Keratoconus (KCN) is a progressive bilateral corneal ectatic disorder. It manifests as characteristic cone-like steepening of the cornea associated with irregular stromal thinning, resulting in a cone-like bulge (protrusion) and significant loss of vision.
Optical effects include a significant and variable reduction in visual acuity, image distortion, and increased sensitivity to glare and light. The significant asymmetry reduces the ability of spherocylindrical spectacle lenses to adequately correct vision.
KCN may remain subclinical (i.e., undetected) and simply be classified as slightly asymmetric oblique astigmatism.
The manifest clinical onset of keratoconus (KCN) may occur at puberty (late teens for male and early twenties for female population) and may progress (continuous stromal thinning and corneal steepening) until the third to fourth decade. Beyond this age, it is very rare that there is any progression. In rare cases, KCN may become manifest at a later age, following alteration in the endocrinologic status such as gestation or pregnancy.
The manifestation and the progression of the disease are highly variable and are most often asymmetric between the two eyes of the same patient. It is widely accepted that there is no unilateral KCN, in the sense of unilateral disease; even when there are no clinical signs of the disease in the fellow eye, it is still considered that is simply not manifest in that eye. Severe KCN may develop in acute hydrops.
The etiology and pathogenesis of KCN are not known. Several associations have been identified, which include rigid gas permeable (RGP) contact lens wear, chronic eye rubbing, Down syndrome, atopic disease, Leber congenital amaurosis, connective tissue disease, tapetoretinal degeneration, and inheritance. Often, KCN presents with no other associated systemic or ocular disease. Some rare associations exist as a result of a chromosomal translocation, abnormal enzyme function, and loss of collagen and/or ground substance.,. Significant associations of KCN include Down syndrome, with an incidence ranging from 0.5% to 15%, which 10 to 300 times more common than in the general population, Leber congenital amaurosis (up to 30% of patients older than 15 years), and mitral valve prolapse (58%).
Persistent eye rubbing appears to either cause or exaggerate KCN.,  Persistent eye rubbing and hard contact lens wear may induce mechanical trauma that may be associated with keratoconus progression in individuals that are genetically predisposed. The mechanical alteration is possibly associated with some form of keratocyte change to a repair phenotype in response to rubbing-associated trauma.
While environmental factors likely play a role in disease prognosis, KCN is considered hereditary. At least 6% to 8% of reported cases have a positive family history or show evidence of familial transmission.
A peer-review literature search may reveal that the estimates for KCN incidence estimates may range between 50 and 230 per 100,000 (about 1 per 2,000).,, The reported numbers are variable. This may be because of the rarity of the disease, but most importantly, on and the non-standard criteria used to establish the diagnosis. The most common citation for the 1:2,000 number stems from a study which was conducted without the use of corneal topography (diagnosis by scissors movement on retinoscopy).
More specific and sensitive diagnostic tools may allow subtle KCN forms to be detected in the future. New studies conducted internationally suggest a prevalence as high as 1:375 in some populations. 
KCN has been traditionally classified as a non-inflammatory disease. With the exception of the significant loss of vision, other classic signs of inflammation (such as heat, redness, swelling, pain) are not usually present.
Clinical findings that are associated with KCN are, by order of importance, the asymmetrical thinning of the corneal stroma and the highly irregular corneal topography, which is often (wrongly) reported as steep astigmatism. Other clinical findings that can be observed biomicroscopically include the Fleischer iron rings, Munson sign, Rizzuti sign, and/or Vogt striae.
Advanced KCN often presents with breaks in Bowman’s layer (which are filled by eruptions of underlying stromal collagen) and deposition of iron (ferritin particles) in the corneal epithelium basal layers. The basal epithelium cells may show degeneration and epithelial infiltration into Bowman’s layer.
