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Keratoconus: An updated review

Open AccessPublished:January 04, 2022DOI:https://doi.org/10.1016/j.clae.2021.101559

      Abstract

      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.

      Keywords

      1. Introduction

      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 [
      • Romero-Jiménez M.
      • Santodomingo-Rubido J.
      • Wolffsohn J.S.
      Keratoconus: a review.
      ]. 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 [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ]. The latter, together with recent developments of contact lens and surgical options for keratoconus, have ultimately lead to improved clinical management [
      • Loukovitis E.
      • Kozeis N.
      • Gatzioufas Z.
      • Kozei A.
      • Tsotridou E.
      • Stoila M.
      • et al.
      The proteins of keratoconus: a literature Review exploring their contribution to the pathophysiology of the disease.
      ,
      • Khaled M.L.
      • Helwa I.
      • Drewry M.
      • Seremwe M.
      • Estes A.
      • Liu Y.
      Molecular and histopathological changes associated with keratoconus.
      ]. 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 [
      • Grzybowski A.
      • Mcghee C.N.J.
      The early history of keratoconus prior to Nottingham’s landmark 1854 treatise on conical cornea: a review.
      ].
      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 [
      • Li X.
      • Rabinowitz Y.S.
      • Rasheed K.
      • Yang H.
      Longitudinal study of the normal eyes in unilateral keratoconus patients.
      ,
      • Zadnik K.
      • Barr J.T.
      • Gordon M.O.
      • Edrington T.B.
      Biomicroscopic signs and disease severity in keratoconus.
      ,
      • Kennedy R.H.
      • Bourne W.M.
      • Dyer J.A.
      A 48-year clinical and epidemiologic study of keratoconus.
      ]. Corneal thinning occurs in the central or paracentral cornea, most commonly infero-temporally [
      • Romero-Jiménez M.
      • Santodomingo-Rubido J.
      • González-Méijome J.M.
      The thinnest, steepest, and maximum elevation corneal locations in noncontact and contact lens wearers in keratoconus.
      ]. Traditionally, keratoconus has been described as a noninflammatory disease [,
      • Krachmer J.H.
      • Feder R.S.
      • Belin M.W.
      Keratoconus and related noninflammatory corneal thinning disorders.
      ]; however, several studies have reported associations with significant alterations in inflammatory mediators [
      • Wisse R.P.L.
      • Kuiper J.J.W.
      • Gans R.
      • Imhof S.
      • Radstake T.R.D.J.
      • Van Der Lelij A.
      Cytokine expression in keratoconus and its corneal microenvironment: A systematic review.
      ,
      • Jun A.S.
      • Cope L.
      • Speck C.
      • Feng X.
      • Lee S.
      • Meng H.
      • et al.
      Subnormal cytokine profile in the tear fluid of keratoconus patients.
      ,
      • Lema I.
      • Durán J.A.
      Inflammatory molecules in the tears of patients with keratoconus.
      ,
      • Lema I.
      • Sobrino T.
      • Durán J.A.
      • Brea D.
      • Díez-Feijoo E.
      Subclinical keratoconus and inflammatory molecules from tears.
      ,
      • Balasubramanian S.A.
      • Mohan S.
      • Pye D.C.
      • Willcox M.D.P.
      Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus.
      ], indicating that keratoconic eyes often experience some form of ocular inflammation [
      • Wisse R.P.L.
      • Kuiper J.J.W.
      • Gans R.
      • Imhof S.
      • Radstake T.R.D.J.
      • Van Der Lelij A.
      Cytokine expression in keratoconus and its corneal microenvironment: A systematic review.
      ,
      • Galvis V.
      • Sherwin T.
      • Tello A.
      • Merayo J.
      • Barrera R.
      • Acera A.
      Keratoconus: an inflammatory disorder?.
      ,
      • McMonnies C.W.
      Inflammation and keratoconus.
      ]. Although a bilateral condition, one eye is typically more severely affected than the other [
      • Nichols J.J.
      • Steger-May K.
      • Edrington T.B.
      • Zadnik K.
      The relation between disease asymmetry and severity in keratoconus.
      ,
      • Burns D.M.
      • Johnston F.M.
      • Frazer D.G.
      • Patterson C.
      • Jackson A.J.
      Keratoconus: an analysis of corneal asymmetry.
      ,
      • Jones-Jordan L.A.
      • Walline J.J.
      • Sinnott L.T.
      • Kymes S.M.
      • Zadnik K.
      Asymmetry in keratoconus and vision-related quality of life.
      ,
      • Chopra I.
      • Jain A.K.
      Between eye asymmetry in keratoconus in an Indian population.
      ,
      • Zadnik K.
      • Steger-May K.
      • Fink B.A.
      • Joslin C.E.
      • Nichols J.J.
      • Rosenstiel C.E.
      • et al.
      Between-eye asymmetry in keratoconus.
      ]. The condition affects all ethnicities and both sexes. It is commonly an isolated ocular condition, but sometimes coexists with other ocular and systemic diseases [].

      3. Epidemiology

      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 [

      Epidemiology is a science of high importance. Nat Commun 2018;9. doi: 10.1038/s41467-018-04243-3.

      ], and formulate and evaluate healthcare policies [
      • Spronk I.
      • Korevaar J.C.
      • Poos R.
      • Davids R.
      • Hilderink H.
      • Schellevis F.G.
      • et al.
      Calculating incidence rates and prevalence proportions: Not as simple as it seems.
      ]. 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’ [
      • Spronk I.
      • Korevaar J.C.
      • Poos R.
      • Davids R.
      • Hilderink H.
      • Schellevis F.G.
      • et al.
      Calculating incidence rates and prevalence proportions: Not as simple as it seems.
      ]. The prevalence of a condition is assessed in a cross-sectional sample, and the incidence is assessed employing longitudinal study designs [

      Keiding N. Age-specific incidence and prevalence: a statistical perspective. J R Stat Soc Ser A (Statistics Soc 1991;154:371. doi: 10.2307/2983150.

      ].
      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.
      StudyYearLocationSample Size (Catchment Population/n° keratoconus)Population mean/median Age [range] (years)Diagnostic criteriaStudy Duration (years)Study DesignSourceIncidence [95% CI]Prevalence [95% CI]Male/Female ratio
      Hofstetter
      • Hofstetter H.W.
      A keratoscopic survey of 13,395 eyes.
      1959Indianapolis, USA13,395/16 eyesNA [1-78]Placido-disc keratoscopy0.03Prospective, cross-sectionalPopulationNA120 (0.12%) [NA]a0.22
      Tanabe et al.
      • Tanabe U.
      • Fujiki K.
      • Ogawa A.
      • Ueda S.
      • Kanai A.
      Prevalence of keratoconus patients in Japan.
      1985Japan8,539,000/742 subjectsNA [25-29]NA21Retrospective, cross-sectionalPopulationNA9 (0.009%) [NA]2.86
      Ihalainen
      • Ihalainen A.
      Clinical and epidemiological features of keratoconus genetic and external factors in the pathogenesis of the disease.
      1986Finland260,000/75 patientsNA [15-69]Retinoscopy + keratometry20RetrospectiveHospital/clinic1.530 (0.03%) [NA]1.68
      Kennedy et al.
      • Kennedy R.H.
      • Bourne W.M.
      • Dyer J.A.
      A 48-year clinical and epidemiologic study of keratoconus.
      1986Minnesota, USACensus data/64 subjects25 [12-76]Retinoscopy + keratometry48RetrospectiveHospital/clinic2.0 [NA]54.5 (0.0545%) [NA]1.2
      Santiago et al.
      • Santiago P.Y.
      • Assouline M.
      • Ducoussau F.
      • Bazin S.
      • Ballion J.C.
      • Mezraoui A.
      • et al.
      P 143 Prevalence of keratoconus and corneal topography in young male subjects.
      1995France670/18 subjectsNA [18-22]Topography (power and indices)NAProspective, cross-sectionalPopulation (Army recruits)NA750 (0.75%) [NA]NA
      Gorskova and Sevost’ianov
      • Gorskova E.N.
      • Sevost’ianov E.N.
      Epidemiology of keratoconus in the Urals.
      1998Urals, RussiaNANANANANAHospital/clinicNA0.2–0.4 (0.0002–0.0004%) [NA]3
      Pearson et al.
      • Pearson A.R.
      • Soneji B.
      • Sarvananthan N.
      • Sanford-Smith J.H.
      Does ethnic origin influence the incidence or severity of keratoconus?.
      2000Midlands, United Kingdom∼900,000/271 patients for incidence and 338 patients for prevalenceNA [10-44]Diagnosis by ophthalmologist10RetrospectiveHospital/clinicAsianb = 19.6 [7.0–31.3]

