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Keratoconus
Keratoconus
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Keratoconus (from Greek: kerato- horn, cornea; and konos cone), is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve.

Keratoconus can cause substantial distortion of vision, with multiple images, streaking and sensitivity to light all often reported by the patient. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. However, despite the disease's unpredictable course, keratoconus can often be successfully managed with little or no impairment to the patient's quality of life. However for many Keratoconus does affect quality of life, self confidence and the ability to do simple tasks. Random eye pain, dry eye and lack of depth of vision can cause issues in the workplace. Individuals with keratoconus can suffer considerable stress as they try to cope at work and in every day life with impaired vision, poorly fitted lens, pain and photosensitivity.

In most cases, corrective lenses are effective enough to allow the patient to continue to drive legally and likewise function normally. They must be fitted by an expert in complex keratoconic eyes. Choices include hard RGP, scerals and the hybrid lenses. Some people are lens intolerant. Further progression of the disease may require surgery, for which there are several options, including Intacs intrastromal corneal ring segments, corneal collagen cross-linking, or when all avenues are exhausted corneal transplantation. A new procedure is called KXL, which is promising.

Keratoconus affects around one person in a thousand; difficulties with differential diagnosis cause uncertainty as to its prevalence. It seems to occur in populations throughout the world, although is observed more frequently in certain ethnic groups such as South Asians. The exact cause of keratoconus is uncertain, but has been associated with detrimental enzyme activity within the cornea. Environmental and genetic factors are considered possible causes, but the findings remain inconclusive. The progression of keratoconus is rapid in patients having Downs syndrome.

Signs and symptoms

People with early keratoconus typically notice a minor blurring of their vision and come to their clinician seeking corrective lenses for reading or driving.^[2]^[3] At early stages, the symptoms of keratoconus may be no different from those of any other refractive defect of the eye. As the disease progresses, vision deteriorates, sometimes rapidly. Visual acuity becomes impaired at all distances, and night vision is often quite poor. Some individuals have vision in one eye that is markedly worse than that in the other eye. The disease is often bilateral, though asymmetrical in many patients. Some develop photophobia (sensitivity to bright light), eye strain from squinting in order to read, or itching in the eye,^[2] but there is normally little or no sensation of pain.

The classic symptom of keratoconus is the perception of multiple 'ghost' images, known as monocular polyopia. This effect is most clearly seen with a high contrast field, such as a point of light on a dark background. Instead of seeing just one point, a person with keratoconus sees many images of the point, spread out in a chaotic pattern. This pattern does not typically change from day to day, but over time it often takes on new forms. Patients also commonly notice streaking and flaring distortion around light sources. Some even notice the images moving relative to one another in time with their heart beat.

The predominant optical aberration of the eye as an optical system in keratoconus is the so-called coma.^[4]^[5]

Diagnosis

A schematic digram showing change in cornea

Prior to any physical examination, the diagnosis of keratoconus frequently begins with an ophthalmologist's or optometrist's assessment of the patient's medical history, particularly the chief complaint and other visual symptoms, the presence of any history of ocular disease or injury which might affect vision, and the presence of any family history of ocular disease. An eye chart, such as a standard Snellen chart of progressively smaller letters, is then used to determine the patient's visual acuity. The eye examination may proceed to measurement of the localised curvature of the cornea with a manual keratometer,^[6] with detection of irregular astigmatism suggesting a possibility of keratoconus. Severe cases can exceed the instrument's measuring ability.^[3] A further indication can be provided by retinoscopy, in which a light beam is focused on the patient's retina and the reflection, or reflex, observed as the examiner tilts the light source back and forth. Keratoconus is amongst the ophthalmic conditions that exhibit a scissor reflex action of two bands moving toward and away from each other like the blades of a pair of scissors.^[3]^[7]

If keratoconus is suspected, the ophthalmologist or optometrist will search for other characteristic findings of the disease by means of slit lamp examination of the cornea.^[8] An advanced case is usually readily apparent to the examiner, and can provide for an unambiguous diagnosis prior to more specialised testing. Under close examination, a ring of yellow-brown to olive-green pigmentation known as a Fleischer ring can be observed in around half of keratoconic eyes.^[9] The Fleischer ring, caused by deposition of the iron oxide hemosiderin within the corneal epithelium, is subtle and may not be readily detectable in all cases, but becomes more evident when viewed under a cobalt blue filter.^[3] Similarly, around 50% of subjects exhibit Vogt's striae, fine stress lines within the cornea caused by stretching and thinning.^[9] The striae temporarily disappear while slight pressure is applied to the eyeball.^[3] A highly pronounced cone can create a V-shaped indentation in the lower eyelid when the patient's gaze is directed downwards, known as Munson's sign.^[2] Other clinical signs of keratoconus will normally have presented themselves long before Munson's sign becomes apparent,^[10] and so this finding, though a classic sign of the disease, tends not to be of primary diagnostic importance.