Stroma histopathology can be affected as well, mainly observed as scarring and opacity, compaction and loss of fibrils arrangement (stromal striae), decrease in collagen lamellae density, normal and degenerating fibroblasts in addition to keratocytes, and fine granular and microfibrillar material associated with the keratocytes.,
KCN has been known since the early days of ophthalmology. The term keratoconus was established later on; originally, there were various names, such as hyperkeratosis or conically formed cornea, all of which described an abnormally deformed and thin cornea, one way or another.
The original description of KCN dates to the early 18th century. It was first (1854) adequately described and distinguished from other ectatic conditions in the milestone treatise by Nottingham. Possible treatments were also suggested early on. Photinos Pannas (1831- 1902), Professor at the University of Paris, presented a management approach based on glass contact lenses.
While KCN is often accompanied by significant myopia, this is not by itself a criterion. The two most significant presentations are irregular corneal astigmatism and focal stromal thinning. We should distinguish the focal thinning from a generally thin cornea. Also, significant astigmatism, if symmetrical, is not a KCN criterion. It is stressed that the astigmatism noted in KCN is highly asymmetrical. The corneal thinning and the asymmetric astigmatism both occur in the area of the corneal protrusion, which is often infero-temporal. Thus topography, tomography, and pachymetry are the prime diagnostics used in the diagnosis and evaluation of KCN,,, in addition to biomicroscopic (slit-lamp) evaluation.
The first use of Placido topography for the diagnosis and classification of KCN was presented by Marc Amsler (1938). Topography can document subtle corneal surface irregularity before other clinical or biomicroscopic signs could be identified. Amsler documented a classification scheme ranging from early changes in cornea shape to clinically detectable keratoconus. Then, he classified KCN into clinically recognizable stages and two latent (subclinical) stages recognizable only by Placido disk corneal topography: forme-fruste and early or mild KCN.
Today, several ocular imaging modalities, including corneal topography, tomography, and biomechanical evaluation devices have enhanced our ability to detect early KCN in a quantifiable and reproducible manner. Corneal topography is the primary diagnostic tool for KCN detection. The color-coded corneal curvature maps generated by corneal topography may offer a visualization of anterior corneal surface irregularity, mostly noted by a typically infero-temporally located cone area of substantially increased steepening, often as high as 65 D, and a supero-nasally located flat area of decreased steepening, often as low as 35 D. Alternatively, the corneal aberrations map presented by these devices may show substantial amounts of high-order aberrations: a clear presence of coma as the primary aberration, followed by spherical aberration.
Pachymetry data obtained with Scheimpflug-imaging devices, such as the Pentacam (in the past, scanning slit-scan such as the Orbscan), are also used. In addition to the corneal curvature, these devices offer detailed pachymetry maps that present a corneal thinning. The thinnest cornea correlates well with the location of the maximum corneal steepening (cone location). These devices also can be used to produce anterior and posterior corneal surface elevation maps. A characteristic asymmetry in posterior surface elevation is considered a specific and sensitive indicator for the disease.
Other specific quantitative values produced by Placido topography or Scheimpflug imaging topometry that can be used as progression determinants of the disease are anterior surface irregularity indices, such as the Index of Height Decentration (IHA).
Lately, the use of anterior-segment optical coherence tomography (OCT) has been progressively used in the clinical diagnosis of keratoconus. The use of OCT can provide meridional cross-section (B-Scan) images of the cornea, revealing the asymmetric corneal thinning and posterior curvature asymmetry. More recent is the use of spectral-domain OCT as a corneal pachymetry tool, revealing corneal thickness asymmetry associated with KCN.
The investigation of corneal epithelial thickness distribution, facilitated by the most recent Fourier-domain OCT devices, can be a very sensitive and specific indicator for KCN. A key feature of the epithelium is that its thickness is such that it acts as a mask for underlying stromal thickness irregularities. Thus, it can be thinner (even less than 20 micrometers) over the most protruding part of the cornea and thicker (even more than 70 micrometers) over the flatter areas. This epithelial thickness distribution, if not accounted for, results in a false presentation of a slightly more uniform corneal thickness, masking early signs of corneal thickness irregularities measured with other devices so far, such as those based on Scheimpflug imaging, and reducing the degree of corneal curvature irregularity, as measured by Placido topography.
