Keratoconus and Keratoectasia

S E C T I O N I I

33

Clinical Characteristics of Keratoconus

C H A P T E R 3

Stephen S. Khachikian, MD, and Michael W. Belin, MD, FACS

Keratoconus is a non-inflammatory thinning disor-der in which the cornea assumes a conical shape.1,2 Earliest references to the disorder are attributed to

the French Dudell in 1729, when he described a patient with protruding conical corneas and associated poor vision. The German anatomist and surgeon, Burchard Mauchart, provided a slightly more detailed account of the condi-tion in 1748.3 Mauchart presented an early description of a case of likely keratoconus, which he called staphyloma diaphanum.

The disorder was described in much greater detail by a British physician John Nottingham in 1854 in his book Practical Observations on Conical Cornea: And On the Short Sight, and Other Defects of Vision Connected With It.4 Nottingham provided a meticulous account of the clinical signs of a conical cornea with thinning, protrusion, and weakness. This was the first time that the condition (later termed keratoconus) was described as a single entity unique from other ectatic diseases with similar findings. In 1859, Sir William Bowman, an English surgeon, expanded on the condition when he described the use of the retinoscope and the retinoscopic reflex to further classify keratoconus.5 Bowman’s work described the technique of pulling the iris into a slit configuration (stenopeic slit) to improve vision in patients with keratoconus.

The disorder received its current name “keratoconus” when Johann Horner wrote a thesis entitled “Treatment of Keratoconus.”6 The accepted management of keratoconus at that time was one ascribed to a fellow German ophthalmolo-gist, Albrecht von Graefe. This treatment technique used silver nitrate to scar the cornea, changing the shape to reduce corneal steepening and thereby improve vision. A miotic

agent and pressure patching was also employed to hasten healing, further flatten the cornea, and sharpen images.

In 1888, a less invasive approach to treatment was intro-duced by Eugene Kalt, a French physician.7 Kalt fabricated a glass scleral shell to be used as a contact lens in patients with keratoconus. This early contact lens improved vision by flattening the cornea and reducing astigmatism. These lenses were a vast improvement over glasses and the stenopeic slit, which only marginally improved vision in advanced disease.

Early gross descriptions of keratoconus were limit-ed in their ability to effectively classify the condition. Keratoconus was initially broadly defined based on the shape and location of the cone. These included round, or nipple cones with a central conical protrusion, and oval cones, often with inferior sagging and projection. Amsler’s studies in the early 20th century contributed greatly to the clinical detection of the disease. Amsler used a Placido’s disk to classify early keratoconus into keratoconus fruste and mild keratoconus (Figure 3-1).2,8 These classifications were based on the deviation of horizontal axis symmetry from the normal. A 1- to 4-degree deviation was labeled keratoconus fruste and a 4- to 8-degree deviation was early or mild keratoconus. In 1980, Perry further classified advanced cones using histopathologial evaluation. He noted that nipple-shaped cones are typically limited in diameter and have a center mostly in the lower nasal quadrant, while oval or sagging cones are larger and more commonly in the inferotemporal quadrant close to the periphery.9 Perry found that the oval cone is usually associated with a higher incidence of corneal hydrops, with increased scarring and greater difficulty in fitting contact lenses.

From: Wang M, ed. Keratoconus &Keratoectasia: Prevention, Diagnosis, and Treatment (pp. 29–36) © 2009 SLACK Incorporated

While using the Placido disk to define keratoconus was a major advancement, there were limitations to this tech-nique. One issue encountered is that in order to produce an obviously distorted image on Placido topography, the cornea must be quite distorted itself. If the irregularity is only minor, while it may have a drastic effect on a patient’s vision, it is not likely to be visible by gross inspection of the reflected image. It is generally accepted that astigmatism of at least 3 diopters (D) must be present to be detected by traditional keratoscopy.10 More recently, the descriptions of keratoconic patterns are dependent on Placido-based videokeratography and the use of various indices to define the severity of the disease process, including those by Rabinowitz and colleagues and Madea and colleagues.11,12

The union of computer analysis and digital video by Klyce in 1984 transformed the gross examination of the cornea by incorporating computer imaging.13 The first color-coded map of corneal curvature (Figure 3-2) was published in 1987 and led to multiple commercially avail-able computerized videokeratoscopes.14 Computerized videokeratoscopes are capable of digitizing information from thousands of points on the corneal surface to produce detailed color-coded maps depicting corneal curvature. Videokeratoscopy has become an essential clinical tool for assessing corneal anatomy and has allowed the identifica-tion of more subtle changes in corneal curvature.