A handheld keratoscope, sometimes known as Placido's disk, can provide a simple non-invasive visualization of the surface of the cornea by projecting a series of concentric rings of light onto the cornea. A more definitive diagnosis can be obtained using corneal topography, in which an automated instrument projects the illuminated pattern onto the cornea and determines its topology from analysis of the digital image. The topographical map indicates any distortions or scarring in the cornea, with keratoconus revealed by a characteristic steepening of curvature which is usually below the centreline of the eye.^[11] The technique can record a snapshot of the degree and extent of the deformation as a benchmark for assessing its rate of progression. It is of particular value in detecting the disorder in its early stages when other signs have not yet presented.^[12]

Once keratoconus has been diagnosed, its degree may be classified by several metrics:^[13]

The steepness of greatest curvature from mild (< 45 D), advanced (up to 52 D) or severe (> 52 D);
The morphology of the cone: nipple (small: 5 mm and near-central), oval (larger, below-center and often sagging), or globus (more than 75% of cornea affected);
The corneal thickness from mild (> 506 μm) to advanced (< 446 μm).

Increasing use of corneal topography has led to a decline in use of these terms.^[13]

Cause

Despite considerable research, the etiology of keratoconus remains unclear.^[11] Several sources suggest that keratoconus likely arises from a number of different factors: genetic, environmental or cellular, any of which may form the trigger for the onset of the disease.^[14]^[15]

Genetic Causes

A genetic predisposition to keratoconus has been observed,^[16] with the disease running in certain families,^[17] and incidences reported of concordance in identical twins.^[8] The frequency of occurrence in close family members is not clearly defined, though it is known to be considerably higher than that in the general population,^[11] and studies have obtained estimates ranging between 6% and 19%.^[18] Two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q.^[18] Most genetic studies agree on an autosomal dominant model of inheritance.^[2]

A rare, autosomal dominant form of severe keratoconus with anterior polar cataract is caused by a mutation in the seed region of mir-184, a microRNA that is highly expressed in the cornea and anterior lens. ^[19]

Keratoconus is diagnosed more often in people with Down syndrome, though the reasons for this link have not yet been determined.^[20]

Environmental Causes

Keratoconus has been associated with atopic diseases, which include asthma, allergies, and eczema, and it is not uncommon for several or all of these diseases to affect one person. A number of studies suggest that vigorous eye rubbing contributes to the progression of keratoconus, and that patients should be discouraged from the practice.^[21]^[22]^[23]^[24]^[25]^[26] Iatrogenic keratoconus has also been observed following LASIK surgery, caused by removal of excessive stromal bed tissue.^[27]

Pathophysiology

Once initiated, the disease normally develops by progressive dissolution of Bowman's layer,^[3] which lies between the corneal epithelium and stroma. As the two come into contact, cellular and structural changes in the cornea adversely affect its integrity and lead to the bulging and scarring that are characteristic of the disorder. Within any individual keratoconic cornea, there may be found regions of degenerative thinning coexisting with regions undergoing wound healing.

The visual distortion experienced by the patient comes from two sources, one being the irregular deformation of the surface of the cornea; the other being scarring that occurs on its exposed highpoints. These factors act to form regions on the cornea that map an image to different locations on the retina and give rise to the symptom of monocular polyopia. The effect can worsen in low light conditions as the dark-adapted pupil dilates to expose more of the irregular surface of the cornea. Scarring appears to be an aspect of the corneal degradation; however, a recent, large, multi-center study suggests that abrasion by contact lenses may increase the likelihood of this finding by a factor of over two.^[28] A number of patients complain of chronic eye rubbing and also think it as a possible cause to the disease but it is not so; however, it has been observed that keratoconus progresses faster due to eye-rubbing.

