In 2015, a landmark paper published in Cornea was the first attempt to come to a generalized agreement by corneal experts from around the world pertaining to the definitions, diagnosis, and management of keratoconus and other forms of corneal ectasia (Gomes et al, 2015). One of the key statements coming out of this paper was that “true unilateral keratoconus does not exist, although unilateral clinical presentation may occur.” This infers that the disease in some form is always bilateral, even while available clinical diagnostic methods may not detect keratoconic abnormalities in what may appear to be a clinically normal cornea. New diagnostic technologies are allowing us to find abnormalities consistent with keratoconus in eyes that formerly appeared normal, which is a critical element in our ability today to stop or at least minimize progression of the disease.

Classical Definitions

Keratoconus is classically defined as a progressive non-inflammatory corneal ectatic disorder associated with irregular stromal thinning that result in a cone-like protrusion and significant loss of vision (Asimellis and Kaufman, 2007). Classification of keratoconus has typically been described according to the Amsler-Krumeich system, which utilized diagnostic data based on refractive error, corneal curvature via keratometry, slit lamp findings, and central corneal thickness typically derived from ultrasonic pachymetry. When this classification was developed, even Placido-based corneal topography was not clinically utilized.

Contemporary Definitions

Gomes et al (2015) also stated that to diagnose keratoconus, the following must be present: 1) abnormal posterior corneal elevation; 2) abnormal corneal thickness distribution; and 3) clinically non-inflammatory corneal thinning.

This definition has a potential impact on our detection of unilateral disease. Even modern Placido-based topographers can detect none of the above-mentioned criteria. Utilization of more advanced technologies, such as corneal tomography (either Scheimpflug or optical coherence) is currently the most widely accepted method to make an earlier diagnosis of keratoconus (prior to potential vision loss).

Scheimpflug Corneal and Anterior Segment Tomography

Scheimpflug corneal and anterior segment tomography can provide corneal descriptors and diagnostic models for the detection of ectatic corneal anomalies. These include anterior and posterior corneal curvature, global corneal pachymetry, and anterior and posterior corneal elevation. Advanced ectasia analysis software for Scheimpflug tomography has further allowed clinicians to detect early cases of keratoconus and other forms of corneal ectasia with high levels of sensitivity and specificity (Belin et al, 2007). This software makes detection decisions based only on elevation and pachymetry data, not curvature.

Often with Scheimpflug tomography, the anterior corneal curvature and elevation are normal, yet there are abnormalities of posterior elevation and of pachymetric progression from the thinnest point out to the corneal periphery. These cases would typically appear clinically normal. They would also appear normal on Placido topography, but they would clearly be abnormal with Scheimpflug tomography. Subclinical keratoconus has been identified with this technology; however, a significant fraction of cases could still go undetected, and the false-positive rate may be an issue (Galletti et al, 2015) (Figure 1).

Figure 1. (A) OD: Clinically keratoconic and abnormal anterior corneal curvature, elevation, posterior elevation, and global pachymetry. (B) OS: Clinically normal and normal anterior curvature and elevation; however, abnormal posterior elevation and global pachymetry.

Epithelial Thickness Maps

Li et al (2012) reported that 35% of asymptomatic fellow keratoconic eyes developed clinical findings of keratoconus within a period of six years, and 50% developed findings in approximately 16 years, supporting the idea that keratoconus is a bilateral disease but may be highly asymmetric. Epithelial remodeling often manifests prior to changes in anterior corneal surface topography, making early diagnosis difficult.

The latest modality for anatomical screening of keratoconus is epithelial thickness maps. With the help of a very-high-frequency (VHF) digital ultrasound, the epithelium was shown to remodel to maintain a smooth outer corneal surface as the underlying stroma became irregular. In keratoconus, the epithelium thinned out directly over the underlying cone while thickening around the cone, exhibiting a doughnut-like appearance.

Epithelial remodeling may be sufficient in early keratoconus to fully mask an underlying stromal cone so that the front-surface corneal topography would appear normal. Based on such findings, Reinstein et al (2015) demonstrated that epithelial thickness mapping could be used in early detection of keratoconus, more so than topography. Statistical analysis software to distinguish ectatic from normal corneas is an important next step that is currently being developed (Figure 2).

Figure 2. (A) OD: Normal Scheimpflug tomography. (B) OD: Abnormal epithelial thickness map (obtained by anterior segment optical coherence tomography) showing apical thinning of the epithelium inferior temporally with moderately elevated epithelial thickness variation.

Corneal Biomechanical Characteristics

Keratoconus is a disease of abnormal collagen lamellae in multiple layers of corneal tissue. Specifically, abnormal patterns, a reduction of several collagen types in the corneal epithelium and stroma, and an altered expression and activity of lysyl oxidase contribute to a weakening of covalent bonds between collagen and elastin fibrils. These weakened bonds lead to mechanical deterioration of corneal integrity, resulting in subclinical to very pronounced visual and functional defects. Getting down to the molecular level and understanding the specific course of events points to keratoconus being a bilateral, yet asymmetrical disease (Wojic et al, 2014).

Studies have shown that keratoconic corneas significantly differ from normal corneas when clinical measurement of biomechanical properties is used (Tian et al, 2014). Software has been developed that combines data from both Scheimpflug tomography and corneal biomechanical measurements (Ambrósi, 2017). By statistically weighting the various diagnostic elements appropriately, we can find cases with normal tomography yet abnormal biomechanical outcomes. Once again, what we formerly thought were true unilateral keratoconus cases now show biomechanical abnormalities in the tomographically normal eye (Figure 3).

Figure 3. Normal Scheimpflug tomography in an eye that has abnormal corneal biomechanics; the eye is felt to be abnormal when combining the data.

Concluding Remarks

Keratoconus experts agree that true unilateral disease does not exist. Our ability to detect abnormalities in what were thought to be normal eyes is expanding as we continue to develop more advanced technologies. The early diagnosis of keratoconus prior to the disease impacting vision is critical in light of our ability to halt the progression. CLS

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