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Department of Pharmacy, Biotechnology, Nutrition, Optics and Optometry, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
Contact Lens and Visual Optics Laboratory, School of Optometry and Vision Science, Centre for Vision and Eye Research, Queensland University of Technology, Brisbane, Australia
Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity. Traditionally, the condition has been described as a noninflammatory disease; however, more recently it has been associated with ocular inflammation. Keratoconus normally develops in the second and third decades of life and progresses until the fourth decade. The condition affects all ethnicities and both sexes. The prevalence and incidence rates of keratoconus have been estimated to be between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 cases per 100,000 persons/year, respectively, with highest rates typically occurring in 20- to 30-year-olds and Middle Eastern and Asian ethnicities. Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings. A family history of keratoconus, eye rubbing, eczema, asthma, and allergy are risk factors for developing keratoconus. Detecting keratoconus in its earliest stages remains a challenge. Corneal topography is the primary diagnostic tool for keratoconus detection. In incipient cases, however, the use of a single parameter to diagnose keratoconus is insufficient, and in addition to corneal topography, corneal pachymetry and higher order aberration data are now commonly used. Keratoconus severity and progression may be classified based on morphological features and disease evolution, ocular signs, and index-based systems. Keratoconus treatment varies depending on disease severity and progression. Mild cases are typically treated with spectacles, moderate cases with contact lenses, while severe cases that cannot be managed with scleral contact lenses may require corneal surgery. Mild to moderate cases of progressive keratoconus may also be treated surgically, most commonly with corneal cross-linking. This article provides an updated review on the definition, epidemiology, histopathology, aetiology and pathogenesis, clinical features, detection, classification, and management and treatment strategies for keratoconus.
In 2010, a comprehensive review of keratoconus was published in Contact Lens & Anterior Eye, which became the most cited article of the journal to date [
]. This article reviewed the definition, epidemiology, clinical features, classification, histopathology, aetiology and pathogenesis, and management and treatment strategies for keratoconus. Over the last decade, numerous epidemiological studies have been conducted allowing for better estimates of the incidence and prevalence of keratoconus. Many other studies have also contributed to a better understanding of keratoconus, particularly due to the adoption of new technologies for imaging the human cornea. Improvements in corneal topography and the advent of corneal tomography has increased the ability of eye care practitioners to diagnose corneal ectasia at a much earlier stage than was previously possible. These imaging techniques, along with the increased use of wavefront aberrometry, have allowed better characterisation of the optical, anatomical, biomechanical and histopathological changes associated with keratoconus [
]. The latter, together with recent developments of contact lens and surgical options for keratoconus, have ultimately lead to improved clinical management [
]. The present article provides an updated review of keratoconus and expands on areas of recently acquired knowledge. In preparing this review, each author was given the lead to prepare one or more of the different sections or subsections covered in the review, although some sections/subsections had contributions from other authors. Adopting a search strategy using the keywords “keratoconus” and “definition” or “epidemiology” or “histopathology” or “aetiology” or “pathogenesis” or “features” or “clinical features” or “detection” or “classification” or “management” or “treatment”, articles were retrieved from two search databases (i.e., PubMed and Embase). Other searches were also made using different combinations of key terms at the authors’ discretion. Articles available in the database from their inception to between January and July 2021 were included, with the cut-off date for the search for articles being freely chosen by each individual author, although other articles were added to this review at a later date as part of the review process. Pertinent articles for each section were identified; abstracts reviewed; and relevant papers read in full, along with additional relevant papers identified in the reference lists. When several research papers reporting on similar findings appeared during the literature search, the most updated article(s) was typically used for review.