A number of studies have indicated that keratoconic corneas show signs of increased activity by proteases,^[14] a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors.^[29] Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea.^[30] It seems likely that, whatever the pathogenetical process, the damage caused by activity within the cornea results in a reduction in its thickness and biomechanical strength. While keratoconus is considered a non-inflammatory disorder, one study shows that wearing rigid contact lenses by patients leads to overexpression of pro-inflammatory cytokines, such as IL-6, TNF-alpha, ICAM-1, and VCAM-1 in the tear fluid.^[31]

Treatment

Contact lenses

Rigid gas permeable lens for keratoconus

In early stages of keratoconus, spectacles or soft contact lenses can suffice to correct for the mild astigmatism. As the condition progresses, these may no longer provide the patient with a satisfactory degree of visual acuity, and most clinical practitioners will move to managing the condition with rigid contact lenses, known as rigid gas-permeables, or RGPs. RGP lenses provide a good level of visual correction, but do not arrest progression of the condition.^[32]

In keratoconic patients, rigid contact lenses improve vision by means of tear fluid filling the gap between the irregular corneal surface and the smooth regular inner surface of the lens, thereby creating the effect of a smoother cornea. Many specialized types of contact lenses have been developed for keratoconus, and affected people may seek out both doctors specialized in conditions of the cornea, and contact lens fitters who have experience managing patients with keratoconus. The irregular cone presents a challenge^[14] and the fitter will endeavour to produce a lens with the optimal contact, stability and steepness. Some trial-and-error fitting may prove necessary.^[10]

Traditionally, contact lenses for keratoconus have been the 'hard' or rigid gas-permeable variety, although manufacturers have also produced specialized 'soft' or hydrophilic lenses and, most recently, silicone hydrogel lenses. A soft lens has a tendency to conform to the conical shape of the cornea, thus diminishing its effect. To counter this, hybrid lenses have been developed which are hard in the centre and encompassed by a soft skirt. However, soft or earlier generation hybrid lenses did not prove effective for every patient.^[33] Early generation lenses like SoftPerm have been discontinued.^[34] The fourth generation of hybrid lens technology has improved significantly, giving more patients an option that combines the comfort of a soft lens with the visual acuity of an RGP lens.^[35] The new generation of technology fixes the issues that were prevalent in earlier generations and allows contact lenses to be fit for the majority of patients.^[36]

Some patients also find good vision correction and comfort with a "piggyback" lens combination, in which gas-permeable rigid lenses are worn over soft lenses, both providing a degree of vision correction.^[37] One form of piggyback lens makes use of a soft lens with a countersunk central area to accept the rigid lens. Fitting a piggyback lens combination requires experience on the part of the lens fitter, and tolerance on the part of the keratoconic patient.

Scleral lenses are sometimes prescribed for cases of advanced or very irregular keratoconus; these lenses cover a greater proportion of the surface of the eye and hence can offer improved stability.^[38] The larger size of the lenses may make them unappealing or uncomfortable to some; however, their easier handling can find favour with patients with reduced dexterity, such as the elderly.

Surgical options

Corneal transplant

Between 10% and 25% of cases of keratoconus^[15]^[39]^[40] will progress to a point where vision correction is no longer possible, thinning of the cornea becomes excessive, or scarring as a result of contact lens wear causes problems of its own, and a corneal transplantation or penetrating keratoplasty becomes required. Keratoconus is the most common grounds for conducting a penetrating keratoplasty, generally accounting for around a quarter of such procedures.^[41] The corneal transplant surgeon trephines a lenticule of corneal tissue and then grafts the donor cornea to the existing eye tissue, usually using a combination of running and individual sutures. The cornea does not have a direct blood supply, and so donor tissue is not required to be blood type matched. Eye banks check the donor corneas for any disease or cellular irregularities.

The acute recovery period can take four to six weeks and full post-operative vision stabilization often takes a year or more but most transplants are very stable in the long term.^[40] The National Keratoconus Foundation reports that penetrating keratoplasty has the most successful outcome of all transplant procedures, and when performed for keratoconus in an otherwise healthy eye, its success rate can be 95% or greater.^[15] The sutures used usually dissolve over a period of three to five years but individual sutures can be removed during the healing process if they are causing irritation to the patient.