      White = 4.5 [1.7–7.3]
      Asianb = 229 (0.229%) [NA]

      White = 57 (0.057%) [NA]
      Asianb = 1.5

      Whites = 1.85
      Ota et al
      • Ota R.
      • Fujiki K.
      • Nakayasu K.
      Estimation of patient visit rate and incidence of keratoconus in the 23 wards of Tokyo.
      2002Tokyo, Japan2,456,406 /220 patientsNA [15-34]NA1Retrospective, longitudinalHospital/clinic9 [NA]NA2.31
      Georgiou et al
      • Georgiou T.
      • Funnell C.L.
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      • O’Conor R.
      Influence of ethnic origin on the incidence of keratoconus and associated atopic disease in Asians and white patients.
      2004United Kingdom176,774/74 patientsNA [13-36]History of progressive, irregular, myopic astigmatism, and clinical signs6Retrospective, longitudinalHospital/clinicAsianc = 25

      White = 3.3
      NA2.52
      Assiri et al.
      • Assiri A.A.
      • Yousuf B.I.
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      Incidence and severity of keratoconus in Asir province, Saudi Arabia.
      2005Asir, Saudi Arabia654,163/125 patientsNA [6-28]Visual acuity, family history, keratometry, retinoscopy, ophthalmoscopy, and clinical signs1ProspectiveHospital/clinic20 [NA]NA0.69
      Jonas et al
      • Jonas J.B.
      • Nangia V.
      • Matin A.
      • Kulkarni M.
      • Bhojwani K.
      Prevalence and associations of keratoconus in rural Maharashtra in central India: the central India eye and medical study.
      2009Maharashtra, India4,677/128 subjectsEntire sample: 49.5 ± 13.4 [30 to 100]Keratometry > 48DNAProspective, cross-sectionalPopulationNA2737 (2.737%) [10.3–36.7]d0.29
      Ljubic
      • Ljubic A.D.
      Keratoconus and its prevalence in Macedonia.
      2009Skope, Macedonia2 million/136e subjectsEntire sample: NA

      Keratoconus cohort: 26.81 ± 1.25 [NA]
      Keratometry ≥ 48D8Retrospective, longitudinalHospital/clinicNA6.8 (0.0068%) [NA]1.13
      Reeves et al.
      • Reeves S.W.
      • Ellwein L.B.
      • Kim T.
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      Keratoconus in the Medicare population.
      2009USA5% Medicare beneficiaries ≥ 65 years/1165≥ 65NA5Longitudinal, retrospective, cross-sectionalPopulationNA17.5 (0.0175%) [NA]No difference
      Millodot et al.
      • Millodot M.
      • Shneor E.
      • Albou S.
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      Prevalence and associated factors of keratoconus in Jerusalem: a cross-sectional study.
      2011Jerusalem, Israel981/23 subjectsEntire sample: 24.4 ± 5.7 [18-54]

      Keratoconus cohort: NA
      Topography (power, pattern, and indices)1.33Prospective, cross-sectionalPopulation (college students)NA2340 (2.340%) [1400–3300]2.28
      Waked et al.
      • Waked N.
      • Fayad A.M.
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      • El Rami H.
      Dépistage du kératocône dans une population universitaire au Liban.
      2012Beirut, Lebanon92/3Entire sample: 23.6 ± 1 [22-26]Questionnaire + Topography0.33Prospective, cross-sectionalHospital/clinic (medical students)NA3261 (3.261%) [NA]1.43
      Xu et al.
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      • Wang Y.X.
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      • You Q.S.
      • Jonas J.B.
      Prevalence and associations of steep cornea/keratoconus in greater Beijing. The Beijing eye study.
      2012Beijing, China3468/27Entire sample: 64.6 ± 9.8 [50-92]

      Keratoconus cohort: 64.2 ± 11.3
      Optical low-coherence reflectometry ≥ 48DNAProspective, cross-sectionalPopulation (subjects ≥ 50 years)NA900 (0.9%) [600–1200]0.17
      Ziaei et al
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      • Javadi M.A.
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      Epidemiology of keratoconus in an Iranian population.
      2012Yazd, Iran990,818/536 subjectsEntire sample: NA

      Keratoconus group: 25.7 ± 9
      Topography (pattern and indices) + clinical examination1ProspectivePopulation22.3 [19.5–25.4]NA1.11
      Hashemi et al.
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      Prevalence of keratoconus in a population-based study in Shahroud.
      2013Shahroud, Iran4592/35Entire sample: 50.83 ± 0.12 [40-64]

      Keratoconus cohort: 47.6 ± 4.7 [NA]
      Topography (Holladay criteria)NAProspective, cross-sectionalPopulationNA760 (0.76%) [510–1010]0.58
      Hashemi et al.
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      2013Teheran, Iran426/14Entire sample: 40.8 ± 17.1 [14-80]

      Keratoconus cohort: 53.6 ± 14.9 [22-74]
      Topography + thinnest corneal pointNAProspective, cross-sectionalPopulationNA3300 (3.3%) [1000–5500]0.75
      Hashemi et al.
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      2014Mashhad, Iran1027/26Entire sample: 26.1 ± 2.3 [20-34]

      Keratoconus cohort: NA
      Topography + thinnest corneal pointNAProspective, cross-sectionalPopulation (university students)NA2500 (2.5%) [1600–3500]0.86
      Shneor et al.
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      Prevalence of Keratoconus among young Arab students in Israel.
      2014Haifa, Israel314/10Entire sample: 25.1 ± 8.8 [18-60]

      Keratoconus cohort: 25.1 ± 8.8 [19-28]
      Topography (power and indices) + clinical examination0.42Prospective, cross-sectionalPopulation (university students)NA3180 (3.18%) [1200–5100]0.25
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      2014Monterrey, Mexico500/9 subjectsEntire sample:

      NA [10-20]

      Keratoconus cohort: 16.1 [NA]
      NANARetrospective, cross-sectionalHospital/clinicNA1800 (1.8%) [0–30]0.33
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      2015Nablus, Palestine620/9Entire sample: 20.1 ± 1.6 [17-27]

      Keratoconus cohort: NA
      Topography indicesNAProspective, cross-sectionalPopulation (university students)NA1500 (1.5%) [NA]Higher in females
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      2017The Netherlands1,635,517/218 for incidence

      4,357,044/NA for prevalence
      Entire sample: NA [10-40]

      Keratoconus cohort: NA
      Diagnosis by ophthalmologist1Retrospective, longitudinalPopulation13.3 [11.6–15.2]265 (0.265%)
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      1.54
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      2018South Korea47,990,761/17,931 for prevalence

      47,986,173/13,343 for incidence
      Entire sample: NA

      Keratoconus cohort (prevalence):

      31.2 ± 14.2[0->85] Keratoconus cohort (incidence):

      31.9 ± 15.1 [0->85]
      Diagnosis by ophthalmologist6 for prevalence

      5 for incidence
      Retrospective, longitudinalPopulation5.66 [5.47–5.66]37.36 (0.03736%) [36.82–37.91]1.00
      Torres Netto et al.
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      2018Riyadh, Saudi Arabia522/25 patientsEntire sample: 16.8 ± 4.2 [6-21]

      Keratoconus cohort: NA
      Topography (power and indices) + subjective screening criteriaNAProspective, cross-sectionalHospital/clinic (paediatric patients)NA4790 (4.79%) [2920–6620]NA
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      2019Denmark28,020,821/1008 subjects for incidence

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      Keratoconus prevalence among high school students in New Zealand.
      2019Wellington, New Zealand1,916/10 subjectsEntire sample: 14.6 [NA]

      Keratoconus cohort: 14.9 [12.7– 16.1]
      Topography (power, pattern and indices)NAProspective, cross-sectionalPopulation (high school students)NAEntire cohort: 520 (0.52%) [NA]

      Maori islanders: 2250 (2.25%) [NA]
      2.33
      Armstrong et al. 2020
      • Armstrong B.K.
      • Smith S.D.
      • Romac Coc I.
      • Agarwal P.
      • Mustapha N.
      • Navon S.
      Screening for keratoconus in a high-risk adolescent population.
      2020Abu Dhabi, United Arab Emirates339/9 subjectsEntire sample: NA [10-19]