2. Definition
The word keratoconus derives from the Greek words ‘kéras’, meaning cornea, and ‘cōnus’, meaning cone, which together means ‘cone-shaped’ cornea. Although the presentation, clinical features, and refractive consequences of keratoconus were described with reasonable accuracy by a few European oculists in the early 18th and 19th centuries, it was not until 1854 that John Nottingham provided a comprehensive understanding of what is currently understood as keratoconus, which allowed the condition to be distinguished from other corneal ectasias [
Today, keratoconus is considered a bilateral and asymmetric ocular disease which results in progressive thinning and steepening of the cornea leading to irregular astigmatism and decreased visual acuity [
]. The condition affects all ethnicities and both sexes. It is commonly an isolated ocular condition, but sometimes coexists with other ocular and systemic diseases [
Determining the prevalence and incidence of a particular disease is critical, because it can aid in identifying potential underlying causative factors, assessing methods to prevent, monitor, and treat the condition [
]. The prevalence of a condition is defined as ‘the part (percentage or proportion) of a defined population affected by a particular medical disorder at a given point in time, or over a specified period of time’ while the incidence rate represents ‘the frequency of new occurrences of a medical disorder in the studied population at risk of the medical disorder arising in a given period of time’ [
Early studies in which the diagnosis of keratoconus was based upon the scissor movement observed during retinoscopy, irregular keratometry mires, and the subjective assessment of clinical signs were more likely to identify advanced keratoconus. However, the widespread use of corneal topography, and more recently corneal tomography, together with built-in software to aid in keratoconus detection has facilitated the ability to diagnose patients with keratoconus even at incipient stages of the disease, ultimately leading to greater rates of keratoconus being reported in studies conducted in recent years (Table 1).
Table 1Prevalence and incidence rates of keratoconus reported as per 100,000 persons and 100,000 person-years, respectively in studies conducted around the world. NA, not available; aReported prevalence for definite keratoconus cases only; bAsian are mostly Indian; cAsian are mostly Pakistani; dPrevalence recalculated based on number of subjects rather than number of eyes; eCorrected value provided by study author (personal communication); fPopulation-based studies with claims health data from national or insurance registration.
Epidemiological studies indicate substantial global variation as the prevalence and incidence rates of keratoconus have been estimated to be between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 per 100,000 persons/year, respectively (Table 1; Fig. 1, Fig. 2), with the highest prevalence and incidence rates typically occurring in 20 to 30 year olds [
]. Differences between studies have been attributed to differences in geographic location and ethnicity, the definition of keratoconus and diagnostic criteria, study design, and the age and cohort of subjects assessed (Table 1; Fig. 1, Fig. 2). Furthermore, fair comparisons between studies of keratoconus are difficult to make due to differences in the criteria used for defining the numerators and denominators used for calculating the incidence and prevalence rates [
Fig. 1Reported prevalence rates (per 100,000 persons) of keratoconus around the world. In countries where several epidemiological studies have been conducted, the results of the study with the largest sample size and those representing the most predominant ethnic group are reported.
Fig. 2Reported incidence rates (per 100,000 persons/year) of keratoconus around the world. In countries where several epidemiological studies have been conducted, the results of the study with the largest sample size and those representing the most predominant ethnic group are reported.
In hospital/clinic-based studies, a high prevalence of keratoconus has been reported in the Middle East with rates up to 4,790 per 100,000 in Saudi Arabia adolescents [
] (Table 1 and Fig. 1). Incidence rates of keratoconus from hospital/clinic studies have been reported to be as low as 1.5 per 100,000 persons/year in Finland [
] (Table 1 and Fig. 2). However, hospital/clinic-based epidemiological data should be interpreted with caution since the true prevalence of keratoconus within the wider population may be underestimated. Patients with keratoconus presenting to a hospital/clinic are likely to be those who are symptomatic and with access to health care, thus early forms of the disease might not be detected. Furthermore, these studies do not take into account the number of patients treated outside of the hospital/clinic(s) where the study is conducted [
]. Therefore, population-based epidemiological studies provide a more representative estimate of the true prevalence and incidence of keratoconus in the general population. In population based studies, the prevalence of keratoconus has been reported to be as low as 4 in Denmark [
The prevalence and incidence of keratoconus varies with regard to ethnicity and geographical location (Table 1 and Fig. 1, Fig. 2). Studies of predominantly Caucasian populations report prevalence rates under 1,000 per 100,000 persons, whereas studies conducted in Asian and Middle East populations report prevalence rates between 1,500 and 5,000 per 100,000 persons. Similarly, the incidence of keratoconus in Caucasians appears to be around 2 to 4 per 100,000 persons/year compared to around 20 per 100,000 persons/year in Asia and the Middle East. Two studies conducted in the United Kingdom found a significantly higher prevalence and incidence of keratoconus in Asians (primarily Indian and Pakistani) compared to Caucasians [
] which might indicate that such differences are related to ethnicity rather than geographic location. Similarly, a more recent study of high school students in New Zealand found a significantly higher prevalence of keratoconus in Maori islanders in comparison with a predominantly Caucasian cohort [
Although some studies have reported greater rates of keratoconus in males, many studies have found the opposite (or no significant difference), which most likely indicates that keratoconus affects both sexes similarly (Table 1).