In the USA, corneal transplants (also known as corneal grafts) for keratoconus are usually performed under sedation as outpatient surgery. In other countries, such as Australia and the UK, the operation is commonly performed with the patient undergoing a general anaesthetic. All cases require a careful follow-up with an eye surgeon (ophthalmologist) for a number of years. Frequently, vision is greatly improved after the surgery, but even if the actual visual acuity does not improve, because the cornea is a more normal shape after the healing is completed, patients can more easily be fitted with corrective lenses. Complications of corneal transplants are mostly related to vascularization of the corneal tissue and rejection of the donor cornea. Vision loss is very rare, though difficult-to-correct vision is possible. When rejection is severe, repeat transplants are often attempted, and are frequently successful.^[42] Keratoconus will not normally reoccur in the transplanted cornea; incidences of this have been observed, but are usually attributed to incomplete excision of the original cornea or inadequate screening of the donor tissue.^[43] The long-term outlook for corneal transplants performed for keratoconus is usually favorable once the initial healing period is completed and a few years have elapsed without problems.

Corneal ring segment inserts

A recent surgical alternative to corneal transplant is the insertion of intrastromal corneal ring segments. A small incision is made in the periphery of the cornea and two thin arcs of polymethyl methacrylate are slid between the layers of the stroma on either side of the pupil before the incision is closed.^[44] The segments push out against the curvature of the cornea, flattening the peak of the cone and returning it to a more natural shape. The procedure, carried out on an outpatient basis under local anaesthesia, offers the benefit of being reversible and even potentially exchangeable as it involves no removal of eye tissue.^[44]

The principal intrastromal ring available is known by the trade name of Intacs. Internationally, Ferrara Rings are also available. Intacs are a patented technology and are placed outside the optical zone versus the smaller prismatic Ferrara rings that are placed just inside the 5 mm optical zone. Intacs are the only corneal implants that have gone through the FDA Phase I, II and III clinical trials and were first approved by the Food and Drug Administration (FDA) in the United States in 1999 for myopia; this was extended to the treatment of keratoconus in July 2004.^[45]

A pair of *Intacs* after insertion into the cornea

Clinical studies on the effectiveness of intrastromal rings on keratoconus are in their early stages, and results have so far been generally encouraging,^[46]^[47] though they have yet to enter into wide acceptance with the refractive surgery community. In common with penetrating keratoplasty, the requirement for some vision correction in the form of spectacles or hydrophilic contact lenses may remain subsequent to the operation. Potential complications of intrastromal rings include accidental penetration through to the anterior chamber when forming the channel, post-operative infection of the cornea, and migration or extrusion of the segments.^[47] The rings offer a good chance of vision improvement even in otherwise hard to manage eyes, but results are not guaranteed and in a few cases may worsen.

Early studies on intrastromal corneal rings involved use of two segments to cause global flattening of the cornea.^[48] A later study reported that better results could be obtained for those cones located more to the periphery of the cornea by using a single Intacs segment. This leads to preferential flattening of the cone below, but also to steepening the over-flat upper part of the cornea.^[49]

Corneal collagen crosslinking with riboflavin

A treatment developed at the Technische Universität Dresden, and which has shown early success is Corneal Collagen Crosslinking with Riboflavin, also known as CXL, CCR, CCL and KXL.^[51] A one-time application of riboflavin solution is administered to the eye and is activated by illumination with UV-A light for approximately 30 minutes.^[29]^[52] The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. The corneal epithelial layer is generally removed in order to increase penetration of the riboflavin into the stroma.

Clinical trials are ongoing,^[when?] but crosslinking is seeing increasing adoption by the ophthalmological community, and has shown success in retarding or stopping progression of the disease.^[53] Early results from an Australian study are very promising in reporting stabilization in all treated eyes, and a slight correction in visual acuity in most patients.^[54] The procedure, with epithelium removed, is approved for use throughout Europe, and commenced clinical trials in the USA in 2008.^[55] Over 300 patients have now^[when?] been treated in the United States in those trials, which are composed of two randomized, controlled, multi-site clinical trials for the treatment of progressive keratoconus and post LASIK ectasia.^[56] Avedro Inc., the trial’s sponsor,^[57]^[58] is closing^[when?] the follow-up phase of the study and completing the necessary steps to file the results with the FDA.^[56]

In some cases, collagen crosslinking may also be combined with other treatments to improve corneal asymmetry or optical refraction. Successful treatment methods include corneal ring segment inserts (INTACS or Ferrara Rings),^[59] Topography Guided Laser ^[53] or Keraflex.^[60]^[61] Corrective lenses are normally required after these treatments but with smaller, more normalised prescriptions. Increased corneal symmetry allows for more comfortable contact lens wear, often of daily disposable lenses. These newer methods may have an important role in limiting deterioration of vision, increasing unaided/uncorrected vision and reducing the case for corneal transplantation.^[62] ^[63]