      Keratoconus cohort: NA
      Topography indices + clinical examination0.25Prospective, cross-sectionalPopulation (secondary school students)NA1500 (1.5%) [700–2900]NA
      Özalp et al.
      • Özalp O.
      • Atalay E.
      • Yıldırım N.
      Prevalence and risk factors for keratoconus in a university-based population in Turkey.
      2021Eskişehir, Turkey585/14 subjectsEntire sample: 21.6 ± 2.6 [≥18 to ≤ 30]

      Keratoconus cohort: NA
      Topography (power and indices) + pachymetryNAProspective, cross-sectionalPopulation (university students and faculty members)NA2393 (2.393%) [1426–4015]Higher in males
      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 [
      • Flockerzi E.
      • Xanthopoulou K.
      • Goebels S.C.
      • Zemova E.
      • Razafimino S.
      • Hamon L.
      • et al.
      Keratoconus staging by decades: a baseline ABCD classification of 1000 patients in the Homburg Keratoconus Center.
      ,
      • Hwang S.
      • Lim D.H.
      • Chung T.Y.
      Prevalence and incidence of keratoconus in South Korea: a nationwide population-based study.
      ,
      • Gordon-Shaag A.
      • Millodot M.
      • Shneor E.
      • Liu Y.
      The genetic and environmental factors for keratoconus.
      ]. 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 [
      • Spronk I.
      • Korevaar J.C.
      • Poos R.
      • Davids R.
      • Hilderink H.
      • Schellevis F.G.
      • et al.
      Calculating incidence rates and prevalence proportions: Not as simple as it seems.
      ].
      Figure thumbnail gr1
      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.
      Figure thumbnail gr2
      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 [
      • Torres Netto E.A.
      • Al-Otaibi W.M.
      • Hafezi N.L.
      • Kling S.
      • Al-Farhan H.M.
      • Randleman J.B.
      • et al.
      Prevalence of keratoconus in paediatric patients in Riyadh, Saudi Arabia.
      ] compared to 0.2 to 0.4 per 100,000 in Russia [
      • Gorskova E.N.
      • Sevost’ianov E.N.
      Epidemiology of keratoconus in the Urals.
      ] (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 [
      • Ihalainen A.
      Clinical and epidemiological features of keratoconus genetic and external factors in the pathogenesis of the disease.
      ] to over 20 per 100,000 persons/year in Asian and Middle East populations [
      • Pearson A.R.
      • Soneji B.
      • Sarvananthan N.
      • Sanford-Smith J.H.
      Does ethnic origin influence the incidence or severity of keratoconus?.
      ,
      • Georgiou T.
      • Funnell C.L.
      • Cassels-Brown A.
      • O’Conor R.
      Influence of ethnic origin on the incidence of keratoconus and associated atopic disease in Asians and white patients.
      ,
      • Assiri A.A.
      • Yousuf B.I.
      • Quantock A.J.
      • Murphy P.J.
      • Assiri A.A.
      Incidence and severity of keratoconus in Asir province, Saudi Arabia.
      ] (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 [
      • Gordon-Shaag A.
      • Millodot M.
      • Shneor E.
      • Liu Y.
      The genetic and environmental factors for keratoconus.
      ]. 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 [
      • Bak-Nielsen S.
      • Ramlau-Hansen C.H.
      • Ivarsen A.
      • Plana-Ripoll O.
      • Hjortdal J.
      Incidence and prevalence of keratoconus in Denmark – an update.
      ] and up to 22 per 100,000 persons in the Middle East [
      • Ziaei H.
      • Jafarinasab M.R.
      • Javadi M.A.
      • Karimian F.
      • Poorsalman H.
      • Mahdavi M.
      • et al.
      Epidemiology of keratoconus in an Iranian population.
      ] (Table 1 and Fig. 1), and the incidence of keratoconus has been reported to be as low as 3.6 in Denmark [
      • Bak-Nielsen S.
      • Ramlau-Hansen C.H.
      • Ivarsen A.
      • Plana-Ripoll O.
      • Hjortdal J.
      Incidence and prevalence of keratoconus in Denmark – an update.
      ], up to 22.3 per 100,000 persons/year in Iran [
      • Ziaei H.
      • Jafarinasab M.R.
      • Javadi M.A.
      • Karimian F.
      • Poorsalman H.
      • Mahdavi M.
      • et al.
      Epidemiology of keratoconus in an Iranian population.
      ] (Table 1 and Fig. 2).
      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 [
      • Pearson A.R.
      • Soneji B.
      • Sarvananthan N.
      • Sanford-Smith J.H.
      Does ethnic origin influence the incidence or severity of keratoconus?.
      ,
      • Georgiou T.
      • Funnell C.L.
      • Cassels-Brown A.
      • O’Conor R.
      Influence of ethnic origin on the incidence of keratoconus and associated atopic disease in Asians and white patients.
      ] 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 [
      • Papali’i-Curtin A.T.
      • Cox R.
      • Ma T.
      • Woods L.
      • Covello A.
      • Hall R.C.
      Keratoconus prevalence among high school students in New Zealand.
      ].
      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 [
      • Khaled M.L.
      • Helwa I.
      • Drewry M.
      • Seremwe M.
      • Estes A.
      • Liu Y.
      Molecular and histopathological changes associated with keratoconus.
      ,
      • Galvis V.
      • Sherwin T.
      • Tello A.
      • Merayo J.
      • Barrera R.
      • Acera A.
      Keratoconus: an inflammatory disorder?.
      ,
      • Mathew J.H.
      • Goosey J.D.
      • Bergmanson J.P.G.
      Quantified histopathology of the keratoconic cornea.
      ,
      • Hollingsworth J.G.
      • Efron N.
      • Tullo A.B.
      In vivo corneal confocal microscopy in keratoconus.
      ]. 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 [
      • Khaled M.L.
      • Helwa I.
      • Drewry M.
      • Seremwe M.
      • Estes A.
      • Liu Y.
      Molecular and histopathological changes associated with keratoconus.
      , ,
      • Sherwin T.
      • Brookes N.H.
      Morphological changes in keratoconus: pathology or pathogenesis.
      ]. 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 [
      • Naderan M.
      • Jahanrad A.
      • Balali S.
      Histopathologic findings of keratoconus corneas underwent penetrating keratoplasty according to topographic measurements and keratoconus severity.
      ,
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in keratoconus.
      ,
      • Fernandes B.F.
      • Logan P.
      • Zajdenweber M.E.
      • Santos L.N.
      • Cheema D.P.
      • Burnier M.N.
      Histopathological study of 49 cases of keratoconus.
      ], some studies have reported either no significant change [
      • Erie J.C.
      • Patel S.V.
      • McLaren J.W.
      • Nau C.B.
      • Hodge D.O.
      • Bourne W.M.
      Keratocyte density in keratoconus. A confocal microscopy study.
      ] or an increase in epithelial thickness [
      • Uçakhan Ö.Ö.
      • Kanpolat A.
      • Ylmaz N.
      • Özkan M.
      In vivo confocal microscopy findings in keratoconus.
      ,
      • Hollingsworth J.G.
      • Efron N.
      • Tullo A.B.
      In vivo corneal confocal microscopy in keratoconus.
      ]. Furthermore, one study reported that epithelial thinning was negatively correlated with disease severity [
      • Bitirgen G.
      • Ozkagnici A.
      • Bozkurt B.
      • Malik R.A.
      In vivo corneal confocal microscopic analysis in patients with keratoconus.
      ], whereas another study found epithelial thickening was associated with breaks in the anterior limiting lamina [
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in 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 [
      • Romero-Jiménez M.
      • Santodomingo-Rubido J.
      • González-Méijome J.M.
      The thinnest, steepest, and maximum elevation corneal locations in noncontact and contact lens wearers in keratoconus.
      ].
      The epithelium losses its cellular uniformity and is compromised by the loss or damage to the anterior limiting lamina [
      • Mathew J.H.
      • Goosey J.D.
      • Bergmanson J.P.G.
      Quantified histopathology of the keratoconic cornea.
      ], with epithelial changes being more pronounced with increasing severity of the disease [
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ]. The epithelium may display basal cell degeneration, exhibiting enlargement and irregular arrangement [
      • Bitirgen G.
      • Ozkagnici A.
      • Bozkurt B.
      • Malik R.A.
      In vivo corneal confocal microscopic analysis in patients with keratoconus.
      ,
      • Mocan M.C.
      • Yilmaz P.T.
      • Irkec M.
      • Orhan M.
      In vivo confocal microscopy for the evaluation of corneal microstructure in keratoconus.
      ,
      • Scroggs M.W.
      • Proia A.D.
      Histopathological variation in keratoconus.
      ], and a decrease in basal cell density compared to normal corneas [
      • Weed K.H.
      • MacEwen C.J.
      • Cox A.
      • McGhee C.N.J.
      Quantitative analysis of corneal microstructure in keratoconus utilising in vivo confocal microscopy.
      ], which correlates with disease severity [
      • Niederer R.L.
      • Perumal D.
      • Sherwin T.
      • McGhee C.N.J.
      Laser scanning in vivo confocal microscopy reveals reduced innervation and reduction in cell density in all layers of the keratoconic cornea.
      ]. 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 [
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ]. 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 [,
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ,
      • Sawaguchi S.
      • Fukuchi T.
      • Abe H.
      • Kaiya T.
      • Sugar J.
      • Yue B.V.J.T.
      Three-dimensional scanning electron microscopic study of keratoconus corneas.
      ]. Superficial iron deposits and scarring are other less frequently observed changes in the corneal epithelium typically affecting one in five eyes with keratoconus [
