Keratoconus (KC), a form of corneal ectasia, is a bilateral, asymmetrical, noninflammatory pathology characterized by progressive, localized thinning and protrusion of corneal tissue (Gokhale, 2013). Subclinical forms may be entirely symptom free and difficult to detect by traditional diagnostic methods; however, more advanced forms are commonly associated with rapid and symptomatic visual changes and prominent tissue irregularity, with end stage disease resulting in a potential need for corneal transplantation. Because of its detrimental and debilitating outcomes, this hereditary disease has received worldwide attention over the last several decades, with recent advancements in early detection, management, and treatment strategies to limit or halt progression (Eiden, 2014).
Incidence and Prevalence
Incidence is defined as new cases diagnosed within a time period, usually one year. Prevalence is the number of identified cases at a specific point in time. This becomes relevant when we consider that the onset of KC typically takes place between the ages of 10 to 40 years. Therefore, the prevalence of the disease is always higher than the annual incidence.
Previously, the frequency of KC was most commonly reported to be 1 in 2,000, a value based on a registration study in Olmsted County, MN, conducted between 1935 and 1982 (Kennedy et al, 1986); the study reported a prevalence of 54.5 per 100,000 cases. The diagnosis was based on the detection of scissors reflex with retinoscopy and keratometry outcomes. A group of 64 newly diagnosed residents (35 males, 29 females) were further broken down into cases of unilateral and bilateral disease (41% [26 patients] and 59% [38 patients], respectively). At the time, no significant trends in incidence rates over time were documented in the study, but it was noted that KC cases were evenly spread between the sexes.
As advancement in technologies such as corneal topography led the way for earlier detection of subclinical cases, the prevalence of KC was found to be much more common.
A recent epidemiological study by Godefrooij (2016), conducted via data extraction from the largest health insurance provider in the Netherlands, concluded that in KC among 10 to 40 year olds, the annual incidence of the disease was 1:7,500 (13.3 cases per 100,000), and the estimated prevalence was 1:375 (265 cases per 100,000). These values are five- to 10-fold higher than previously documented. The Achmea Health Database (AHD) was used for the collection of data during the period from Jan. 1, 2011 to Dec. 31, 2014. The data included date of birth and death (if applicable), gender, and date of the entered diagnosis and treatment combination code (DTC)—457 for keratoconus/corneal dystrophy. A total of 4,357,044 individuals were registered in the AHD in 2014, with a total of 1,635,517 individuals in the relevant age category for newly diagnosed KC; within this group, 218 new diagnoses of KC were identified. The mean age of the group was 28.3 years, and 60.6% of patients were male.
Influence of Ethnic Origin on Distribution of Keratoconus
KC affects all countries and all races, yet it has become clear that KC prevalence is not the same throughout the world. Northern Europe, the Urals, and the Northern United States have lower prevalence; the same is also noted for Japan. Alternatively, in countries of the Middle East, India, and China, KC is highly prevalent. One of the highest prevalence rates for keratoconus was described in a study of college age students in Jerusalem (Millodot et al, 2011). This study, which was based on corneal topography documentation of well-defined cases, found a keratoconus prevalence rate of 2.34%!
It is unknown whether the difference in prevalence is due to environmental factors, such as hot climates where oxidative damage caused by ultraviolet light is of great significance; socioeconomic status, in which poorer nutrition profiles are more dominant; cultural traditions, in which familial intermarriages are popular; or a combination of various factors (Cozma et al, 2005; Gordon-Shaag et al, 2015).
What is known is that for the 10- to 44-year-old age group, the prevalence of the disease ratio in Asians to whites is 4 to 1. A relative incidence in the same age group is 4.4 to 1. As compared to the white population, Asian patients also present with the condition at a younger age and require corneal grafting at an earlier age (Pearson et al, 2000).
The Role of Genetics
Differences in KC prevalence and age of onset among ethnic populations point to strong genetic influences in the pathogenesis of the disease. Although the most common type of KC is sporadic, studies have identified large numbers of familial KC, with rates ranging from 5% to 27.9% (Gordon-Shaag et al, 2015). The study, which indicated a rate of 27.9% of KC in at least one family member, noted that affected first-degree relatives represented 20.5% (Shneor et al, 2013). In the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, most percentages of positive general family history were typically less than 20% (Wagner et al, 2007). In Caucasian populations, the rate of positive family history in a KC patient is 5%; in an Asian subgroup, it is 25% (Gordon-Shaag et al, 2015). This variation in rates of positive family history may seem unusual; however, we would expect a higher level of positive family history in a population that has a greater prevalence of the disease. The significant variation in percentage of family members who have the disease may also allude to the different expression of KC alleles with different modes of inheritance.
The genetic effect of consanguinity, a trend more commonly seen among the developing countries, plays an important role in the pathogenesis of KC. It may account for the differences in prevalence among ethnic groups and possibly geographic regions. As an example, if a set of parents are first cousins, they may be carriers of the mutant allele in the exact locus responsible for corneal ectasia or thinning. The autosomal recessive inheritance in this situation is unlike the presumed autosomal dominant inheritance commonly noted in cases of KC found across Western countries, where consanguinity is far less common (Gordon-Shaag et al, 2015).
Although the natural history and pattern of KC progression is variable, the KC process typically begins right around the age of puberty and progresses over the course of 10 to 20 years, after which it eventually stops (Gokhale, 2013). The severity of the disease at the time the progression stops can vary from mild unilateral or bilateral irregular astigmatism to severely ectatic, scarred corneas in need of a keratoplasty. In countries such as India, KC presents at a younger age and progresses at a more rapid rate as compared to Western populations. Due to earlier age of onset being associated with greater risk for rapid progression, and thus a greater likelihood of more severe side effects, it is imperative to diagnose the condition early to try to halt it, with the hopes of preventing any visually significant and often debilitating effects.
Because we know that the prevalence of KC is so much higher than previously thought, and especially in cases with positive family history of the disease, screening high-risk patients in a primary eyecare setting using new advanced technologies can dramatically impact the course of a life destined for significant visual impairment. Scheimpflug imaging tomography assesses the anterior and posterior corneal surface layers for early signs of abnormal elevation or thinning. Wavefront aberrometry identifies higher-order aberrations commonly associated with advanced and subclinical forms of KC. Anterior segment optical coherence tomography and high-frequency corneal ultrasound can identify a consistent pattern of central corneal epithelial thinning abutted by an area of subsequent thickening, known as a “doughnut pattern” and commonly detected in very early stages of KC. Technologies used to assess corneal biomechanics are also being developed, which may detect abnormalities diagnostic of keratoconus at even earlier phases (Eiden, 2014).
Treatment Methods to Halt Progression
On a cellular level, the pathophysiology behind KC is an increase in lysosomal and proteolytic enzyme (a.k.a., protease) expression and a reduction in protease inhibitors, all leading to a breakdown or a weakening of the corneal collagen infrastructure (Alhayek and Lu, 2015). Such destructive acts are responsible for major changes in what is meant to be a stable, transparent, and tough refractive surface. With the advent of corneal cross-linking (CXL) we now have the ability to impact the natural history of the disease. Studies have shown that CXL is highly effective in controlling KC progression (Meiri et al, 2016). With this in mind, we now have observed a paradigm shift in our management of keratoconus. CLS
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