Radial keratotomy

Radial keratotomy is a refractive surgery procedure where the surgeon makes a spoke-like pattern of incisions into the cornea to modify its shape. This early surgical option for myopia has been largely superseded by LASIK and other similar procedures. LASIK itself is absolutely contraindicated in keratoconus and other corneal thinning conditions as removal of corneal stromal tissue will further damage an already thin and weak cornea.^[64]

For similar reasons, radial keratotomy has also generally not been used for keratoconic patients.^[65]^[66] However, an Italian clinic has reported some success with a modified asymmetric radial keratotomy procedure,^[67] in which the incisions are confined to one sector of the eye. The corneal thickness is first measured using a pachymeter, then the surgeon makes cuts to a depth of 70–80% of the measured thickness. The patient may initially experience photophobia and fluctuation of vision, in common with other forms of refractive surgery.^[67] This technique has yet to go through the official experimentation and follow-up period which is generally required by the Italian National Health Service to accept a new surgery technique before it can be offered to patients.

DALK transplants

One way of reducing the risk of rejection is to use a newer technique called a Deep Anterior Lamellar Keratoplasty, referred to as DALK. In a DALK graft, only the outermost epithelium and the main bulk of the cornea, the stroma, are replaced; the patient's rearmost endothelium layer and the Descemet's membrane are left, giving some additional structural integrity to the post-graft cornea.^[68] Furthermore, it is possible to transplant tissue from a donor which has been freeze-dried. The freeze-drying process ensures that this tissue is dead, so there is no chance of a rejection.^[68]

Some surgeons prefer to remove the donor epithelium, others leave the donor's cells in place. Removing it can cause a slight improvement in overall vision, but a corresponding increase in visual recovery time.

Epikeratophakia

Rarely, a non-penetrating keratoplasty known as an epikeratophakia (or epikeratoplasty) may be performed in cases of keratoconus. The corneal epithelium is removed and a lenticule of donor cornea grafted on top of it.^[14] The procedure requires a greater level of skill on the part of the surgeon, and is less frequently performed than a penetrating keratoplasty as the outcome is generally less favorable. However, it may be seen as an option in a number of cases, particularly for young patients.^[69]

Prognosis

Patients with keratoconus typically present initially with mild astigmatism and myopia, commonly at the onset of puberty, and are diagnosed by the late teenage years or early 20s. The disease can however present or progress at any age: in rare cases keratoconus can present in children or not until later adulthood.^[3] A diagnosis of the disease at an early age may indicate a greater risk of severity in later life.^[11]^[70] Patients' vision will seem to fluctuate over a period of months, driving them to change lens prescriptions frequently, but as the condition worsens, contact lenses are required in the majority of cases. The course of the disorder can be quite variable, with some patients remaining stable for years or indefinitely, while others progress rapidly or experience occasional exacerbations over a long and otherwise steady course. It tends to progress more rapidly in patients when the first presentation is in second decade of life. Most commonly, keratoconus progresses for a period of ten to twenty years^[10] before the course of the disease generally ceases in the third and fourth decades of life.

In advanced cases, bulging of the cornea can result in a localized rupture of Descemet's membrane, an inner layer of the cornea. Aqueous humor from the eye's anterior chamber seeps into the cornea before Descemet's membrane reseals. The patient experiences pain and a sudden severe clouding of vision, with the cornea taking on a translucent milky-white appearance known as a corneal hydrops.^[71] Although disconcerting to the patient, the effect is normally temporary and after a period of six to eight weeks the cornea usually returns to its former transparency. The recovery can be aided non-surgically by bandaging with an osmotic saline solution. Although a hydrops usually causes increased scarring of the cornea, occasionally it will benefit a patient by creating a flatter cone, aiding the fitting of contact lenses.^[71] Occasionally, the cornea thins to the point that a partial rupture occurs at the level of Descemet´s membrane, resulting in a small, bead-like swelling on the cornea that may become filled with fluid (cornea hydropsy). When this occurs, severe vision decrease may occur until the edema slowly resolves. Corneal transplantation is not usually indicated while the hydropsy persists.