4. Histopathology
All corneal layers have been reported to experience histopathological changes in keratoconus, which are much more pronounced in the central compared to the peripheral cornea; however, in early forms of the disease only the anterior cornea appears to be compromised [
]. There is some controversy as to whether the endothelium is affected in keratoconus, since many patients with keratoconus wear different types of contact lenses, including rigid corneal, corneoscleral and scleral lenses, soft and hybrid (i.e., rigid corneal lens with a peripheral soft skirt) lenses, and piggyback systems (i.e., rigid corneal lens fitted over a soft contact lens) which can alter endothelial morphology, and the endothelium can be difficult to image as the disease progresses [
]. Histopathological changes are primarily found in the corneal epithelium, anterior limiting lamina (Bowman’s layer) and stroma, while the posterior limiting lamina (Descemet’s membrane) appears to be much less frequently affected.
Although corneal epithelial thinning around the apical cone region is believed to be the most common histopathological change associated with keratoconus [
]. In keratoconus, it has been proposed that epithelial thinning might occur due to apoptosis because of chronic epithelial injury subsequent to environmental risk factors, which in turn release apoptotic cytokines (see Section 5). Of interest is that the thinnest corneal location in eyes with keratoconus does not overlap with the location of the maximum axial and tangential curvatures or the maximum front and back elevation locations, although all these points are typically located in the inferior-temporal cornea. This indicates that in keratoconus the point of maximal corneal curvature is displaced relative to the thinnest corneal location [
]. Using confocal microscopy, it has been reported that in severe cases, the epithelium displays superficial cells, which are elongated and spindle shaped, larger and irregularly spaced wing cell nuclei, and flattened basal cells [
]. Breaks in the corneal epithelium, accompanied by a downgrowth of basal cells into the anterior limiting lamina, and an accumulation of ferritin particles within and between epithelial cells (most prominently in the basal layer), have also been reported in keratoconus [
]. Superficial iron deposits and scarring are other less frequently observed changes in the corneal epithelium typically affecting one in five eyes with keratoconus [
Increased visibility of corneal nerves at the sub-basal corneal nerve plexus, located between the basal epithelium and anterior limiting lamina, as a result of corneal thinning is sometimes seen in keratoconus patients with different grades of severity [
]. A study conducted in a small number of eyes using in-vivo confocal microscopy reported that keratoconic corneas exhibit abnormal sub-basal nerve architecture compared with normal corneas [
]. Furthermore, at the apex of the cone, a tortuous network of nerve fibre bundles was noted, many of which formed closed loops; and at the topographic base of the cone, nerve fibre bundles followed the contour of the cone base, with many of the bundles running concentrically in this region [
Breaks in the anterior limiting lamina are one of the most common histopathological signs seen in keratoconus typically affecting over seven in ten keratoconic eyes [
]. The breaks normally show Z-shaped interruptions due to collagen bundle separation, which are filled with proliferative collagenous tissue derived from the anterior stroma and positive nodules of Schiff’s periodic acid [
]. The keratoconic cornea has been reported to show a reduction in the number of lamellae, particularly in regions associated with cone development without breaks in the anterior limiting lamina or scarring [
]. The width and angle relative to the anterior limiting lamina of collagen lamellae have been reported to be significantly larger and smaller, respectively, relative to those in the normal cornea [
]. Ectasia and thinning in keratoconus are associated with lamellar splitting into multiple bundles of collagen fibrils and loss of anterior lamellae. These structural changes, possibly in addition to lateral shifting of lamellae due to the pressure gradient over the cornea, provide a potential explanation to the central loss of mass ultimately leading to reduced stromal thickness [
]. These bands, which are believed to represent collagen lamellae under stress, correspond with the appearance of Vogt's striae on slit-lamp biomicroscopy examination.