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in keratoconus.
      ,
      • Fernandes B.F.
      • Logan P.
      • Zajdenweber M.E.
      • Santos L.N.
      • Cheema D.P.
      • Burnier M.N.
      Histopathological study of 49 cases of 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 [
      • Li X.
      • Rabinowitz Y.S.
      • Rasheed K.
      • Yang H.
      Longitudinal study of the normal eyes in unilateral keratoconus patients.
      ,
      • Sherwin T.
      • Brookes N.H.
      Morphological changes in keratoconus: pathology or pathogenesis.
      ]. Keratoconic eyes have decreased corneal innervation, sensation, and basal and sub-basal epithelial density in comparison to normal eyes [
      • Patel D.V.
      • McGhee C.N.J.
      Mapping the corneal sub-basal nerve plexus in keratoconus by in vivo laser scanning confocal microscopy.
      ,
      • Mannion L.S.
      • Tromans C.
      • O’Donnell C.
      An evaluation of corneal nerve morphology and function in moderate keratoconus.
      ,
      • Patel D.V.
      • Ku J.Y.F.
      • Johnson R.
      • McGhee C.N.J.
      Laser scanning in vivo confocal microscopy and quantitative aesthesiometry reveal decreased corneal innervation and sensation in keratoconus.
      ], with central sub-basal nerve density correlating with disease severity [
      • Niederer R.L.
      • Perumal D.
      • Sherwin T.
      • McGhee C.N.J.
      Laser scanning in vivo confocal microscopy reveals reduced innervation and reduction in cell density in all layers of the keratoconic cornea.
      ]. Localised nerve thickening within the epithelium has also been reported [
      • Brookes N.H.
      • Loh I.P.
      • Clover G.M.
      • Poole C.A.
      • Sherwin T.
      Involvement of corneal nerves in the progression of keratoconus.
      ]. 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 [
      • Patel D.V.
      • McGhee C.N.J.
      Mapping the corneal sub-basal nerve plexus in keratoconus by in vivo laser scanning confocal microscopy.
      ]. 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 [
      • Patel D.V.
      • McGhee C.N.J.
      Mapping the corneal sub-basal nerve plexus in keratoconus by in vivo laser scanning confocal microscopy.
      ].
      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 [
      • Naderan M.
      • Jahanrad A.
      • Balali S.
      Histopathologic findings of keratoconus corneas underwent penetrating keratoplasty according to topographic measurements and keratoconus severity.
      ,
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in keratoconus.
      ]. 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 [
      • Sherwin T.
      • Brookes N.H.
      Morphological changes in keratoconus: pathology or pathogenesis.
      ,
      • Sawaguchi S.
      • Fukuchi T.
      • Abe H.
      • Kaiya T.
      • Sugar J.
      • Yue B.V.J.T.
      Three-dimensional scanning electron microscopic study of keratoconus corneas.
      ]. Despite being acellular, cellular components have been observed in the anterior limiting lamina [
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in keratoconus.
      ,
      • Sherwin T.
      • Brookes N.H.
      • Loh I.P.
      • Poole C.A.
      • Clover G.M.
      Cellular incursion into Bowman’s membrane in the peripheral cone of the keratoconic cornea.
      ], including epithelial cells and stromal keratocytes [
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ], and anterior keratocyte nuclei have been reported to wrap around corneal nerves as they pass through this layer [
      • Brookes N.H.
      • Loh I.P.
      • Clover G.M.
      • Poole C.A.
      • Sherwin T.
      Involvement of corneal nerves in the progression of keratoconus.
      ]. Hyperreflective keratocyte nuclei observed in keratoconus are thought to indicate the presence of fibroblastic cells [
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ].
      The well-organised architecture of the corneal stroma, which is responsible for the transparency of the cornea, is compromised in keratoconus [
      • Khaled M.L.
      • Helwa I.
      • Drewry M.
      • Seremwe M.
      • Estes A.
      • Liu Y.
      Molecular and histopathological changes associated with keratoconus.
      ]. 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 [
      • Morishige N.
      • Wahlert A.J.
      • Kenney M.C.
      • Brown D.J.
      • Kawamoto K.
      • Chikama T.I.
      • et al.
      Second-harmonic imaging microscopy of normal human and keratoconus cornea.
      ]. 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 [
      • Morishige N.
      • Shin-Gyou-Uchi R.
      • Azumi H.
      • Ohta H.
      • Morita Y.
      • Yamada N.
      • et al.
      Quantitative analysis of collagen lamellae in the normal and keratoconic human cornea by second harmonic generation imaging microscopy.
      ]. Furthermore, it has been proposed that collagen lamellae are expanded in association with protrusion of the cone [
      • Morishige N.
      • Shin-Gyou-Uchi R.
      • Azumi H.
      • Ohta H.
      • Morita Y.
      • Yamada N.
      • et al.
      Quantitative analysis of collagen lamellae in the normal and keratoconic human cornea by second harmonic generation imaging microscopy.
      ]. A gross rearrangement of vertical and horizontal collagen lamellae occurs in keratoconus [
      • Meek K.M.
      • Tuft S.J.
      • Huang Y.
      • Gill P.S.
      • Hayes S.
      • Newton R.H.
      • et al.
      Changes in collagen orientation and distribution in keratoconus corneas.
      ]. A decrease in the interfibrillar distance of collagen sheets and the increase of proteoglycans have also been reported [
      • Akhtar S.
      • Bron A.J.
      • Salvi S.M.
      • Hawksworth N.R.
      • Tuft S.J.
      • Meek K.M.
      Ultrastructural analysis of collagen fibrils and proteoglycans in keratoconus.
      ]. 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 [
      • Mathew J.H.
      • Goosey J.D.
      • Söderberg P.G.
      • Bergmanson J.P.G.
      Lamellar changes in the keratoconic cornea.
      ]. Alternating dark and light bands, most commonly found in the posterior stroma, have been seen in keratoconus patients using confocal microscopy [
      • Hollingsworth J.G.
      • Efron N.
      Observations of banding patterns (Vogt striae) in keratoconus: a confocal microscopy study.
      ]. 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 [
      • Sykakis E.
      • Carley F.
      • Irion L.
      • Denton J.
      • Hillarby M.C.
      An in depth analysis of histopathological characteristics found in keratoconus.
      ,
      • Fernandes B.F.
      • Logan P.
      • Zajdenweber M.E.
      • Santos L.N.
      • Cheema D.P.
      • Burnier M.N.
      Histopathological study of 49 cases of keratoconus.
      ]. Breakage in the posterior limiting lamina, allowing aqueous to enter the corneal stroma and epithelium, is a serious complication, known as corneal hydrops, [
      • Fan Gaskin J.C.
      • Patel D.V.
      • McGhee C.N.J.
      Acute corneal hydrops in keratoconus – new perspectives.
      ,
      • Thota S.
      • Miller W.L.
      • Bergmanson J.P.G.
      Acute corneal hydrops: a case report including confocal and histopathological considerations.
      ] which may require surgical treatment [
      • Rajaraman R.
      • Singh S.
      • Raghavan A.
      • Karkhanis A.
      Efficacy and safety of intracameral perfluoropropane (C3F 8) tamponade and compression sutures for the management of acute corneal hydrops.
      ,
      • Yahia Chérif H.
      • Gueudry J.
      • Afriat M.
      • Delcampe A.
      • Attal P.
      • Gross H.
      • et al.
      Efficacy and safety of pre-Descemet’s membrane sutures for the management of acute corneal hydrops in keratoconus.
      ].
      Although the corneal endothelium is generally unaffected in keratoconus, this issue is controversial [
      • Khaled M.L.
      • Helwa I.
      • Drewry M.
      • Seremwe M.
      • Estes A.
      • Liu Y.
      Molecular and histopathological changes associated with keratoconus.
      ]. While several studies found no endothelial change with disease progression [
      • Weed K.H.
      • MacEwen C.J.
      • Cox A.
      • McGhee C.N.J.
      Quantitative analysis of corneal microstructure in keratoconus utilising in vivo confocal microscopy.
      ,
      • Efron N.
      • Hollingsworth J.G.
      New perspectives on keratoconus as revealed by corneal confocal microscopy.
      ,
      • Sandali O.
      • El Sanharawi M.
      • Temstet C.
      • Hamiche T.
      • Galan A.
      • Ghouali W.
      • et al.
      Fourier-domain optical coherence tomography imaging in keratoconus: a corneal structural classification.
      ,
      • El-Agha M.S.H.
      • El Sayed Y.M.
      • Harhara R.M.
      • Essam H.M.
      Correlation of corneal endothelial changes with different stages of keratoconus.
      ], one study reported a slight increase in endothelial cell density in keratoconus [
      • Lema I.
      • Durán J.A.
      Inflammatory molecules in the tears of patients with keratoconus.
      ], while two others reported a significant decrease in endothelial cell density, particularly in moderate to severe keratoconus [
      • Fernandes B.F.
      • Logan P.
      • Zajdenweber M.E.
      • Santos L.N.
      • Cheema D.P.
      • Burnier M.N.
      Histopathological study of 49 cases of keratoconus.
      ,
      • Uçakhan Ö.Ö.
      • Kanpolat A.
      • Ylmaz N.
      • Özkan M.
      In vivo confocal microscopy findings in keratoconus.
      ,
      • Mocan M.C.
      • Yilmaz P.T.
      • Irkec M.
      • Orhan M.
      In vivo confocal microscopy for the evaluation of corneal microstructure in keratoconus.
      ].