Epidemiology

The National Eye Institute reports that keratoconus is the most common corneal dystrophy in the United States, affecting approximately 1 in 2,000 Americans,^[72]^[73] but some reports place the figure as high as 1 in 500.^[74] The inconsistency may be due to variations in diagnostic criteria,^[3] with some cases of severe astigmatism interpreted as those of keratoconus, and vice versa.^[10] A long-term study found a mean incidence rate of 2.0 new cases per 100,000 population per year.^[73] It is suggested that males and females, and all ethnicities appear equally susceptible, though some recent studies have cast doubt upon this,^[75] suggesting a higher prevalence amongst females; the literature, however, varying as to its extent. Also, a study carried out in the UK^[76] suggests that people of a South Asian heritage are 4.4 times as likely to suffer from keratoconus as Caucasians, and are also more likely to be affected with the condition earlier.

Keratoconus is normally bilateral^[73] (affecting both eyes) although the distortion is usually asymmetric and is rarely completely identical in both corneas.^[3] Unilateral cases tend to be uncommon, and may in fact be very rare if a very mild condition in the better eye is simply below the limit of clinical detection.^[10] It is common for keratoconus to be diagnosed first in one eye and not until later in the other. As the condition then progresses in both eyes, the vision in the earlier-diagnosed eye will often persist to be poorer than that in its fellow.

History

*Practical observations on conical cornea*, Nottingham's ground-breaking text on keratoconus, 1854

In a 1748 doctoral dissertation, the German oculist Burchard Mauchart provided an early description of a case of keratoconus,^[11] which he called staphyloma diaphanum. However, it was not until 1854 that British physician John Nottingham clearly described keratoconus and distinguished it from other ectasias of the cornea.^[11] Nottingham reported the cases of "conical cornea" that had come to his attention, and described several classic features of the disease, including polyopia, weakness of the cornea, and difficulty matching corrective lenses to the patient's vision.^[1] In 1859 British surgeon William Bowman used an ophthalmoscope (recently invented by Hermann von Helmholtz) to diagnose keratoconus, and described how to angle the instrument's mirror so as to best see the conical shape of the cornea.^[77] Bowman also attempted to restore the vision by pulling on the iris with a fine hook inserted through the cornea and stretching the pupil into a vertical slit, like that of a cat. He reported that he had had a measure of success with the technique, restoring vision to an 18-year old woman who had previously been unable to count fingers at a distance of 8 inches (20 cm). By 1869, when the pioneering Swiss ophthalmologist Johann Horner wrote a thesis entitled On the treatment of keratoconus,^[78] the disorder had acquired its current name. The treatment at that time, endorsed by the leading German ophthalmologist Albrecht von Graefe, was an attempt to physically reshape the cornea by chemical cauterization with a silver nitrate solution and application of a miosis-causing agent with a pressure dressing.^[11] In 1888 the treatment of keratoconus became one of the first practical applications of the then newly invented contact lens, when the French physician Eugène Kalt manufactured a glass scleral shell which improved vision by compressing the cornea into a more regular shape.^[79] Since the start of the twentieth century, research on keratoconus has both improved understanding of the disease and greatly expanded the range of treatment options. The first successful transplantation of cornea to treat keratoconus was done in 1936 by Ramon Castroviejo.^[80]^[81]

Related disorders

Several other non-inflammatory eye disorders, generally rarer than keratoconus, also cause thinning of the cornea:^[10]

Keratoglobus: Keratoglobus is a very rare condition that causes corneal thinning primarily at the margins, resulting in a spherical, slightly enlarged eye. It may be genetically related to keratoconus.^[14]
Pellucid Marginal Degeneration: Pellucid marginal degeneration causes thinning of a narrow (1–2 mm) band of the cornea, usually along the inferior corneal margin. It causes irregular astigmatism that can often be corrected by spectacles. Differential diagnosis may be made by slit-lamp examination.^[8]
Posterior keratoconus: Keratoconus and posterior keratoconus are distinct disorders, despite their similar names. Posterior keratoconus is a rare abnormality, usually congenital, which causes a non-progressive thinning of the inner surface of the cornea, while the curvature of the anterior surface remains normal. Normally only a single eye is affected.^[14]