More recently, elevation-based topographic devices have been used to characterize the condition and have been useful in detecting false-positive curvature findings and detect-ing early disease.15-17 These devices have the advantage of assessing both the anterior and posterior changes on the cor-neal surface and providing a pachymetric map (Figure 3-3). Because progressive corneal thinning is the main pathogenic mechanism of ectatic conditions, elevation topography may provide greater sensitivity in the detection of the disease and allow a more detailed classification of keratoconus.18

EpidEmiologyAs the detection of keratoconus has been enhanced over

the past 20 years by computer imaging, the incidence and prevalence have also been affected. The current reports on prevalence of keratoconus vary greatly between 50 and 203 per 100,000 people in the general population.1,2,19-22 The incidence is about 50 per 100,000, although this is equally variable. This variation is likely largely dependent on the criteria used to establish the diagnosis. Keratoconus is diagnosed in all ethnicities, and it is generally accepted that males and females are equally affected. It should be noted, however, that 2 major cohort studies suggest that there may be a slight preponderance of the condition in males.23-25

The onset of keratoconus typically begins at puberty and undergoes variable progression until the third or fourth decade. Many people, however, only develop refractive error early in the disease course, and so, in the absence of other signs or symptoms, the diagnosis of keratoconus is often delayed. It may not be until the late second or early third decade that a change in the examination or vision prompts further evaluation. Often, the patient can no longer be refracted to 20/20, or clinically detectable anatomic signs suggestive of keratoconus develop. Rarely, slowed disease progression may delay the diagnosis even further. Fewer than 10% of patients are diagnosed after 40 years of age, and progression of the disease will often slow by the fourth decade.25-27

Keratoconus is considered a bilateral condition although asymmetry is very common. A patient may have clinical signs of the disease and reduced BSCVA in one eye, with only limited topographic evidence of keratoconus in the fellow eye (Figure 3-4). The reason for this asymmetry is poorly understood. The use of videokeratography has enhanced our ability to detect subtle disease, however, this has also led to an increasing number of patients with only subtle changes in one eye and no topographic findings in

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Figure 3-1. Placido disk. By evaluating the reflection of the Placido rings on the cornea the examiner can assess topographic abnormalities determine the amount of astigmatism.

Figure 3-2. Videokeratoscopic anterior curvature image of a keratoectasia in a patient who underwent LASIK for high myopia, followed by an enhancement for what was thought to be regression. (Courtesy of Tracy Swartz, OD, MS.)

CliniCAl ChArACteriStiCS oF KerAtoConuS 35

the other.28,29 The findings make the diagnosis of true ker-atoconus difficult. Marked asymmetry in the disease pro-cess appears to be more common because of the increase in refractive surgery screening where “normal” patients with

simple refractive error undergo topographic analysis, and irregularities are noted on curvature or elevation maps.

Although keratoconus has been documented in patients in conjunction with numerous ocular and systemic dis-

Figure 3-3. Pentacam Scheimpflug topography display of a patient with keratoconus showing anterior curvature, anterior and posterior elevation and pachym-etry maps.

A B

Figure 3-4. Four-view composite maps of a patient with asymmetric keratoconus. Mild inferior steepening in the right eye demonstrates early keratoconus (A)while more severe disease is seen in the opposite eye (B).

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eases, there are few accepted associations. These include eye rubbing, atopy, Down Syndrome, Leber’s congenital amaurosis, retinitis pigmentosa, Marfan Syndrome and mitral valve prolapse.30 Certain aspects of these conditions do overlap, with eye rubbing being associated with Down syndrome and atopy, and connective tissue defects linking keratoconus with Marfan syndrome and mitral valve pro-lapse. Overwhelmingly, however, keratoconus is found as a sporadic condition without any other associated process.

CliniCAl prEsEntAtionThe symptoms of keratoconus are highly variable, rang-

ing from refractive error due to moderate astigmatism, to severely distorted vision and reduced BSCVA. Monocular polyopia, or multiple ghost images, are a common com-plaint. Other symptoms such as subjective burred vision, despite 20/20 Snellen acuity, and unexplained light sen-sitivity have also been documented.23 Often, frequent changes in refractive error or inability to adequately fit contact lenses leads to topographic testing, which reveals the diagnosis. Many times, the patient has been treated for “high astigmatism” and subjectively reduced vision because early in the disease process the clinical signs were not readily apparent.

