more advanced disease.

EPIDEMIOLOGY — Patients present at puberty or early adulthood and experience disease progression through the fourth decade. Prevalence in the general population is reported as ranging from 50 to 230 per 100,000 [1-3]. A 2020 meta-analysis that reviewed data for 7,158,241 participants from 15 countries reported a prevalence of 138 per 100,000 persons [4]. There is no significant sex difference in incidence and prevalence [1-6]. Some evidence suggests a higher incidence in Asian people from the Indian subcontinent [7,8]. Another study did not support the association between Asian persons and keratoconus. However, the study did find that Black and Latino persons have approximately 50 percent higher odds of having keratoconus when compared with White persons [9].

RISK FACTORS

●Systemic disorders – Several studies have linked keratoconus to systemic disorders including Down syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta [9,10]. For example, one study of 110 persons with Down syndrome reported that 31 to 39 percent were found to have keratoconus when screened with corneal topography [11].

●Environment – Atopic disease, asthma, and hay fever have been associated with keratoconus; however, not all studies have found an association [3,10,11].

●Eye-rubbing – Reports based on clinical observation have implicated eye rubbing as a risk factor for keratoconus [10,11].

●Family history – The number of pairs of identical twins with the disease suggest that a genetic abnormality may be one of several factors involved in the etiology of this disorder [12,13]. A family history of keratoconus has been reported in 6 to 8 percent of cases, but the definitive role of inheritance patterns has not been determined. This disorder has weak penetrance and significant variability of expression [14].

PATHOPHYSIOLOGY — Keratoconus is a noninflammatory disorder of the cornea. Keratoconic corneas have lower collagen content compared with normal corneas [6]. The corneas of patients with keratoconus demonstrate abnormalities in their molecular structure, but a specific biochemical disease pattern has not been established. Similar molecular changes are seen in eyes with corneal scars, suggesting that these changes could be secondary to the disease sequela [15]. The corneal thinning seen in keratoconus is possibly the result of a multifactorial degradation process that results in the loss of structural elements of the cornea. The cause of this thinning is not clear [3].

CLINICAL FEATURES — Patients present at puberty or early adulthood with blurry vision or a sudden decrease in visual acuity. Symptoms progress until the fourth decade. While vision is initially corrected by spectacles, as the disease progresses, patients may develop irregular astigmatism and require contact lenses for refractive correction.

Clinical features which may more specifically suggest the diagnosis include the following:

●Asymmetric visual complaints – Although keratoconus is usually a bilateral disease, patients may present with asymmetric symptoms as one eye may be much more severely affected than the other. One study in 64 patients reported that 41 percent had unilateral disease at the time of diagnosis [2].

●Difficulty with visual correction – As the disease progresses, patients experience difficulties with their spectacle correction and contact lens fitting. Patients may require frequent changes in spectacles due to progressive myopia and astigmatism.

●Munson's sign – In advanced keratoconus, patients may have a v-shaped indentation of the lower eyelid on downgaze caused by a large protuberant cone.

●Corneal hydrops – As keratoconus progresses, some patients can present with photophobia and a sudden painful drop in visual acuity that is due to corneal hydrops. The symptoms are caused by the sudden onset of severe corneal edema caused by tears in the Descemet membrane and loss of functionality of the endothelium as a result.

Corneal hydrops may occur in about 3 percent of patients with keratoconus. The mean age of onset of corneal hydrops is 25 years of age and is thought to be more common in men [16]. The treatment of corneal hydrops is discussed below. (See 'Corneal hydrops treatment' below.)

DIAGNOSIS — Although no one finding can definitely establish the presence of keratoconus, ophthalmologists are able to diagnose it by history and clinical exam. The signs and symptoms vary depending on the stage of the disorder.

Early in the disease, the ophthalmologist may suspect keratoconus because of difficulty correcting a patient’s vision to 20/20 visual acuity. The cornea may appear normal on slit lamp examination, but other methods may aid in the diagnosis of keratoconus. For example, keratometry may show distorted mires centrally or inferiorly [2,3]. Newer technologies, such as corneal topography, can also assist in making the diagnosis and evaluating disease progression [17].

As the disease progresses, slit lamp findings become common and include (see "Slit lamp examination"):

●Fleisher ring – Brown-colored staining around the base of the cone is a subtle early sign and can be noted even when the cone is minimally elevated. It is composed of iron deposited within the epithelium by the tear film. The iron flows with the tear film around the base of the cone. The ring is best seen with the cobalt blue filter on the slit lamp.