      5. Aetiology and pathogenesis

      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 [
      • Brookes N.H.
      • Loh I.P.
      • Clover G.M.
      • Poole C.A.
      • Sherwin T.
      Involvement of corneal nerves in the progression of keratoconus.
      ].

      5.1 Genetics

      Keratoconus has long been considered to have a genetic component, given its association with other genetic syndromes (such as Down’s syndrome [
      • Mathan J.J.
      • Gokul A.
      • Simkin S.K.
      • Meyer J.J.
      • Patel D.V.
      • McGhee C.N.J.
      Topographic screening reveals keratoconus to be extremely common in Down syndrome.
      ], Leber’s congenital amaurosis [
      • Elder M.J.
      Leber congenital amaurosis and its association with keratoconus and keratoglobus.
      ,
      • Damji K.F.
      • Sohocki M.M.
      • Khan R.
      • Gupta S.K.
      • Rahim M.
      • Loyer M.
      • et al.
      Leber’s congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p.
      ], Ehlers-Danlos syndrome [
      • Robertson I.
      Keratoconus and the Ehlers Danlos syndrome: a new aspect of keratoconus.
      ] and Noonan syndrome [
      • Lee A.
      • Sakhalkar M.V.
      Ocular manifestations of Noonan syndrome in twin siblings: a case report of keratoconus with acute corneal hydrops.
      ]), its prevalence in first-degree relatives [
      • Rabinowitz Y.S.
      • Galvis V.
      • Tello A.
      • Rueda D.
      • García J.D.
      Genetics vs chronic corneal mechanical trauma in the etiology of keratoconus.
      ,
      • Gordon-Shaag A.
      • Millodot M.
      • Essa M.
      • Garth J.
      • Ghara M.
      • Shneor E.
      Is consanguinity a risk factor for keratoconus?.
      ,
      • Almusawi L.A.
      • Hamied F.M.
      Risk factors for development of keratoconus: a matched pair case-control study.
      ,
      • Lapeyre G.
      • Fournie P.
      • Vernet R.
      • Roseng S.
      • Malecaze F.
      • Bouzigon E.
      • et al.
      Keratoconus prevalence in families: a French study.
      ] and occurrence in monozygotic twins [
      • Edwards M.
      • McGhee C.N.J.
      • Dean S.
      The genetics of keratoconus.
      ,
      • Tuft S.J.
      • Hassan H.
      • George S.
      • Frazer D.G.
      • Willoughby C.E.
      • Liskova P.
      Keratoconus in 18 pairs of twins.
      ]. 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 [
      • Wang Y.
      • Rabinowitz Y.S.
      • Rotter J.I.
      • Yang H.
      Genetic epidemiological study of keratoconus: Evidence for major gene determination.
      ]. Keratoconus follows an apparently autosomal dominant/recessive mode of inheritance in some families [
      • Bisceglia L.
      • De Bonis P.
      • Pizzicoli C.
      • Fischetti L.
      • Laborante A.
      • Di Perna M.
      • et al.
      Linkage analysis in keratoconus: Replication of locus 5q21.2 and identification of other suggestive loci.
      ,
      • Gonzalez V.
      • McDonnell P.J.
      Computer-assisted corneal topography in parents of patients with keratoconus.
      ]. However, sporadic cases show no Mendelian patterns of inheritance [
      • Kriszt Á.
      • Losonczy G.
      • Berta A.
      • Vereb G.
      • Takács L.
      Segregation analysis suggests that keratoconus is a complex non-mendelian disease.
      ], 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 [
      • Lapeyre G.
      • Fournie P.
      • Vernet R.
      • Roseng S.
      • Malecaze F.
      • Bouzigon E.
      • et al.
      Keratoconus prevalence in families: a French study.
      ,
      • Chen S.
      • Li X.Y.
      • Jin J.J.
      • Shen R.J.
      • Mao J.Y.
      • Cheng F.F.
      • et al.
      Genetic Screening Revealed Latent Keratoconus in Asymptomatic Individuals. Front Cell.
      ,
      • Shneor E.
      • Frucht-Pery J.
      • Granit E.
      • Gordon-Shaag A.
      The prevalence of corneal abnormalities in first-degree relatives of patients with keratoconus: a prospective case-control study.
      ].
      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 [
      • Bykhovskaya Y.
      • Rabinowitz Y.S.
      Update on the genetics of keratoconus.
      ]. To date, only a single keratoconus locus (5q21.2) has been replicated across multiple linkage studies [
      • Bisceglia L.
      • De Bonis P.
      • Pizzicoli C.
      • Fischetti L.
      • Laborante A.
      • Di Perna M.
      • et al.
      Linkage analysis in keratoconus: Replication of locus 5q21.2 and identification of other suggestive loci.
      ,
      • Bykhovskaya Y.
      • Li X.
      • Taylor K.D.
      • Haritunians T.
      • Rotter J.I.
      • Rabinowitz Y.S.
      Linkage analysis of high-density SNPs confirms keratoconus locus at 5q chromosomal region.
      ], 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 [
      • Mas Tur V.
      • MacGregor C.
      • Jayaswal R.
      • O’Brart D.
      • Maycock N.
      A review of keratoconus: diagnosis, pathophysiology, and genetics.
      ] 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 [
      • Bykhovskaya Y.
      • Li X.
      • Taylor K.D.
      • Haritunians T.
      • Rotter J.I.
      • Rabinowitz Y.S.
      Linkage analysis of high-density SNPs confirms keratoconus locus at 5q chromosomal region.
      ]. This supports the notion that keratoconus is a multifactorial disease [
      • Kenney M.C.
      • Brown D.J.
      The cascade hypothesis of keratoconus.
      ] 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 [
      • Rabinowitz Y.S.
      • Galvis V.
      • Tello A.
      • Rueda D.
      • García J.D.
      Genetics vs chronic corneal mechanical trauma in the etiology of keratoconus.
      ].