The most frequently noted slit-lamp sign of keratoco-nus is a Fleischer’s ring.23 First described in 1906, this is epithelial deposition of the iron oxide hemosiderin in a line or circle surrounding the cone and is thought to occur because of an irregular tear film over the cornea in this area.31 The ring can be seen even if the corneal thinning and conical shape are not readily apparent. The use of the cobalt blue filter can also highlight the finding. Another common slit-lamp sign is the appearance of fine vertical

striations in Descemet’s membrane and the deep stroma. These are known as Vogt’s striae and are corneal stress lines that parallel the axis of the cone.1,2,31,32 These lines are induced by the corneal protrusion in the area of the cone and can temporarily resolve with gentle limbal pressure. Also associated with keratoconus are prominent, more vis-ible corneal nerves. While Fleisher’s ring, Vogt’s striae, and prominent corneal nerves are common slit-lamp findings, there may be findings suggestive of early keratoconus on ophthalmoscopy or retinoscopy as well. Ophthalmoscopy can show the outline of the early cone as an oil droplet against the background red reflex of the fundus. This is known as the Charleaux “oil droplet” sign. Retinoscopy on a patient with early keratoconus may show scissoring of the reflex as the light passes over the pupil.

As patients develop more moderate keratoconus, they are often found to have central scars (Figure 3-5). Anterior stro-mal scars developing independently or secondary to rigid contact lens wear can be seen. In advanced disease, an acute presentation of corneal hydrops (Figure 3-6) is also not uncommon. In these cases, patients with severe keratoconus present with an acute episode of pain, blurred vision, and light sensitivity. On exam, there is diffuse corneal haze due to edema in the area of the cone. This is caused by breaks in Descemet’s membrane leading to the profound edema along with epithelial disruption. Treatment with topical hyper-tonic saline and aqueous suppressants can often control the condition, and, over time, the cornea will scar.

Also commonly noted in advanced cases of keratoconus is Munson’s sign.33 In patients with Munson’s sign, when the keratoconic eye is in down gaze, there is a change in the normal arc of the lower lid. Rather than seeing a smooth arc of the lid over the corneal surface, the lid is peaked in a V-shaped pattern as it passes over the cone of the cornea.

Figure 3-5. Slit-lamp photograph of a patient with keratoconus showing cor-neal thinning and an anterior stromal scar.

Figure 3-6. Slit-lamp photograph of a patient with hydrops. Note the corneal edema and large epithelial bulla resulting from a sudden break in Descemet’s membrane. This condition often presents with acute pain and decreased vision.

CliniCAl ChArACteriStiCS oF KerAtoConuS 37

Rizzuti’s sign, also in advanced keratoconus, is seen when a conical reflection is created on the nasal cornea when a penlight is shone from the temporal side.34

As keratoconus is progressive, bilateral and asymmetric, a patient with the disease may have all or none of these findings in either eye. This is, in part, due to the hetero-geneous nature of the keratoconus corneas and the likely multifactorial nature of the disease.

Family StudiesWhile the most common presentation for keratoconus

is sporadic, a positive family history has been documented in 8% to 11% of patients.1,2 Dominant genetic heredity was first noted in 1969 when transmission of keratoconus was found to occur over 2 generations.35 Current literature suggests an autosomal dominant form of the disorder, with variable phenotypic expression.2,35 Other heritance patterns, including autosomal recessive and sex-linked transmission have been reported.36 There is no exact heri-tance pattern ascribed to the different cone morphologies, rates of progression, or severity of symptoms in the disease. Improved sensitivity of videokeratoscopy for detecting form fruste keratoconus patterns may increase the per-centage of those with a positive family history. Still, many patients and family members who are asymptomatic with the condition may go undetected, and those with only high astigmatism are difficult to classify in terms of heritabil-ity and penetrance. In familial studies, when assessing the topography of family members of patients with keratoco-nus, up to 50% of family members have been shown to have some level of topographic abnormality.37 Additional stud-ies looking at parents of those with keratoconus showed that in 58% of parents, abnormalities in topographic indices for keratoconus can be found.38 Reports of kerato-conus occurring in multiple generations of family members have also been described.1,35-37 While this provides strong evidence to the heritability component of keratoconus, environmental effects have not been accounted for in these and other studies.