Breaks and deformities in the posterior limiting lamina have been reported to occur in approximately one in five keratoconus eyes –typically affecting more severe cases [
]. Breakage in the posterior limiting lamina, allowing aqueous to enter the corneal stroma and epithelium, is a serious complication, known as corneal hydrops, [
Understanding of the mechanism behind the development of keratoconus is still limited. There are no well-established animal models for the disease; mouse models have been developed, but mouse and human genomes are not organised in a similar pattern. Hence, research has mainly focused on clinical observations and donor corneal samples (extracted during a corneal graft operation) and hence are generally from more severe cases. Obtaining demographically matched, healthy corneas for comparison is also difficult and samples degrade rapidly after extraction. Keratoconus progresses as a combination of simultaneously occurring destructive and healing processes [
]. It has been estimated that a relative of an individual with keratoconus has a 15 to 67 times greater risk of developing keratoconus than an individual with no family history of keratoconus [
], but computer-assisted corneal topography in parents of patients with keratoconus detects the disease in more family members than previously diagnosed, which affects familial analysis [
Loci on 73% (16 out of 22) of human autosomal chromosomes have been suggested to be involved in keratoconus and 59% of these could be considered to show statistically significant associations [
], suggesting that it could be a polygenic disease (two or more affected genes are required for keratoconus to develop). Detailed studies of the key candidate genes (VSX1 and SOD1) and others [
] have been inconclusive, leading to the hypothesis that mutations, in the presence of other gene variants (referred to as modifier genes), are required to elicit keratoconic traits [
] and that multiple genetic factors, together with other factors influence the development of keratoconus traits. Keratoconus may even be a range of diseases that have relatively similar manifestations [
]. Differential expression of several corneal proteins results in changes in the structural integrity and morphology of the keratoconic cornea, through altering its collagen content and keratocyte apoptosis and necrosis in the stroma [
]. Oxidative stress markers and antioxidants are dysregulated in keratoconus, involving an imbalance of redox homeostasis in tears, cornea, aqueous humour and blood [
]. Keratoconus is associated with an overall increase in oxidative stress markers, particularly in reactive oxygen and nitrogen species and malondialdehyde. It is also associated with an overall decrease in antioxidants, including a significant decrease in total antioxidant capacity/status, aldehyde/NADPH dehydrogenase, lactoferrin/transferrin/albumin and selenium/zinc. Oxidative stress markers are higher in tears and in the cornea of keratoconic than in the aqueous humour, and antioxidants were decreased in tears, aqueous humour and blood. Oxidative stress markers increased in stromal cells and antioxidants decreased in endothelium [
di Martino E, Ali M, Inglehearn CF. Matrix metalloproteinases in keratoconus – too much of a good thing? Exp Eye Res 2019;182. doi: 10.1016/j.exer.2019.03.016.
]. At a cellular level, penetration of fine keratocyte processes into the anterior limiting membrane have been observed in localised regions, generally in association with localised indentation of the basal epithelium, often where nerves penetrate between the stroma and epithelium. Increased levels of lysosomal enzymes (Cathepsin B and G) have been measured in these stromal keratocytes in the disrupted regions, which have been hypothesised as the driving force to structural damage to the anterior limiting membrane and underlying stroma [
]. Physical stresses from the intraocular pressure and eye rubbing are likely to exacerbate this degradation. Nerve associated Schwann cells express higher levels of Cathepsin B and G in keratoconic corneas and these enzymes are known to be active in other disease neural tissues [
The degeneration of the proteoglycans around the stromal collagen fibrils in keratoconic corneas leads to breakage of, and degeneration of the microfibrils within, collagen fibrils [
Collagen fibrils and proteoglycans of peripheral and central stroma of the keratoconus cornea – ultrastructure and 3D transmission electron tomography.
]. These changes result in a reduction of the diameter of the collagen fibrils, and the reduced number and different distribution of lamellae, composed of these degenerated fibrils, are biomechanically weak and prone to disorganisation and undulation [
Collagen fibrils and proteoglycans of peripheral and central stroma of the keratoconus cornea – ultrastructure and 3D transmission electron tomography.