      5.2 Cellular biochemistry

      To date, 117 proteins and protein classes have been implicated in the pathophysiology of keratoconus [
      • Loukovitis E.
      • Kozeis N.
      • Gatzioufas Z.
      • Kozei A.
      • Tsotridou E.
      • Stoila M.
      • et al.
      The proteins of keratoconus: a literature Review exploring their contribution to the pathophysiology of the disease.
      ]. 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 [
      • Yam G.H.F.
      • Fuest M.
      • Zhou L.
      • Liu Y.C.
      • Deng L.
      • Chan A.S.Y.
      • et al.
      Differential epithelial and stromal protein profiles in cone and non-cone regions of keratoconus corneas.
      ,
      • Srivastava O.P.
      • Chandrasekaran D.
      • Pfister R.R.
      Molecular changes in selected epithelial proteins in human keratoconus corneas compared to normal corneas.
      ]. Oxidative stress markers and antioxidants are dysregulated in keratoconus, involving an imbalance of redox homeostasis in tears, cornea, aqueous humour and blood [
      • Navel V.
      • Malecaze J.
      • Pereira B.
      • Baker J.S.
      • Malecaze F.
      • Sapin V.
      • et al.
      Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis.
      ]. 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 [
      • Navel V.
      • Malecaze J.
      • Pereira B.
      • Baker J.S.
      • Malecaze F.
      • Sapin V.
      • et al.
      Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis.
      ]. The disease is associated with an up regulation of degradative enzymes and inhibition of the activity of protease inhibitors [
      • Zhou L.
      • Sawaguchi S.
      • Twining S.S.
      • Sugar J.
      • Feder R.S.
      • Yue B.Y.J.T.
      Expression of degradative enzymes and protease inhibitors in corneas with keratoconus.
      ], resulting in corneal thinning [
      • Yam G.H.F.
      • Fuest M.
      • Zhou L.
      • Liu Y.C.
      • Deng L.
      • Chan A.S.Y.
      • et al.
      Differential epithelial and stromal protein profiles in cone and non-cone regions of keratoconus corneas.
      ]. The increase of proteinase activity results in the induction of a degradative process in the cornea [
      • Zhou L.
      • Sawaguchi S.
      • Twining S.S.
      • Sugar J.
      • Feder R.S.
      • Yue B.Y.J.T.
      Expression of degradative enzymes and protease inhibitors in corneas with keratoconus.
      ,
      • Balasubramanian S.A.
      • Pye D.C.
      • Willcox M.D.P.
      Are proteinases the reason for keratoconus.
      ,

      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.

      ].
      In the keratoconic cornea, there is a gradient of damage between the centre of the cone (which shows the greatest level of damage) and the periphery [
      • Brookes N.H.
      • Loh I.P.
      • Clover G.M.
      • Poole C.A.
      • Sherwin T.
      Involvement of corneal nerves in the progression of keratoconus.
      ]. 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 [
      • Sherwin T.
      • Brookes N.H.
      • Loh I.P.
      • Poole C.A.
      • Clover G.M.
      Cellular incursion into Bowman’s membrane in the peripheral cone of the keratoconic cornea.
      ]. 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 [
      • Sherwin T.
      • Brookes N.H.
      • Loh I.P.
      • Poole C.A.
      • Clover G.M.
      Cellular incursion into Bowman’s membrane in the peripheral cone of the keratoconic cornea.
      ].

      5.3 Biomechanical factors

      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 [
      • Alkanaan A.
      • Barsotti R.
      • Kirat O.
      • Khan A.
      • Almubrad T.
      • Akhtar S.
      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 [
      • Meek K.M.
      • Tuft S.J.
      • Huang Y.
      • Gill P.S.
      • Hayes S.
      • Newton R.H.
      • et al.
      Changes in collagen orientation and distribution in keratoconus corneas.
      ,
      • Alkanaan A.
      • Barsotti R.
      • Kirat O.
      • Khan A.
      • Almubrad T.
      • Akhtar S.
      Collagen fibrils and proteoglycans of peripheral and central stroma of the keratoconus cornea – ultrastructure and 3D transmission electron tomography.
      ,
      • Götzinger E.
      • Pircher M.
      • Dejaco-Ruhswurm I.
      • Kaminski S.
      • Skorpik C.
      • Hitzenberger C.K.
      Imaging of birefringent properties of keratoconus corneas hy polarization-sensitive optical coherence 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 [
      • Abdul-Maksoud R.S.
      • Fouad R.A.
      • Elsayed T.G.
      • Ibrahem R.A.
      • Badawi A.E.
      The impact of catalase and glutathione peroxidase-1 genetic polymorphisms on their enzyme activities among Egyptian patients with keratoconus.
      ]. Keratoconic corneas have decreased levels of aldehyde dehydrogenase Class 3 [
      • Gondhowiardjo T.D.
      • Van Haeringen N.J.
      Corneal aldehyde dehydrogenase, glutathione reductase, and glutathione s- transferase in pathologic corneas.
      ] and superoxide dismutase enzymes [
      • Behndig A.
      • Svensson B.
      • Marklund S.L.
      • Karlsson K.
      Superoxide dismutase isoenzymes in the human eye.
      ]. 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 [
      • Navel V.
      • Malecaze J.
      • Pereira B.
      • Baker J.S.
      • Malecaze F.
      • Sapin V.
      • et al.
      Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis.
      ,
      • Göncü T.
      • Akal A.
      • Adibelli F.M.
      • Çakmak S.
      • Sezen H.
      • Yilmaz Ö.F.
      Tear film and serum prolidase activity and oxidative stress in patients with keratoconus.
      ,
      • Kiliç R.
      • Cumurcu T.
      • Sancaktar E.
      • Evliyaoʇlu O.
      • Sezer H.
      Systemic prolidase activity and oxidative stress in keratoconus.
      ,
      • Shetty R.
      • Sharma A.
      • Pahuja N.
      • Chevour P.
      • Padmajan N.
      • Dhamodaran K.
      • et al.
      Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients.
      ].
      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 [
      • Amit C.
      • Padmanabhan P.
      • Elchuri S.V.
      • Narayanan J.
      Probing the effect of matrix stiffness in endocytic signalling pathway of corneal epithelium.
      ].
      Although rigid contact lens wear has also been associated with keratoconus development [
      • Gasset A.R.
      • Houde W.L.
      • Garcia-Bengochea M.
      Hard contact lens wear as an environmental risk in keratoconus.
      ], perhaps as a result of altered cell morphology following lens wear [
      • Ghosh S.
      • Mutalib H.A.
      • Kaur S.
      • Ghoshal R.
      • Retnasabapathy S.
      Effects of contact lens wearing on keratoconus: a confocal microscopy observation.
      ], 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% [
      • Ahuja P.
      • Dadachanji Z.
      • Shetty R.
      • Nagarajan S.A.
      • Khamar P.
      • Sethu S.
      • et al.
      Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of Keratoconus.
      ]. Another strongly associated risk factor in the pathogenesis of keratoconus is eye rubbing [
      • Hashemi H.
      • Heydarian S.
      • Hooshmand E.
      • Saatchi M.
      • Yekta A.
      • Aghamirsalim M.
      • et al.
      The prevalence and risk factors for keratoconus: a systematic review and meta-analysis.
      ]. 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 [
      • Ahuja P.
      • Dadachanji Z.
      • Shetty R.
      • Nagarajan S.A.
      • Khamar P.
      • Sethu S.
      • et al.
      Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of Keratoconus.
      ]. 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 [
      • Kemp E.G.
      • Lewis C.J.
      Immunoglobulin patterns in keratoconus with particular reference to total and specific IgE 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 [
      • Hashemi H.
      • Heydarian S.
      • Hooshmand E.
      • Saatchi M.
      • Yekta A.
      • Aghamirsalim M.
      • et al.
      The prevalence and risk factors for keratoconus: a systematic review and meta-analysis.
      ]. 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 [
      • Almusawi L.A.
      • Hamied F.M.
      Risk factors for development of keratoconus: a matched pair case-control study.
      ], 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 [
      • Özalp O.
      • Atalay E.
      • Yıldırım N.
      Prevalence and risk factors for keratoconus in a university-based population in Turkey.
      ]. 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) [
      • Claessens J.L.J.
      • Godefrooij D.A.
      • Vink G.
      • Frank L.E.
      • Wisse R.P.L.
      Nationwide epidemiological approach to identify associations between keratoconus and immune-mediated diseases.
      ]. 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
      • Bykhovskaya Y.
      • Rabinowitz Y.S.
      Update on the genetics of keratoconus.
      ,
      • Hashemi H.
      • Heydarian S.
      • Hooshmand E.
      • Saatchi M.
      • Yekta A.
      • Aghamirsalim M.
      • et al.
      The prevalence and risk factors for keratoconus: a systematic review and meta-analysis.
      .
      FactorRelative Risk
      Family history of keratoconus6.4
      Eye rubbing3.1
      Eczema3.0
      Asthma1.9
      Allergy1.4