The available options for the management of KCN are highly dependent on the stage of the disease and its progression. If the disease is stabilized (no progression), the emphasis is given in correcting the vision. If the disease is progressing, the emphasis is to slow (arrest) the procession.
Since the effects of KCN in cornea shape distortion and stromal thinning are highly asymmetric, vision correction with spectacles and with spherical/toric soft contact lenses is suboptimal and only applicable to the early stages of KCN. Custom-designed soft contact lenses which incorporate aberration-controlled designs may provide some control of the primary aberrations associated with KCN such as coma and spherical aberration.
Rigid gas permeable (RGP) contact lenses and scleral lenses are the mainstays of vision treatment for modest-to-advanced KCN. Their main advantage is the creation of the tear pool between the lens and the cornea, which naturally neutralizes the ocular aberrations associated with the keratoconic ectasia, thus possibly providing nearly excellent corrected vision. A disadvantage relating to the use of RGP lenses is that they may not be tolerated. RGP lens wear in KCN is often complicated. Primary complains include intolerance, allergic reactions (such as giant papillary conjunctivitis), corneal abrasions, and neovascularization. Alternatives include hydrogel contact lenses, piggyback contact lenses or scleral contact lenses. The latter provide excellent vision and improved comfort.
Corneal collagen cross-linking (CXL) is a minimally invasive outpatient procedure that has been shown to be effective in the arrest of the progression of KCN. It leads to an increase of stromal rigidity, thus slowing and eventually stabilizing the progression of the keratectasia. This has been demonstrated in ex vivo studies through mechanical (tensile test) and biological testing (enzymatic digestion). CXL application, when successful, leads to far less need for penetrating keratoplasty.
When activated with UVA light (365 nm), riboflavin 5‘-phosphate functions as a photo enhancer and generates singlet oxygen and reactive species which are responsible for cross-linking. The classical, or Dresden protocol, involves epithelial debridement (to facilitate penetration of riboflavin and a high level of UVA absorption in the stroma), soaking the exposed stroma with riboflavin for about 30 minutes (to allow sufficient saturation in the stroma), and irradiation by 3 mW/cm2 of UVA for 30 minutes. Total energy dissipated is 5.4 J/cm2. A drug and device combination product was approved for cross-linking for the treatment of progressive keratoconus by the US Food and Drug Administration (FDA) in April 2016.
Other CXL protocols have been suggested and are in use outside the United States, which involve the use of increased irradiation and shorter exposure time. CXL has also been combined with topography-guided laser-ablation corneal surface normalization (Athens protocol) in an effort to combine the effects of ectasia arrest (CXL) with improved visual function.
While CXL does not necessarily improve the quality of vision, it is important to stress that early diagnosis may make a significant difference in the success of keratoconus management. If the disease is diagnosed at an early stage, then both the corneal irregularity and thinning may be only minimally affected. In those cases, the effect of biomechanical stabilization provided by CXL will prevent future vision loss.
Other treatment modalities include intra-corneal ring segments (INTACS). This is a small curved PMMA ring or set of rings that is implanted in the cornea to help flatten corneal curvature in an effort to improve vision.
Corneal transplant is considered the last resort when the cornea is too thin to receive CXL and the symptoms are severe. The cornea is replaced fully (penetrating keratoplasty) or in part (lamellar keratoplasty) with healthy donor cornea tissue. 