]; hence, these changes eventually result in alteration of the curvature of the cornea ultimately leading to cone formation. Polymorphisms of the antioxidant enzymes (catalase and glutathione peroxidase) have been shown to act as independent predictors of the severity of keratoconus, perhaps due to mechanical insult to the cornea, highlighting the role of oxidative stress in the pathogenesis of the disease [
]. Both enzymes play important roles in the reactive oxygen processes of different species. The reactive oxygen accumulation causes cytotoxic deposition of malondialdehyde and peroxynitrites, which could potentially damage corneal tissue [
Matrix stiffness, which regulates the physiology of the cells in tissues throughout the body and plays an important role in maintaining their homeostasis, is altered in keratoconus. Additionally, it has been reported to regulate cell division, proliferation, migration, extracellular uptake, and various other physiological processes. There is a connection between endocytosis and matrix stiffness in keratoconus which may explain the link between mechanical and biochemical factors [
], it seems unlikely that contact lens wear could trigger the development of keratoconus.
5.4 Risk factors
Several environmental and familial factors are associated with an increased risk of developing keratoconus (Table 2). Allergy and atopy have long been associated with keratoconus, with the majority of studies showing a positive association and the reported prevalence being 11 to 30% [
]. A common mediator to these major risk factors is Immunoglobulin E, which has been identified as elevated, even in some patients with keratoconus without inflammatory symptoms and signs [
]. In keratoconus patients, the incidence of elevated levels of total serum Immunoglobulin E was between 52% and 59% for raised serum specific Immunoglobulin E levels [
]. A recent systematic review and meta-analysis, in which 3996 articles were retrieved, of which 29 were analyzed including 7,158,241 participants from 15 countries, identified the odds ratios (OR) of having keratoconus to be 3.09 times (95% CI: 2.17–4.00) for those reporting eye rubbing, 1.42 times (95% CI: 1.06–1.79) for those with allergy, 1.94 times (95% CI: 1.30–2.58) for those with asthma and 2.95 times for those with eczema (95% CI: 1.30–4.59); however, the odds ratio for those with a family history of keratoconus was 6.42 (95% CI: 2.59–10.24), showing the significant influence of genetics [
]. One other recent study reported eye rubbing (odds ratio: 4.93), family history of keratoconus (odds ratio: 25.52) and parental consanguinity (odds ratio: 2.89) to be significant risk factors for keratoconus [
], whereas another study also reported eye rubbing (odds ratio: 3.53,) and consanguineous marriage (odds ratio: 12.87) to be independent risk factors for keratoconus [
]. Another recent study, which involved an analysis of 2,051 keratoconus cases and 12,306 matched controls, identified novel associations between keratoconus and Hashimoto's thyroiditis (OR = 2.89; 95% CI: 1.41 to 5.94) and inflammatory skin conditions (OR = 2.20; 95% CI: 1.37 to 3.53), and confirmed known associations between keratoconus and atopic conditions, including allergic rash (OR = 3.00; 95% CI: 1.03 to 8.79), asthma and bronchial hyperresponsiveness (OR = 2.51; 95% CI: 1.63 to 3.84), and allergic rhinitis (OR = 2.20; 95% CI: 1.39 to 3.49) [
]. These latter results indicate that keratoconus appears positively associated with multiple immune-mediated diseases, which provides an argument that systemic inflammatory responses may influence its onset.
Table 2Environmental and familial risk factors for keratoconus
] (Table 3). The condition typically affects both eyes, although with different degrees of severity, and it has well-established signs and symptoms, although there is no clear consensus regarding the signs and symptoms associated with early keratoconus (Table 3) [
]. The early stages of the disease are commonly referred to as subclinical or form-fruste keratoconus, although there is a lack of unified criteria in the use of these two terms [
]. Subclinical keratoconus typically refers to an eye with topographic signs of keratoconus (or suspicious topographic findings) with normal corneal slit-lamp findings and keratoconus in the fellow eye [
]. It has been recently reported that eyes with form fruste keratoconus have an increased central epithelial to stromal thickness ratio and asymmetric superior-nasal epithelial thinning, whereas keratometric and corneal volumetric alterations are more prominent in subclinical keratoconus [
]. Characteristics of eyes with subclinical keratoconus also include an asymmetrically displaced anterior and posterior corneal apex, corneal thinning, and loss of corneal volume [
Table 3Signs and symptoms based on keratoconus severity. Of note is that the time course for the development of keratoconus signs and symptoms, and their association with disease severity are highly variable. VA, visual acuity; BCVA, best corrected visual acuity; D, dioptres.