References

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^ Nakagawa T, Maeda N, Kosaki R; et al. (2009). "Higher-order aberrations due to the posterior corneal surface in patients with keratoconus". Investigative Ophthalmology & Visual Science. 50 (6): 2660–5. doi:10.1167/iovs.08-2754. PMID 19029032. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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^ ^a ^b ^c ^d ^e ^f ^g Caroline P, Andre M, Kinoshita B, and Choo, J. "Etiology, Diagnosis, and Management of Keratoconus: New Thoughts and New Understandings". Pacific University College of Optometry. Retrieved 2008-12-15.{{cite web}}: CS1 maint: multiple names: authors list (link)
^ Maguire LJ, Bourne WM (1989). "Corneal topography of early keratoconus". American Journal of Ophthalmology. 108 (2): 107–12. PMID 2757091. {{cite journal}}: Unknown parameter |month= ignored (help)
^ ^a ^b Gupta D. "Keratoconus: A clinical update" (PDF). Archived from the original (PDF) on May 15, 2006. Retrieved 2006-03-26. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c ^d ^e ^f Arffa R (1997). Grayson's Diseases of the Cornea. Chap. 17. Mosby. pp. 452–454. ISBN 0-8151-3654-4. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)
^ ^a ^b ^c Brown D. National Keratoconus Foundation: Research Overview. http://www.nkcf.org. Accessed 12 Feb 2006.
^ Edwards M, McGhee CN, Dean S (2001). "The genetics of keratoconus". Clinical & Experimental Ophthalmology. 29 (6): 345–51. doi:10.1046/j.1442-9071.2001.d01-16.x. PMID 11778802. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Zadnik K, Barr JT, Edrington TB; et al. (1998). "Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study". Investigative Ophthalmology & Visual Science. 39 (13): 2537–46. PMID 9856763. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b Merin S (2005). Inherited Eye Disorders: Diagnosis and Management. Boca Raton: Taylor & Francis. ISBN 1-57444-839-0. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)
^ Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, Willoughby CE (2011). "Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract". The American Journal of Human Genetics. doi:10.1016/j.ajhg.2011.09.014. Retrieved 14/10/2011. {{cite journal}}: Check date values in: |accessdate= (help)CS1 maint: multiple names: authors list (link)
^ Rabinowitz YS (1998). "Keratoconus". Survey of Ophthalmology. 42 (4): 297–319. doi:10.1016/S0039-6257(97)00119-7. PMID 9493273.
^ Koenig SB (2008). "Bilateral recurrent self-induced keratoconus". Eye & Contact Lens. 34 (6): 343–4. doi:10.1097/ICL.0b013e31818c25eb. PMID 18997547. {{cite journal}}: Unknown parameter |month= ignored (help)
^ McMonnies CW, Boneham GC (2003). "Keratoconus, allergy, itch, eye-rubbing and hand-dominance". Clinical & Experimental Optometry. 86 (6): 376–84. doi:10.1111/j.1444-0938.2003.tb03082.x. PMID 14632614. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Bawazeer AM, Hodge WG, Lorimer B (2000). "Atopy and keratoconus: a multivariate analysis". The British Journal of Ophthalmology. 84 (8): 834–6. doi:10.1136/bjo.84.8.834. PMC 1723585. PMID 10906086. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Jafri B, Lichter H, Stulting RD (2004). "Asymmetric keratoconus attributed to eye rubbing". Cornea. 23 (6): 560–4. doi:10.1097/01.ico.0000121711.58571.8d. PMID 15256993. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Ioannidis AS, Speedwell L, Nischal KK (2005). "Unilateral keratoconus in a child with chronic and persistent eye rubbing". American Journal of Ophthalmology. 139 (2): 356–7. doi:10.1016/j.ajo.2004.07.044. PMID 15734005. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Lindsay RG, Bruce AS, Gutteridge IF (2000). "Keratoconus associated with continual eye rubbing due to punctal agenesis". Cornea. 19 (4): 567–9. doi:10.1097/00003226-200007000-00034. PMID 10928781. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ McLeod SD, Kisla TA, Caro NC, McMahon TT (2000). "Iatrogenic keratoconus: corneal ectasia following laser in situ keratomileusis for myopia". Archives of Ophthalmology. 118 (2): 282–4. PMID 10676799. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Barr JT, Wilson BS, Gordon MO; et al. (2006). "Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study". Cornea. 25 (1): 16–25. doi:10.1097/01.ico.0000164831.87593.08. PMID 16331035. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b Spoerl E, Wollensak G, Seiler T (2004). "Increased resistance of crosslinked cornea against enzymatic digestion". Current Eye Research. 