      6. Clinical features

      Keratoconus usually develops in the second and third decade decades of life and progresses until the fourth decade, when it stabilises [
      • Flockerzi E.
      • Xanthopoulou K.
      • Goebels S.C.
      • Zemova E.
      • Razafimino S.
      • Hamon L.
      • et al.
      Keratoconus staging by decades: a baseline ABCD classification of 1000 patients in the Homburg Keratoconus Center.
      ,
      • Hwang S.
      • Lim D.H.
      • Chung T.Y.
      Prevalence and incidence of keratoconus in South Korea: a nationwide population-based study.
      ,
      • Gordon-Shaag A.
      • Millodot M.
      • Shneor E.
      • Liu Y.
      The genetic and environmental factors for keratoconus.
      ], although it can develop earlier [
      • Valdez-García J.E.
      • Sepúlveda R.
      • Salazar-Martínez J.J.
      • Lozano-Ramírez J.F.
      Prevalence of keratoconus in an adolescent population.
      ,
      • Torres Netto E.A.
      • Al-Otaibi W.M.
      • Hafezi N.L.
      • Kling S.
      • Al-Farhan H.M.
      • Randleman J.B.
      • et al.
      Prevalence of keratoconus in paediatric patients in Riyadh, Saudi Arabia.
      ,
      • Papali’i-Curtin A.T.
      • Cox R.
      • Ma T.
      • Woods L.
      • Covello A.
      • Hall R.C.
      Keratoconus prevalence among high school students in New Zealand.
      ,
      • Armstrong B.K.
      • Smith S.D.
      • Romac Coc I.
      • Agarwal P.
      • Mustapha N.
      • Navon S.
      Screening for keratoconus in a high-risk adolescent population.
      ] or later in life [
      • Jonas J.B.
      • Nangia V.
      • Matin A.
      • Kulkarni M.
      • Bhojwani K.
      Prevalence and associations of keratoconus in rural Maharashtra in central India: the central India eye and medical study.
      ,
      • Xu L.
      • Wang Y.X.
      • Guo Y.
      • You Q.S.
      • Jonas J.B.
      Prevalence and associations of steep cornea/keratoconus in greater Beijing. The Beijing eye study.
      ,
      • Hashemi H.
      • Beiranvand A.
      • Khabazkhoob M.
      • Asgari S.
      • Emamian M.H.
      • Shariati M.
      • et al.
      Prevalence of keratoconus in a population-based study in Shahroud.
      ,
      • Hashemi H.
      • Khabazkhoob M.
      • Fotouhi A.
      Topographic keratoconus is not rare in an Iranian population: the Tehran eye study.
      ] (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) [
      • Romero-Jiménez M.
      • Santodomingo-Rubido J.
      • Wolffsohn J.S.
      Keratoconus: a review.
      , ,
      • Gomes J.A.P.
      • Tan D.
      • Rapuano C.J.
      • Belin M.W.
      • Ambrósio R.
      • Guell J.L.
      • et al.
      Global consensus on keratoconus and ectatic diseases.
      ]. 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 [
      • Henriquez M.A.
      • Hadid M.
      • Izquierdo L.
      A systematic review of subclinical keratoconus and forme fruste keratoconus.
      ]. 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 [
      • Henriquez M.A.
      • Hadid M.
      • Izquierdo L.
      A systematic review of subclinical keratoconus and forme fruste keratoconus.
      ]. Form fruste keratoconus typically refers to an eye with normal topography, normal corneal slit-lamp findings, and keratoconus in the fellow eye [
      • Henriquez M.A.
      • Hadid M.
      • Izquierdo L.
      A systematic review of subclinical keratoconus and forme fruste keratoconus.
      ]. 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 [
      • Toprak I.
      • Vega A.
      • Alió Del Barrio J.L.
      • Espla E.
      • Cavas F.
      • Alió J.L.
      Diagnostic value of corneal epithelial and stromal thickness distribution profiles in forme fruste keratoconus and 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 [
      • Toprak I.
      • Cavas F.
      • Velázquez J.S.
      • Alio del Barrio J.L.
      • Alio J.L.
      Subclinical keratoconus detection with three-dimensional (3-D) morphogeometric and volumetric analysis.
      ].
      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.
      StageSignsSymptoms
      1 – SubclinicalSuspicious 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 – ModerateThose 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 – SevereThose 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 [
      • Toprak I.
      • Vega A.
      • Alió Del Barrio J.L.
      • Espla E.
      • Cavas F.
      • Alió J.L.
      Diagnostic value of corneal epithelial and stromal thickness distribution profiles in forme fruste keratoconus and subclinical 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 [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ,
      • Toprak I.
      • Vega A.
      • Alió Del Barrio J.L.
      • Espla E.
      • Cavas F.
      • Alió J.L.
      Diagnostic value of corneal epithelial and stromal thickness distribution profiles in forme fruste keratoconus and subclinical keratoconus.
      ]. Corneal thinning typically occurs in the central or paracentral cornea, often in the inferior-temporal corneal quadrant [
      • Romero-Jiménez M.
      • Santodomingo-Rubido J.
      • González-Méijome J.M.
      The thinnest, steepest, and maximum elevation corneal locations in noncontact and contact lens wearers in keratoconus.
      ], although occasional superior localisations have also been reported [
      • Hashemi H.
      • Khabazkhoob M.
      • Yazdani N.
      • Ostadimoghaddam H.
      • Norouzirad R.
      • Amanzadeh K.
      • et al.
      The prevalence of keratoconus in a young population in Mashhad, Iran.
      ,
      • Prisant O.
      • Legeais J.M.
      • Renard G.
      Superior keratoconus.
      ,
      • Tananuvat N.
      • Leeungurasatien P.
      • Wiriyaluppa C.
      Superior keratoconus with hydrops.
      ,
      • Weed K.H.
      • McGhee C.N.J.
      • MacEwen C.J.
      Atypical unilateral superior keratoconus in young males.
      ]. Nipple and oval cones located in the central or paracentral cornea are most common, whilst globus cones and peripherally located cones are rare [
      • Rafati S.
      • Hashemi H.
      • Nabovati P.
      • Doostdar A.
      • Yekta A.
      • Aghamirsalim M.
      • et al.
      Demographic profile, clinical, and topographic characteristics of keratoconus patients attending at a tertiary eye center.
      ].
      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 [
      • Naderan M.
      • Jahanrad A.
      • Farjadnia M.
      Clinical biomicroscopy and retinoscopy findings of keratoconus in a Middle Eastern population.
      ]. 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 [
      • Fleischer B.
      Über Keratoconus und eigenartige Pigmenfbildung in der kornea.
      ]. 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 [
      • Edrington T.B.
      • Zadnik K.
      • Barr J.T.
      ,
      • Zadnik K.
      • Barr J.T.
      • Edrington T.B.
      • Everett D.F.
      • Jameson M.
      • McMahon T.T.
      • et al.
      Baseline findings in the collaborative longitudinal evaluation of keratoconus (CLEK) study.
      ] and it has been proposed that the presence of these two signs may confirm diagnosis in borderline cases [
      • Kriszt Á.
      • Losonczy G.
      • Berta A.
      • Takács L.
      Presence of Fleischer ring and prominent corneal nerves in keratoconus relatives and normal controls.
      ]. Superficial and deep corneal opacities and increased visibility of corneal nerves are also commonly observed in keratoconus [
      • Li X.
      • Rabinowitz Y.S.
      • Rasheed K.
      • Yang H.
      Longitudinal study of the normal eyes in unilateral keratoconus patients.
      ]. 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 [
      • Zadnik K.
      • Barr J.T.
      • Gordon M.O.
      • Edrington T.B.
      Biomicroscopic signs and disease severity in keratoconus.
      ].
      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 [
      • Barr J.T.
      • Wilson B.S.
      • Gordon M.O.
      • Rah M.J.
      • Riley C.
      • Kollbaum P.S.
      • et al.
      Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study.
      ]. This slit lamp finding also corresponds with stromal haze and hyperreflectivity as observed using confocal microscopy [
      • Hollingsworth J.G.
      • Bonshek R.E.
      • Efron N.
      Correlation of the appearance of the keratoconic cornea in vivo by confocal microscopy and in vitro by light microscopy.
      ]. In severe cases, highly pronounced cones can create a V-shaped deformation of the lower eyelid during downgaze, known as Munson's sign [
      • Naderan M.
      • Jahanrad A.
      • Farjadnia M.
      Clinical biomicroscopy and retinoscopy findings of keratoconus in a Middle Eastern population.
      ,
      • Gold J.
      • Chauhan V.
      • Rojanasthien S.
      • Fitzgerald J.
      Munson’s sign: An obvious finding to explain acute vision loss.
      ]. 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 [
      • Rizzuti A.B.
      Diagnostic illumination test for keratoconus.
      ]. 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 [

      Kumar M, Shetty R, Lalgudi VG, Khamar P, Vincent SJ. Scleral lens visual rehabilitation of sequential bilateral corneal hydrops with post-lasik ectasia. Eye Contact Lens 2020;Online ahe. doi: 10.1097/icl.0000000000000766.