Stage
Signs
Symptoms
1 – Subclinical
Suspicious topography; normal slit-lamp findings; and ∼ 6/6 VA achievable with spectacle correction.
None or slight blurring of vision
2 – Early
‘Scissor reflex’; Charlouex's oil droplet reflex; mild, localised corneal steepening and thinning; increasing keratometric differences between inferior and superior cornea; increases in corneal aberrations (particularly coma-like aberrations); mild changes in refractive error; and reduction of spectacle BCVA.
Mild blurring or slightly distorted vision
3 – Moderate
Those of stage 2 (normally of greater severity) plus: significant corneal thinning; Vogt’s striae; Fleischer’s ring; < 6/6 spectacle BCVA, but ∼ 6/6 spectacle BCVA with contact lenses; increased refractive changes; increased visibility of corneal nerves; corneal scarring and opacities normally absent.
Moderate blurring and distorted vision
4 – Severe
Those of stage 3 (normally of greater severity) plus: severe corneal thinning and steepening (>55D); corneal scarring; < 6/7.5 VA with contact lens correction; Rizzuti’s sign; Munson’s sign; corneal opacities; and corneal hydrops;
Severe blurring and distorted vision, and monocular polyopia (typically reported as ‘ghost’ images)
Detecting the earliest stages of keratoconus remains a challenge, although it is particularly important as it can lead to better management and long-term prognosis. In its early stages, the symptoms of keratoconus can mimic the symptoms of simple refractive errors, and if a corrected visual acuity of 6/6 (i.e., 20/20) is achieved without obvious clinical signs of keratoconus, detection of the disease is unlikely unless corneal imaging is performed. Particular attention should be given to the results of the axial curvature map from the corneal topographer to depict any patterns typically associated with keratoconus [
]. As keratoconus progresses, symptoms can include mild blurring or slightly distorted vision along with a reduction in spectacle best corrected visual acuity. Other common signs preceding ectasia include mild, localised corneal steepening, an increasing difference between the inferior and superior corneal curvature, and increasing anterior corneal aberrations, particularly coma-like aberrations [
Several clinical signs are associated with keratoconus. The ‘scissor reflex’ is observed during retinoscopy assessment. Charlouex's oil droplet reflex is also commonly seen in early keratoconus using retroillumination with a dilated pupil, which produces a dark, round shadow in the corneal midperiphery [
]. Fleischer’s ring and Vogt’s striae can be observed as the disease severity increases (Table 3). Fleischer’s ring is believed to be a subepithelial deposition of iron oxide hemosiderin within the posterior limiting lamina membrane that manifests as yellow–brown to olive-green pigmentation in an arc or ring shape around the base of the cone [
]. Vogt’s striae may be seen as fine as well as relatively thick, vertical, stress lines within the posterior stroma and posterior limiting lamina due to stretching and thinning of the cornea, that disappear while exerting gentle pressure to the globe, although they may also have a fanlike appearance around the base of the cone. Occasionally, striae can be observed without the use of a slit lamp. Fleischer’s ring and Vogt's striae are observed in one or both eyes in 86% and 65%, respectively of patients with keratoconus [
]. Although these signs can manifest at any point during disease development and progression, the more advanced the disease the greater the likelihood that Vogt's striae, Fleischer's ring, and/or corneal scarring will be present [
Epithelial or subepithelial corneal scarring is also a characteristic sign of keratoconus (Fig. 3), and is more commonly observed in patients with: a younger age at diagnosis; corneal staining; greater corneal curvature (i.e., >55 D or steeper than 6.13 mm); and who wear contact lenses [
]. Rizzuti’s sign, a bright reflection of the nasal area of the limbus when light is directed to the temporal limbal area, is another sign frequently observed in advanced stages [
]. Severe keratoconus may result in corneal hydrops, characterised by marked corneal oedema due to a break in the posterior limiting lamina, which allows aqueous to enter the corneal stroma and epithelium. Although hydrops can be self-limiting within ∼3 months, acute cases may require corneal suturing or intracameral gas injection depending upon the severity [
]. Corneal hydrops can results in central vision-impairing scar tissue and corneal irregularity, necessitating in many cases the need for scleral contact lenses to achieve functional vision [