●Vogt striae – Vogt striae are vertical stress lines in the thinnest part of the cornea at the level of the posterior stroma and Descemet membrane. Unlike Haab striae and folds secondary to corneal edema, Vogt striae disappear when gentle pressure is applied to the cornea.

●Central and inferior paracentral corneal thinning – Central and inferior paracentral corneal thinning, along with mild cone formation and protrusion, is an early manifestation of keratoconus.

●Corneal scarring – Corneal scarring is the result of spontaneous breaks in Bowman's layer as the cornea thins (picture 2). It is estimated that 20 percent of patients with keratoconus will have corneal scarring [18].

Ophthalmologists may use other technologies in the diagnosis and evaluation of keratoconus:

●Retinoscopy – The scissoring reflex is an early sign of developing keratoconus seen on retinoscopy. The ophthalmologist may see two light bands moving towards and then away from each other, similar to the action seen with scissors. The reflex is due to irregular astigmatism.

●Keratometry – Keratometry may demonstrate irregular mires and progressive corneal steepening [1].

●Corneal topography or tomography – The introduction of corneal topography has helped in the identification of subtle presentations, which can lead to an earlier diagnosis. Major topographic patterns found in keratoconus include asymmetric bowtie, with or without inferior steepening, and skewed radial axes [19]. Corneal tomography is another form of imaging that also allow for measurement of corneal thickness along with local steepness. Once the diagnosis is made, serial corneal topography/tomography is warranted, with frequency dependent on age to monitor for progression [20].

DIFFERENTIAL DIAGNOSIS — Keratoconus is distinguished from progressive myopia by the clinical examination findings discussed above.

The ophthalmologist may also consider other ectatic disorders of the cornea in the differential diagnosis of keratoconus. These include keratoglobus and pellucid marginal degeneration [21].

MANAGEMENT — Corneal collagen cross-linking is recommended for the management of progressive keratoconus or ectasia after refractive surgery. Progression is defined by steepening of anterior cornea surface, steepening of posterior corneal surface, or thinning. Crosslinking is not indicated for cases of keratoconus that present or are recognized in later decades and are stable, or in cases of keratoconus in younger patients that are stable. Crosslinking has been shown to slow the progression by strengthening collagen fibers. The goal of crosslinking is not vision correction; the goal is stabilization of disease. In patients with stable disease, advanced ectatic disease (cornea is too thin), or severe scarring, correction of visual impairment may require spectacles, contact lenses, or surgical interventions.

Collagen cross-linking — Collagen cross-linking is a procedure that uses riboflavin drops, ultraviolet light, and a photosensitizer to strengthen bonds in the cornea.

In a multicenter trial comparing collagen cross-linking to riboflavin drops alone in over 200 patients with progressive keratoconus, improvements in the maximum keratometry value, as well as in corrected and uncorrected distance visual acuity were noted in the treatment group at one year [22]. Earlier trials and cohort studies of collagen cross-linking demonstrated flattening of the cornea and improvement in visual, topographic, and wavefront parameters that were maintained for up to seven years [23-25].

The procedure is generally safe, but transient corneal haze, keratitis, corneal edema, pain, and blurred vision are not uncommon, with resolution occurring between one and six months after the procedure [26]. Rarely, corneal haze is reported after 12 months [27].

Collagen cross-linking is generally not performed in patients with active or history of herpes simplex virus (HSV) keratitis, thin corneas, or corneal hydrops.

Correction of vision

●Spectacles – In the early stages, the treatment of choice is spectacle correction. These are used as long as the visual acuity allows the patient to function.

●Contact lens – As the disease progresses and irregular astigmatism increases, contact lenses may become necessary to maximize the patient’s visual acuity. A large portion of patients with keratoconus can be managed conservatively with contact lenses for an extended period of time [20]. (See "Overview of contact lenses".)

Rigid gas-permeable corneal lenses are the most common contact lens used in keratoconus. The rigid structure allows tears to collect behind the lens, resulting in a spherical shape at the corneal plane [28]. The contact lens neutralizes the irregularity of the cornea with its rigid, regular optical surface. In some patients, particularly if the scarring is irregular or elevated, rigid gas-permeable contact lens wear can become intolerable. For those patients, hybrid lenses (rigid lens in the center with a soft skirt peripherally), piggyback lenses, or scleral lenses may be an option [28,29].

Scleral lenses are rigid gas permeable lenses that sit gently on the sclera without touching the cornea. The lens reservoir is filled with preservative-free saline before placing it in the eye [29]. Benefits include improved comfort and less risk of scar formation or worsening, so much so as to reduce the need for corneal transplants in severe keratoconus [30,31].

Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) is a nonsurgical treatment model that uses a computer- and software-designed custom prosthetic device [32]. In one study, patients fitted with this type of scleral lens achieved better and more rapid visual acuity compared with patients that had undergone corneal transplantation [33].

●Surgical interventions – Intrastromal corneal ring segments were approved by the US Food and Drug Administration (FDA) in 2004 for the management of keratoconus. This technique has also been studied in combination with collagen cross-linking [34]. These thin, semicircular plastic inserts are implanted into the mid-corneal layers to flatten the cornea. The goal is to improve the patient’s visual acuity by reducing the amount of astigmatism. Several authors have reported flattening of the cornea and significant improvement of refractive errors [35,36]. However, this treatment is not useful in patients with more advanced vision loss.

Keratectomy is uncommonly used in the treatment of corneal scars and nodules to improve contact lens tolerance. However, recurrence is possible and can stimulate progression [37,38].

●Keratoplasty (corneal transplantation) – Keratoplasty is the procedure of choice when contact lenses are no longer helpful. Approximately 10 to 15 percent of patients with keratoconus will require keratoplasty; penetrating keratoplasty (full thickness corneal transplant) is the most commonly used procedure [39,40]. This procedure has a success rate of greater than 90 percent in patients with keratoconus [41]. Studies have reported visual acuity of 20/40 or better in 80 to 90 percent of patients [41-43]. Of those patients, 15 percent obtain that visual acuity without correction, 40 percent with spectacle correction, and 26 percent with contact lenses. Graft rejection has been reported in 20 to 35 percent of cases in the first 12 months after surgery. It is associated with loose sutures, trauma, and large grafts [41]. The majority of cases are treated successfully with corticosteroids. A more common complication of penetrating keratoplasty is astigmatism. Treatment options for astigmatism include contact lens correction, refractive surgery, relaxing incisions, wedge resection, and compressive sutures.

Deep anterior lamellar keratoplasty (partial thickness corneal transplant) is another option for keratoplasty that may be used in the treatment of keratoconus [40,44]. It is used infrequently in the United States.

Corneal hydrops treatment — Corneal hydrops generally resolves without intervention over two to four months, although the patient will experience discomfort and compromised vision during that time [5,16,45]. As the tears in Descemet’s membrane heal, endothelial function returns and the corneal edema gradually lessens.

Evidence about effective treatment is lacking [16]. Treatments include pressure patching and bandage contact lenses as well as topical hyperosmotics, cycloplegics, and steroids in an attempt to decrease edema, pain, and inflammation. Intracameral perfluoropropane gas injection has been found to decrease the time to resolution of hydrops but does not change the outcome in terms of visual acuity or need for corneal transplantation. Corneal perforation is very rare. Keratoplasty is not indicated in the acute stage.

After an episode of corneal hydrops, the cornea is left with a scar [3,10]. Paradoxically, the severity of the cone may be reduced as the cornea flattens. This may result in reduced and more manageable astigmatism. Eventually, however, patients may require keratoplasty because of corneal scarring as a result of hydrops.

PROGNOSIS — Keratoconus is a progressive condition. In a 2019 meta-analysis of the natural history of keratoconus, factors associated with a higher likelihood of progression included younger age and keratometry measurements steeper than 55 diopters at presentation [46]. Other factors associated with progression are corneal scaring and worsening visual acuity [18,39]. One study reported a 12 percent rate of keratoplasty over eight years of follow-up [39].

SUMMARY AND RECOMMENDATIONS

●Keratoconus is a noninflammatory disorder of the cornea. It is characterized by progressive thinning and cone-shaped protrusion of the cornea leading to visual impairment. (See 'Pathophysiology' above.)

●Keratoconus is more common in those with a family history of the disorder. It has also been found to be associated with certain systemic disorders. Contact lens use is not clearly a risk factor. Some observations implicate eye rubbing. (See 'Risk factors' above.)

●Patients present at puberty or early adulthood with vision impairment that may be asymmetric. Vision impairment progresses until the fourth decade. Difficulty with vision correction may be the first indication of this disorder. (See 'Clinical features' above.)

●Corneal hydrops may be seen in advanced keratoconus. It is caused by sudden onset of severe corneal edema that can lead to a sudden, painful drop in visual acuity. This typically resolves over a few months. While there is limited evidence for effective treatments, symptomatic therapies are often tried. (See 'Clinical features' above and 'Corneal hydrops treatment' above.)

●Corneal collagen cross-linking is suggested for the management of progressive keratoconus (Grade 2B). It has been shown to slow the progression by strengthening collagen fibers. It is not recommended for patients with advanced disease. In some patients with keratoconus, correction of visual impairment may also require spectacles, contact lenses, or surgical interventions. (See 'Management' above.)