Although keratoconus has associations with certain genetic conditions such as Down Syndrome (chromosome 21) and Leber’s congenital amaurosis (chromosome 17), the inciting genetic abnormality that leads to keratoconus has yet to be determined. Along those lines, studies have been done to assess abnormalities on chromosome 21 in patients with keratoconus. While a gene locus thought to be linked to keratoconus was identified on chromosome 21, no major genes are currently known at that site.39,40 Similar inves-tigations have been made looking into chromosome 17 in patients with LCA but no pathogenic mutations leading to keratoconus have been detected.41

As keratoconus has been associated with other dis-orders of collagen such as mitral valve prolapse, Ehlers-Danlos and osteogenesis imperfecta, abnormalities on

genes known to code for collagen have been evaluated. Collagen gene COL6A1 has been excluded as the gene caus-ing keratoconus in one family with multiple generations of the disease. Subsequent work has excluded multiple other collagen genes as a cause of keratoconus in a single fam-ily.42 Mutations in genes COL8A1 and COL8A2, which code for the alpha 1 and alpha 2 chains of type 8 collagen, were also investigated because they have been shown, in animal models, to cause structural changes in the anterior segment of the eye. These genes are associated with corneal protrusion similar to that of keratoglobus in mice. When these genes were screened in multiple human patients with keratoconus and keratoglobus, however, no pathogenic mutations were found.43

More recent reports looking at target genes and an analysis of mutations leading to keratoconus led to the investigation of a visual system homeobox 1 gene (VSX1). This is a known genetic marker for posterior polymor-phous dystrophy and may also be linked to keratoconus. Investigations to this point suggest that the VSX1 gene mutations are not pathogenic mutations leading to kera-toconus.44 It is encouraging, however, that gene linkage analysis on pedigrees with familial keratoconus have iden-tified multiple loci for susceptible genes warranting further investigation.45-49

Twin studies in keratoconus are limited; however, there are reports of monozygotic twins discordant for kerato-conus.49 Many of these reports either lack modern video-keratoscopy or report patients who may still develop kera-toconus given their young age at the time of presentation. There is evidence, however, that videokeratoscopy in the twin without clinical evidence of keratoconus will show topographic changes consistent with the disease.50 In addi-tion, studies evaluating the genetic identity and process of twinning suggest that even though there are monozygotic twins with discordance for keratoconus, this does not limit the possibility of a predominantly genetic component.49

rECurrEnCE in thE grAftWhile the definitive treatment for keratoconus is pen-

etrating keratoplasty, keratoconus has been reported to occur after PKP in many studies. First reported by Abelson in 1980, examination of the cornea with recurrent kerato-conus revealed histopathological evidence of the disease including apical thinning and breaks in Bowman’s layer.51 The cause for this recurrence remains unknown and may be due to host factors, donor factors, or both. Whether environmental, mechanical, metabolic, or genetic, the fac-tors leading to keratoconus in the host are unlikely to be altered by corneal grafting. The host tissue will repopulate the donor cornea over time, and any genetic or biochemi-cal predisposition that the host has for keratoconus may be transferred to the donor graft. Atopy, eye rubbing, or envi-

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ronmental influences affecting the host may not change significantly after transplantation.

Post-keratoplasty, the topography of the host may remain irregular even years after corneal transplant. This makes identification of corneal changes indicative of recurrent keratoconus difficult. Disease recurrence can easily go unrecognized on topography until an advanced stage, and there is some question as to whether grafting alone contributes to the topographic appearance over time. Nevertheless, histopathologic examination of the donor button manifesting the recurrent disease has confirmed the diagnosis of recurrent keratoconus.51

Another possibility for recurrence of keratoconus in the corneal graft is previously undiagnosed keratoconus in the donor. Early keratoconus can be difficult to identify, and grafted corneas from younger donors may have had kera-

toconus at the time of surgery. Fewer studies suggest this mechanism of recurrence, but cases where fellow eyes of a donor are grafted into hosts without keratoconus, and the latter develop keratoconus make this theory more plausible. Unal et al showed that fellow corneal buttons of a donor without keratoconus went on to manifest the disease in the hosts after grafting.52 Krivoy et al had a similar report of keratoconus developing in a non-keratoconus patient after grafting.53 As noted, it must also be considered that performing a corneal graft alone may incite structural changes that lead to the development of a corneal ectasia. Additionally, a poorly centered host button that bisects the host cone will leave behind cornea with a propensity for ectasia. This residual area on the host may go unnoticed until many years after grafting, but would slowly become more ectatic over time, falsely suggesting recurrence.

Figure 3-7. (A) Slit-lamp photograph of a patient with pellucid marginal degen-eration. Note the inferior band of corneal thinning and the superior corneal flattening. (B) Four-view composite map of a patient with keratoconus. Despite the “crab claw” curvature map, the thinnest portion of the cornea is clearly central rather than peripheral, and the anterior and posterior elevation maps show a central island of elevation consistent with keratoconus. (C) Four-view composite map of a patient with pellucid marginal degeneration. The curvature map shows the traditional vertical flattening, the thinnest portion of the cornea is peripheral, and the anterior and posterior elevation maps show a steepening of the inferior cornea as it falls below the best fit sphere.