]. Significant risk factors independently associated with the development of hydrops in keratoconus (using multivariate analysis to address co-dependencies) include vernal keratoconjunctivitis (adjusted odds ratio (AOR) 15.00x), asthma (AOR 4.92x), and visual acuity in the worse eye (i.e. disease severity, AOR 4.11x) [
Corneal protrusion, the scissors reflex, corneal thinning, Fleischer’s ring, and prominent corneal nerve fibres are the most prevalent clinical signs in keratoconus (Fig. 4), with all signs observed in over 50% of patients with keratoconus [
]. However, the time course of the development of these clinical signs and their association with disease severity are highly variable. Although identifying clinical symptoms and slit-lamp findings in keratoconus are important, corneal topography is currently the primary diagnostic tool for keratoconus detection [
]. In incipient cases, however, the use of a single parameter as a diagnostic factor is not sufficiently accurate, and pachymetry and corneal aberration data are now also commonly used in conjunction with corneal topography to aid early diagnosis and monitor progression and treatment outcomes [
]. In addition to corneal topography that provides two-dimensional imagining of the corneal surface based on curvature data, corneal tomography is a three-dimensional imaging technique that characterises the anterior/posterior corneal surfaces based on curvature data of the anterior surface and elevation data of both the anterior and posterior corneal surfaces, along with corneal thickness distribution [
]. Furthermore, various machine learning algorithms have been developed using routinely collected clinical parameters that can assist in the objective detection of early forms of the disease [
Fig. 4Vertical Scheimpflug image (left) and anterior axial curvature map (right) of a cornea with advanced keratoconus; mean central anterior keratometry 56 D, anterior corneal astigmatism 11.8 D, thinnest corneal pachymetry 381 µm. The white dot on the top left indicates the superior aspect of the image and the arrow indicates the region of central-inferior corneal thinning.
The early detection of keratoconus can lead to improved patient outcomes though more frequent review to monitor disease progression and timely interventions when indicated (e.g., corneal collagen cross-linking), ultimately reducing the need for corneal transplantation. Consequently, most research concerning the detection of keratoconus has focused on identifying the first clinical signs of corneal disease. For example, differentiating between “form fruste keratoconus” (no corneal topography or slit lamp abnormalities, but keratoconus in the fellow eye) or “keratoconus suspects” (preclinical or subclinical keratoconus, typically defined as a cornea with no detectable abnormalities based on slit lamp examination, but inferior corneal steepening/asymmetry with unaffected visual acuity) from non-keratoconic eyes [
]. Additionally, efforts have also been made to obtain consensus from a panel of ophthalmology experts from around the world that resulted in definitions, statements, and recommendations for the diagnosis and management of keratoconus and other ectatic diseases that should help eye care providers around the world to adopt best practices for these often visually debilitating conditions [
]. Studies assessing the diagnostic utility of a particular corneal metric typically report the sensitivity (the ability to correctly identify eyes with keratoconus), the specificity (the ability to correctly identify eyes without keratoconus), and the threshold beyond which a cornea would be considered keratoconic. Importantly, there is currently no single metric that can unequivocally differentiate emerging disease from normal corneal data, so a diagnosis of keratoconus must consider a range of corneal parameters, including their interocular asymmetry. Scoring indices that combine several different corneal parameters have been developed to improve diagnostic accuracy. This section reviews emerging methods of keratoconus detection over the past decade.
7.1 Corneal morphology
7.1.1 Thickness profile
Since the advent of high-resolution anterior segment optical coherence tomography (OCT) imaging, numerous studies have investigated the thickness profile of individual corneal layers in keratoconus. Keratoconic eyes typically display epithelial thinning at the corneal apex (cone), surrounded by an annulus of epithelial thickening, thought to be an epithelial remodelling response in order to provide a smooth optical surface over a an increasingly irregular and steepening anterior stroma [
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