      ]. 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 [
      • Kreps E.O.
      • Claerhout I.
      • Koppen C.
      The outcome of scleral lens fitting for keratoconus with resolved corneal hydrops.
      ], and in some cases corneal transplantation [
      • Fan Gaskin J.C.
      • Patel D.V.
      • McGhee C.N.J.
      Acute corneal hydrops in keratoconus – new perspectives.
      ]. 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) [
      • Barsam A.
      • Brennan N.
      • Petrushkin H.
      • Xing W.
      • Quartilho A.
      • Bunce C.
      • et al.
      Case-control study of risk factors for acute corneal hydrops in keratoconus.
      ].
      Figure thumbnail gr3
      Fig. 3Slit-lamp images showing corneal scarring.
      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 [
      • Naderan M.
      • Jahanrad A.
      • Farjadnia M.
      Clinical biomicroscopy and retinoscopy findings of keratoconus in a Middle Eastern population.
      ]. 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 [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ]. 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 [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ,
      • Zhang X.
      • Munir S.Z.
      • Sami Karim S.A.
      • Munir W.M.
      A review of imaging modalities for detecting early keratoconus.
      ]. 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 [
      • Kanclerz P.
      • Khoramnia R.
      • Wang X.
      Current developments in corneal topography and tomography.
      ], which have found critical to enhance the sensitivity and specificity for detecting corneal ectasia in comparison to corneal topography [
      • Gomes J.A.P.
      • Tan D.
      • Rapuano C.J.
      • Belin M.W.
      • Ambrósio R.
      • Guell J.L.
      • et al.
      Global consensus on keratoconus and ectatic diseases.
      ,
      • Ambrósio R.
      • Belin M.W.
      Imaging of the cornea: topography vs tomography.
      ]. 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 [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ,
      • Cao K.
      • Verspoor K.
      • Sahebjada S.
      • Baird P.N.
      Evaluating the performance of various machine learning algorithms to detect subclinical keratoconus.
      ].
      Figure thumbnail gr4
      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.

      7. Detection

      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 [
      • Keeler R.
      • Singh A.D.
      • Dua H.S.
      Carving the cornea: The von Hippel Trephine.
      ]. 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 [
      • Gomes J.A.P.
      • Tan D.
      • Rapuano C.J.
      • Belin M.W.
      • Ambrósio R.
      • Guell J.L.
      • et al.
      Global consensus on keratoconus and ectatic diseases.
      ]. 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 [
      • Reinstein D.Z.
      • Archer T.J.
      • Gobbe M.
      Corneal epithelial thickness profile in the diagnosis of keratoconus.
      ,
      • Reinstein D.Z.
      • Gobbe M.
      • Archer T.J.
      • Silverman R.H.
      • Coleman J.
      Epithelial, stromal, and total corneal thickness in keratoconus: Three-dimensional display with Artemis very-high frequency digital ultrasound.
      ,
      • Franco J.
      • White C.A.
      • Kruh J.N.
      Analysis of compensatory corneal epithelial thickness changes in keratoconus using corneal tomography.
      ]. A reduction in epithelial basal cell density may also lead to the thinning and fragmentation of the anterior limiting lamina [
      • Sawaguchi S.
      • Fukuchi T.
      • Abe H.
      • Kaiya T.
      • Sugar J.
      • Yue B.V.J.T.
      Three-dimensional scanning electron microscopic study of keratoconus corneas.
      ], which also appears to be indicative of early keratoconus [
      • Xu Z.
      • Jiang J.
      • Yang C.
      • Huang S.
      • Peng M.
      • Li W.
      • et al.
      Value of corneal epithelial and Bowman’s layer vertical thickness profiles generated by UHR-OCT for sub-clinical keratoconus diagnosis.
      ].
      The stroma of keratoconic eyes is also typically thinner infero-temporally (correlating with the average cone location) and thicker superior-temporally compared to non-keratoconic eyes with astigmatism; however, these regional variations are more apparent in the epithelial profile [
      • Zhou W.
      • Stojanovic A.
      Comparison of corneal epithelial and stromal thickness distributions between eyes with keratoconus and healthy eyes with corneal astigmatism ≥2.0 D.
      ], even in subclinical keratoconus [
      • Li Y.
      • Chamberlain W.
      • Tan O.
      • Brass R.
      • Weiss J.L.
      • Huang D.
      Subclinical keratoconus detection by pattern analysis of corneal and epithelial thickness maps with optical coherence tomography.
      ]. For example, Li et al [
      • Li Y.
      • Chamberlain W.
      • Tan O.
      • Brass R.
      • Weiss J.L.
      • Huang D.
      Subclinical keratoconus detection by pattern analysis of corneal and epithelial thickness maps with optical coherence tomography.
      ] reported that an epithelial thickness metric has 96% sensitivity and 100% specificity for distinguishing subclinical keratoconus from normal eyes compared to stromal (92%, 80%) and total corneal thickness (92%, 92%) metrics. This approach using an epithelial thickness metric derived from OCT imaging appears to be more suitable for detecting subclinical keratoconus compared to numerous studies using central or minimum total corneal thickness data [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ].
      A limitation of detecting keratoconus using corneal epithelial thickness profiling is that image segmentation can be difficult in the presence of changes in the anterior limiting lamina and thickness measurements are typically less reliable in keratoconic compared to non-keratoconic corneas [
      • Li Y.
      • Tan O.
      • Brass R.
      • Weiss J.L.
      • Huang D.
      Corneal epithelial thickness mapping by fourier-domain optical coherence tomography in normal and keratoconic eyes.
      ,
      • Vega-Estrada A.
      • Mimouni M.
      • Espla E.
      • Alió del Barrio J.
      • Alio J.L.
      Corneal epithelial thickness intrasubject repeatability and its relation with visual limitation in keratoconus.
      ]. Epithelial thickness metrics should still be considered in conjunction with other clinical measures in the diagnosis of keratoconus [
      • Yang Y.
      • Pavlatos E.
      • Chamberlain W.
      • Huang D.
      • Li Y.
      Keratoconus detection using OCT corneal and epithelial thickness map parameters and patterns.
      ].

      7.1.2 Tomographic indices

      Although anterior corneal curvature and anterior and posterior astigmatism are significantly elevated in keratoconus compared to non-keratoconic eyes, these parameters are not particularly useful in the differentiation of subclinical keratoconus from normal eyes [
      • Martínez-Abad A.
      • Piñero D.P.
      New perspectives on the detection and progression of keratoconus.
      ]. Since changes in the posterior corneal surface may be one of the first clinically detectable signs of keratoconus [
      • Saad A.
      • Gatinel D.
      Topographic and tomographic properties of forme fruste keratoconus corneas.
      ,
      • Rao S.N.
      • Raviv T.
      • Majmudar P.A.
      • Epstein R.J.
      Role of Orbscan II in screening keratoconus suspects before refractive corneal surgery.
      ,
      • Schlegel Z.
      • Hoang-Xuan T.
      • Gatinel D.
      Comparison of and correlation between anterior and posterior corneal elevation maps in normal eyes and keratoconus-suspect eyes.
      ] numerous studies have investigated the utility of posterior corneal metrics. These metrics cannot be obtained from traditional reflection-based topographers, but are measured using Scheimpflug imaging, slit scanning tomography, or optical coherence tomography. One of the most commonly used metrics is the po