KEY CONCEPTS
- •
The progression of keratoconus is variable and is linked to environmental factors and eye-rubbing habits, as well as to multiple genes.
- •
To date, there is no consensus on criteria or cutoff values to define progression in keratoconus. The use of multiple parameters may help to better identify patients who might benefit from cross-linking treatments.
- •
Caution should be taken when assessing progression on a single parameter, as measurement predictability drops as the severity of keratoconus increases.
Clinical Course and Progression of Keratoconus: Current State of the Art
NATURAL CLINICAL COURSE
Keratoconus (KC) is defined as a bilateral and asymmetric progressive corneal ectasia with onset typically during the second decade of life. Although KC may rarely manifest at a later age, progression is uncommon. The average age at diagnosis reported in the literature stands between 25 and 27 years. However, with increased awareness by ophthalmologists and optometrists, studies published over the past 10 years have reported an average age at diagnosis to be less than 20 years. Although KC patients can be of any ethnic or geographic background, worldwide, younger patients at diagnosis are frequently from the Middle East or Asia , and tend to present initially with more severe KC.
The manifestation and progression of the disease are highly variable and are most often asymmetric between the two eyes of the same patient. It is widely accepted that there is no truly unilateral KC. Even when no clinical signs of the disease can be seen in the fellow eye, it is still considered that KC has simply not yet manifested in that eye. This condition is also known in the literature as “subclinical keratoconus,” and it has already been reported that approximately 50% of clinically normal fellow eyes of patients with a unilateral KC progress to KC within 16 years, with a greater risk during the first 6 years of onset. A meta-analysis that reviewed the natural progression of 11,529 untreated KC eyes identified the population below 17 years old with steeper corneas at presentation (above 55 diopters [D] of maximum keratometry (K max )) has increased risk of progression. However, a complex relationship exists between the natural course of the disease and the kinetics of its progression, and patient behaviors such as eye rubbing. More recently, a study of KC in a pediatric population has raised the question of the possible impact of the awareness of the patient and their family about eye rubbing and the potential of this awareness to slow or halt disease progression. In this study, the second eye of the patient, left untreated, remained stable over a 5-year period after cross-linking of the first eye. Although not investigated in a randomized comparative study, the authors hypothesized that the reduction or discontinuation of eye rubbing after cross-linking treatment of the first eye might have contributed to slowing the progression of the second eye.
DEFINITION OF A PROGRESSIVE STATE
Progression of ectatic disease remains challenging to define and therefore explains the diversity of indices presented in the literature that indicate progression. A summary of the current indices is shown in Table 8.1 . The Global Delphi Panel on Keratoconus and Ectatic Disease recognized that there was no clear definition of ectasia progression. The panel suggested that it should be defined by a reliable change for the worse in two or three of the following parameters: radius of the anterior corneal curvature; radius of the posterior corneal curvature and central corneal thickness; or increase in the rate of change of pachymetry from the periphery to the thinnest point. The panel of experts considered that although KC progression frequently leads to a worsening in corrected distance visual acuity (CDVA), a change in both uncorrected distance visual acuity (UCDVA) and CDVA was not required for documenting progression. In addition, they agreed that specific quantitative data were lacking to determine progression and that such data would most probably be specific to a given device. Interestingly, although multiple diagnostic grading systems for ectatic disease have been proposed over the past years, there is still no true correlation or association between those grading systems and the criteria used to monitor disease progression. The oldest grading system, the Amsler-Krumeich scale, which is still the most commonly used, grades the disease from early (grade 1) to severe (grade 4) KC, and is based only on anterior keratometric and corneal thickness measurements, together with refraction and clinical assessment. More recent scales, such as those proposed by Alió and Shabayek and the RETICS classification, have added the measurement of coma aberrations, which reflects the level of corneal asymmetry. However, none of these have been applied to monitoring disease progression The Belin ABCD Classification/Staging display and the Belin ABCD Progression display–both based on information from minimal corneal thickness, the anterior and posterior radius of curvature, and best spectacle distance visual acuity–represent a promising way of being able to establish the relationship between the diagnosis/classification and the progression of the ectasia.
| Publication | Year | K max Ant | Corneal Thickness | Cylinder | Visual Acuity | MRSE | Other Criteria | ||
|---|---|---|---|---|---|---|---|---|---|
| Raiskup-Wolf et al. | 2008 | >1 D in 1 year | Subjective loss of BCVA | ||||||
| Wittig-Silva et al. | 2008 | >1 D over 6–12 months | >1 D over 6–12 months | SE >0.5 D in 6–12 months | |||||
| Vinciguerra et al. | 2009 | >1.5 D in 6 months | Thinning TP >5% in 6 months | >3 D in 6 months | Myopia >3 D in 6 months | ||||
| Hersh et al. | 2011 | >1 D in 2 years | >1 D in 2 years | SE >0.5 D in 2 years | |||||
| O’Brart et al. | 2011 | >0.75 D in 18 months | >0.75 D in 18 months | Worsening >1 line in 18 months | |||||
| Choi and Kim | 2012 | >1.5 D in 1 year | |||||||
| Chatzis and Hafezi | 2012 | >1 D in 1 year | |||||||
| Hashemi et al. | 2013 | >1 D in 1 year | >1 D in 1 year | Worsening >2 lines CDVA in 12 months | SE >1 D in 1 year | ||||
| Mazzotta et al. | 2014 | >1 D in 6 months | Thinning TP >10 μm in 6 months | Worsening >0.5 line UDVA/CDVA in 6 months | SE >0.5 D in 6 months | SAI or IS >0.5 D in 6 months | |||
| Stojanovic et al. | 2014 | >1.5 D in 12 months | >1 D in 12 months | Myopia >1 D in 12 months | |||||
| Shetty et al. | 2015 | >1 D in 6 months | Thinning TP >5% in 6 months | SE >1 D in 6 months | |||||
| Poli et al. | 2015 | >0.7 5 D in 6 months | Thinning TP >10 μm in 6 months | Worsening >1 line UDVA/CDVA in 6 months | SE >0.5 D in 6 months | ||||
| Godefrooij et al. | 2016 | >1 D in 6–12 months | |||||||
| Hersh et al. | 2017 | ≥1 D in 24 months | ≥1 D in 24 months | SE > -0.5 D in 24 months |
One of the most important studies, which contributed to the United States Food and Drug Administration (FDA) approval of collagen cross-linking treatment, was performed on behalf of the United States Crosslinking Study Group and published in 2017. KC progression or ectasia in this study was defined as one or more of the following changes over a period of 24 months: an increase of 1.00 D or more in the steepest keratometry measurement, an increase of 1.00 D or more in manifest cylinder, or an increase of 0.50 D or more in manifest refraction spherical equivalent. As illustrated in Table 8.1 , the challenge of defining progression of ectatic disease remains incomplete and requires further study to designate widely acceptable monitoring guidelines. Significant problems are the disparity of diagnostic tools for measuring corneal properties and a lack of knowledge of the kinetics of disease progression. Further understanding may lead to an optimization of monitoring and to guidelines on the frequency of monitoring. To date, it seems reasonable to follow a KC patient before their third decade every 6 months unless risk factors such as younger age, pregnancy, or even warning signs such as recent isolated progression of the coma or posterior steepening are identified, which would require closer monitoring (every 3 months or more frequently depending on the case).
IDENTIFIED RISK FACTORS OF PROGRESSION
Several risk factors have been identified for KC and its progression and are summarized in Table 8.2 . Some of these risk factors, especially eye rubbing, are preventable.