When primary providers, such as physicians, physician assistants, and nurse practitioners encounter patients with vision problems, referral to an optician, ophthalmic nurse, and ophthalmologist is highly recommended. Keratoconus is primarily managed by eye surgeons. Today, several treatments are available including corneal transplant. So far no treatment is ideal and patient selection is important.  an interprofessional team is best for followup involving both the specialists and primary care providers. [Level V]
|||Keratoconus and related noninflammatory corneal thinning disorders., Krachmer JH,Feder RS,Belin MW,, Survey of ophthalmology, 1984 Jan-Feb [PubMed PMID: 6230745]|
|||Arora R,Lohchab M, Pediatric keratoconus misdiagnosed as meridional amblyopia. Indian journal of ophthalmology. 2019 Apr; [PubMed PMID: 30900595]|
|||Leber congenital amaurosis and its association with keratoconus and keratoglobus., Elder MJ,, Journal of pediatric ophthalmology and strabismus, 1994 Jan-Feb [PubMed PMID: 8195961]|
|||The cascade hypothesis of keratoconus., Cristina Kenney M,Brown DJ,, Contact lens & anterior eye : the journal of the British Contact Lens Association, 2003 Sep [PubMed PMID: 16303509]|
|||Expression of degradative enzymes and protease inhibitors in corneas with keratoconus., Zhou L,Sawaguchi S,Twining SS,Sugar J,Feder RS,Yue BY,, Investigative ophthalmology & visual science, 1998 Jun [PubMed PMID: 9620070]|
|||Loukovitis E,Sfakianakis K,Syrmakesi P,Tsotridou E,Orfanidou M,Bakaloudi DR,Stoila M,Kozei A,Koronis S,Zachariadis Z,Tranos P,Kozeis N,Balidis M,Gatzioufas Z,Fiska A,Anogeianakis G, Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities. Ophthalmology and therapy. 2018 Dec; [PubMed PMID: 30191404]|
|||Rabbanikhah Z,Javadi MA,Rostami P,Aghdaie A,Yaseri M,Yahyapour F,Katibeh M, Association between acute corneal hydrops in patients with keratoconus and mitral valve prolapse. Cornea. 2011 Feb; [PubMed PMID: 21045676]|
|||Keratoconus associated with continual eye rubbing due to punctal agenesis., Lindsay RG,Bruce AS,Gutteridge IF,, Cornea, 2000 Jul [PubMed PMID: 10928781]|
|||Bral N,Termote K, Unilateral Keratoconus after Chronic Eye Rubbing by the Nondominant Hand. Case reports in ophthalmology. 2017 Sep-Dec; [PubMed PMID: 29422858]|
|||Eye rubbing as an apparent cause of recurrent keratoconus., Yeniad B,Alparslan N,Akarcay K,, Cornea, 2009 May [PubMed PMID: 19411974]|
|||Mechanisms of rubbing-related corneal trauma in keratoconus., McMonnies CW,, Cornea, 2009 Jul [PubMed PMID: 19512912]|
|||Gordon-Shaag A,Millodot M,Shneor E,Liu Y, The genetic and environmental factors for keratoconus. BioMed research international. 2015; [PubMed PMID: 26075261]|
|||A review of keratoconus: Diagnosis, pathophysiology, and genetics., Mas Tur V,MacGregor C,Jayaswal R,O'Brart D,Maycock N,, Survey of ophthalmology, 2017 Nov - Dec [PubMed PMID: 28688894]|
|||Rabinowitz YS, Keratoconus. Survey of ophthalmology. 1998 Jan-Feb; [PubMed PMID: 9493273]|
|||A keratoscopic survey of 13,395 eyes., HOFSTETTER HW,, American journal of optometry and archives of American Academy of Optometry, 1959 Jan [PubMed PMID: 13617405]|
|||Grünauer-Kloevekorn C,Duncker GI, [Keratoconus: epidemiology, risk factors and diagnosis]. Klinische Monatsblatter fur Augenheilkunde. 2006 Jun; [PubMed PMID: 16804819]|