BA

C

CliniCAl ChArACteriStiCS oF KerAtoConuS 39

While recurrent “secondary” keratoconus is a rare dis-order, there are many published and likely many unpub-lished reports of its occurrence. The etiology has yet to be clarified, and the treatment is the same as for primary keratoconus.

KErAtoConus vs pElluCid mArginAl dEgEnErAtion

Another bilateral thinning disorder of the cornea, pel-lucid marginal degeneration (PMD) is often confused with Keratoconus. PMD is a relatively rare disorder that in its pure form presents with a distinct clinical picture sepa-rate from keratoconus.54,55 Classically, PMD is a bilateral, progressive, ectatic, non-inflammatory corneal disorder involving thinning of the inferior cornea in a cresenteric pattern (Figure 3-7A).54,55 Characteristically, this thinning occurs 1 to 3 mm from the limbus in the 4 to 8 o’clock position.2 This configuration causes the cornea superior to the ectasia to protrude, causing a “beer belly” configura-tion producing a flat vertical meridian above the thinning with high against-the-rule astigmatism.54 Clinically, this is distinctly different from keratoconus, where the thinning and area of conical protrusion coincide (Figures 3-7B and C). In moderate to advanced cases of PMD, the location of the thinning near the limbus can be differentiated on slit-lamp evaluation.56 In early cases, the clinical distinc-tion between PMD and keratoconus is more difficult as the cornea may appear relatively normal. Videokeratoscopy, Scheimpflug photography, and pachymetric mapping can help in these situations.57

Similar to keratoconus, PMD patients may retain good best spectacle-corrected visual acuity (BSCVA) early in the disease process and diagnosis may be delayed. Compared to the onset of keratoconus, the onset of PMD is thought to be much later in life, beginning in the late second and into third decade. As PMD progresses, the corneal protru-sion becomes more obvious. Unlike keratoconus, however, PMD does not have associated scarring (although hydrops has been reported), and striae and iron deposition are less common.1,2

In advanced disease, PMD is often confused with inferior keratoconus. This idea may be entrenched in attempts at differentiating these diseases with limited diagnostic tech-nologies.58 Placido-based systems rely on the analysis of a reflected image, and so no data are obtainable from the pos-terior corneal surface. Without information about the pos-terior corneal surface, topographically derived pachymetric maps are not possible. Additionally, axial curvature is less reliable when analyzing peripheral pathology. Many think that the “crab claw” appearance on axial curvature maps only occurs with PMD, when in fact this appearance may be present in keratoconus. Tangentially derived topography is

more accurate in identifying the cone location and may help clarify questionable cases.56 Careful attention to the axes of vertical flattening may help distinguish the disorders.

When using elevation-based topography to evaluate the PMD, cross-sectional anterior segment images, anterior and posterior corneal topography, and corneal pachymetry maps are generated. Accurate images of the peripheral cornea (up to 12.0 mm) are also obtained. The peripheral corneal steepening and thinning seen in the Scheimpflug images in these cases can be clearly identified. This con-figuration, with superior corneal protrusion over inferior thinning located adjacent to the limbus, can be seen as separate and unique from keratoconus.5

unilAtErAl KErAtoConusKeratoconus is believed to be a bilateral condition;

however, its highly variable phenotypic expression has led to many cases of seemingly unilateral disease. Current reports, however, suggest that the frequency of unilateral keratoconus is only as high as 4%.59 Improved diagnostic technologies and indices have enabled us to identify sub-clinical changes in patients with clinical signs of kerato-conus in only one eye. Longitudinal studies by Rabinowitz have shown that in those patients with clinically unilateral keratoconus, 50% will develop keratoconus in the fellow eye over a period of 17 years, and most of those patients (83%) will develop it within 6 years.59 A great deal of research has also been done, evaluating the fellow normal eye in patients with unilateral keratoconus to identify changes that will indicate disease progression. Recently, the use of combined elevation and pachymetry data has been used to better assess the “normal” eyes in cases of unilateral kera-toconus.60 Assessment of the posterior corneal surface and the change in pachymetry from the thinnest point to the periphery has been shown to reveal abnormalities in the “normal” fellow eyes of patients with keratoconus (Figure 3-8). While there are many patients who truly appear to have unilateral keratoconus, it is possible that many of these patients have corneal topographic abnormalities that can be seen only on the posterior surface or with thorough pachymetric evaluation.

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Figure 3-8. Belin/Ambrosio keratoconus screening display. This all elevation-based display uses a modified reference shape and pachymetry change of the corneal surface to help diagnose early ectatic disease.

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