|||McMonnies CW, Inflammation and keratoconus. Optometry and vision science : official publication of the American Academy of Optometry. 2015 Feb; [PubMed PMID: 25397925]|
|||Stromal striae: a new insight into corneal physiology and mechanics., Grieve K,Ghoubay D,Georgeon C,Latour G,Nahas A,Plamann K,Crotti C,Bocheux R,Borderie M,Nguyen TM,Andreiuolo F,Schanne-Klein MC,Borderie V,, Scientific reports, 2017 Oct 19 [PubMed PMID: 29051516]|
|||Maharana PK,Sharma N,Vajpayee RB, Acute corneal hydrops in keratoconus. Indian journal of ophthalmology. 2013 Aug; [PubMed PMID: 23925338]|
|||The early history of keratoconus prior to Nottingham's landmark 1854 treatise on conical cornea: a review., Grzybowski A,McGhee CN,, Clinical & experimental optometry, 2013 Mar [PubMed PMID: 23414219]|
|||Dr John Nottingham's 1854 Landmark Treatise on Conical Cornea Considered in the Context of the Current Knowledge of Keratoconus., Gokul A,Patel DV,McGhee CN,, Cornea, 2016 May [PubMed PMID: 26989959]|
|||Piñero DP,Nieto JC,Lopez-Miguel A, Characterization of corneal structure in keratoconus. Journal of cataract and refractive surgery. 2012 Dec; [PubMed PMID: 23195256]|
|||Belin MW,Duncan JK, Keratoconus: The ABCD Grading System. Klinische Monatsblatter fur Augenheilkunde. 2016 Jun; [PubMed PMID: 26789119]|
|||Tang M,Li Y,Chamberlain W,Louie DJ,Schallhorn JM,Huang D, Differentiating Keratoconus and Corneal Warpage by Analyzing Focal Change Patterns in Corneal Topography, Pachymetry, and Epithelial Thickness Maps. Investigative ophthalmology [PubMed PMID: 27482824]|
|||Forme Fruste Keratoconus Imaging and Validation via Novel Multi-Spot Reflection Topography., Kanellopoulos AJ,Asimellis G,, Case reports in ophthalmology, 2013 [PubMed PMID: 24348403]|
|||Corneal topography in keratoconus: state of the art., Cavas-Martínez F,De la Cruz Sánchez E,Nieto Martínez J,Fernández Cañavate FJ,Fernández-Pacheco DG,, Eye and vision (London, England), 2016 [PubMed PMID: 26904709]|
|||Characterizing the wave aberration in eyes with keratoconus or penetrating keratoplasty using a high-dynamic range wavefront sensor., Pantanelli S,MacRae S,Jeong TM,Yoon G,, Ophthalmology, 2007 Nov [PubMed PMID: 17553566]|
|||Detection of ectatic corneal diseases based on pentacam., Lopes BT,Ramos IC,Dawson DG,Belin MW,Ambrósio R Jr,, Zeitschrift fur medizinische Physik, 2016 Jun [PubMed PMID: 26777318]|
|||Assessing progression of keratoconus: novel tomographic determinants., Duncan JK,Belin MW,Borgstrom M,, Eye and vision (London, England), 2016 [PubMed PMID: 26973847]|
|||Revisiting keratoconus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases., Kanellopoulos AJ,Asimellis G,, Clinical ophthalmology (Auckland, N.Z.), 2013 [PubMed PMID: 23935360]|
|||Ramos JL,Li Y,Huang D, Clinical and research applications of anterior segment optical coherence tomography - a review. Clinical [PubMed PMID: 19016809]|
|||OCT-derived comparison of corneal thickness distribution and asymmetry differences between normal and keratoconic eyes., Kanellopoulos AJ,Asimellis G,, Cornea, 2014 Dec [PubMed PMID: 25321940]|
|||OCT corneal epithelial topographic asymmetry as a sensitive diagnostic tool for early and advancing keratoconus., Kanellopoulos AJ,Asimellis G,, Clinical ophthalmology (Auckland, N.Z.), 2014 [PubMed PMID: 25429197]|
|||Anterior segment optical coherence tomography: assisted topographic corneal epithelial thickness distribution imaging of a keratoconus patient., Kanellopoulos AJ,Asimellis G,, Case reports in ophthalmology, 2013 Jan [PubMed PMID: 23687500]|
|||Tear biomarkers for keratoconus., Nishtala K,Pahuja N,Shetty R,Nuijts RM,Ghosh A,, Eye and vision (London, England), 2016 [PubMed PMID: 27493978]|
|||Vinciguerra R,Ambrósio R Jr,Roberts CJ,Azzolini C,Vinciguerra P, Biomechanical Characterization of Subclinical Keratoconus Without Topographic or Tomographic Abnormalities. Journal of refractive surgery (Thorofare, N.J. : 1995). 2017 Jun 1; [PubMed PMID: 28586501]|
|||Corneal surgery in keratoconus: which type, which technique, which outcomes?, Arnalich-Montiel F,Alió Del Barrio JL,Alió JL,, Eye and vision (London, England), 2016 [PubMed PMID: 26783544]|
|||Customized hydrogel contact lenses for keratoconus incorporating correction for vertical coma aberration., Katsoulos C,Karageorgiadis L,Vasileiou N,Mousafeiropoulos T,Asimellis G,, Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists), 2009 May [PubMed PMID: 19422564]|
|||Current optometric practices and attitudes in keratoconus patient management., Ortiz-Toquero S,Martin R,, Contact lens & anterior eye : the journal of the British Contact Lens Association, 2017 Aug [PubMed PMID: 28325632]|
|||Rabinowitz YS, The genetics of keratoconus. Ophthalmology clinics of North America. 2003 Dec; [PubMed PMID: 14741001]|
|||Downie LE,Lindsay RG, Contact lens management of keratoconus. Clinical [PubMed PMID: 26104589]|
|||O'Brart DP, Corneal collagen cross-linking: a review. Journal of optometry. 2014 Jul-Sep; [PubMed PMID: 25000866]|
|||Cross-Linking Biomechanical Effect in Human Corneas by Same Energy, Different UV-A Fluence: An Enzymatic Digestion Comparative Evaluation., Kanellopoulos AJ,Loukas YL,Asimellis G,, Cornea, 2016 Apr [PubMed PMID: 26845317]|
|||Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus., Wollensak G,Spoerl E,Seiler T,, American journal of ophthalmology, 2003 May [PubMed PMID: 12719068]|
|||Crosslinking treatment of progressive keratoconus: new hope., Wollensak G,, Current opinion in ophthalmology, 2006 Aug [PubMed PMID: 16900027]|
|||Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol)., Kanellopoulos AJ,Asimellis G,, Journal of refractive surgery (Thorofare, N.J. : 1995), 2014 Feb [PubMed PMID: 24763473]|
|||Corneal refractive power and symmetry changes following normalization of ectasias treated with partial topography-guided PTK combined with higher-fluence CXL (the Athens Protocol)., Kanellopoulos AJ,Asimellis G,, Journal of refractive surgery (Thorofare, N.J. : 1995), 2014 May [PubMed PMID: 24893359]|
|||Intracorneal ring segments in ectatic corneal disease - a review., Piñero DP,Alio JL,, Clinical & experimental ophthalmology, 2010 Mar [PubMed PMID: 20398105]|
|||Fernández-Vega-Cueto L,Lisa C,Poo-López A,Alfonso JF,Madrid-Costa D, Three-year follow-up of intrastromal corneal ring segment implantation in central keratoconus with regular astigmatism: 'Bow-tie' shape. European journal of ophthalmology. 2019 Mar 8; [PubMed PMID: 30845839]|
|||Lang PZ,Hafezi NL,Khandelwal SS,Torres-Netto EA,Hafezi F,Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea. 2019 Apr; [PubMed PMID: 30681515]|