29 (1): 35–40. doi:10.1080/02713680490513182. PMID 15370365. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Gondhowiardjo TD, van Haeringen NJ, Völker-Dieben HJ; et al. (1993). "Analysis of corneal aldehyde dehydrogenase patterns in pathologic corneas". Cornea. 12 (2): 146–54. doi:10.1097/00003226-199303000-00010. PMID 8500322. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Lema I, Durán JA, Ruiz C, Díez-Feijoo E, Acera A, Merayo J (2008). "Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects". Cornea. 27 (7): 758–63. doi:10.1097/ICO.0b013e31816a3591. PMID 18650659. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ "Corneal Dystrophies (including Keratoconus)". Eye Info. RNIB. Retrieved 20 January 2009.
^ Rubinstein MP, Sud S (1999). "The use of hybrid lenses in management of the irregular cornea". Contact Lens & Anterior Eye. 22 (3): 87–90. doi:10.1016/S1367-0484(99)80044-7. PMID 16303411.
^ "SoftPerm Hybrid Contact Lenses Discountinued=".
^ Davis Robert, Eiden Barry. Hybrid Contact Lens Management. Contact Lens Spectrum: [1].
^ Davis Robert. Recent Hybrid Lens Technology. TreatKerataconus: [2].
^ Yeung K, Eghbali F, Weissman BA (1995). "Clinical experience with piggyback contact lens systems on keratoconic eyes". Journal of the American Optometric Association. 66 (9): 539–43. PMID 7490414. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Pullum KW, Buckley RJ (1997). "A study of 530 patients referred for rigid gas permeable scleral contact lens assessment". Cornea. 16 (6): 612–22. PMID 9395869. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Schirmbeck T, Paula JS, Martin LF, Crósio Filho H, Romão E (2005). "[Efficacy and low cost in keratoconus treatment with rigid gas-permeable contact lens]". Arquivos Brasileiros De Oftalmologia (in Portuguese). 68 (2): 219–22. PMID 15905944.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Javadi MA, Motlagh BF, Jafarinasab MR; et al. (2005). "Outcomes of penetrating keratoplasty in keratoconus". Cornea. 24 (8): 941–6. doi:10.1097/01.ico.0000159730.45177.cd. PMID 16227837. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Mamalis N, Anderson CW, Kreisler KR, Lundergan MK, Olson RJ (1992). "Changing trends in the indications for penetrating keratoplasty". Archives of Ophthalmology. 110 (10): 1409–11. PMID 1417539. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Al-Mezaine H, Wagoner MD (2006). "Repeat penetrating keratoplasty: indications, graft survival, and visual outcome". The British Journal of Ophthalmology. 90 (3): 324–7. doi:10.1136/bjo.2005.079624. PMC 1856933. PMID 16488955. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Rubinfeld RS, Traboulsi EI, Arentsen JJ, Eagle RC (1990). "Keratoconus after penetrating keratoplasty". Ophthalmic Surgery. 21 (6): 420–2. PMID 2381677. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b Yanoff M, Duker J (2004). Ophthalmology (2nd ed.). Mosby. ISBN 0-323-01634-0. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)
^ US FDA, New Humanitarian Device Approval INTACS Prescription Inserts for Keratoconus - H040002
^ Ruckhofer J (2002). "[Clinical and histological studies on the intrastromal corneal ring segments (ICRS(R), Intacs(R))]". Klinische Monatsblätter für Augenheilkunde (in German). 219 (8): 557–74. doi:10.1055/s-2002-34421. PMID 12353173. {{cite journal}}: Unknown parameter |month= ignored (help)
^ ^a ^b Miranda D, Sartori M, Francesconi C, Allemann N, Ferrara P, Campos M (2003). "Ferrara intrastromal corneal ring segments for severe keratoconus". Journal of Refractive Surgery. 19 (6): 645–53. PMID 14640429.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Boxer Wachler, BS; Christie, JP; Chandra, NS; Chou, B; Korn, T; Nepomuceno, R (2003). "Intacs for keratoconus". Ophthalmology. 110 (5): 1031–40. doi:10.1016/S0161-6420(03)00094-0. PMID 12750109.
^ Sharma M, Boxer Wachler BS (2006). "Comparison of single-segment and double-segment Intacs for keratoconus and post-LASIK ectasia". American Journal of Ophthalmology. 141 (5): 891–5. doi:10.1016/j.ajo.2005.12.027. PMID 16546107. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Kymionis GD, Diakonis VF, Coskunseven E, Jankov M, Yoo SH, Pallikaris IG (2009). "Customized pachymetric guided epithelial debridement for corneal collagen cross linking". BMC Ophthalmology. 9: 10. doi:10.1186/1471-2415-9-10. PMC 2744909. PMID 19715585.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ http://www.nkcf.org/research/research-update/139-kxl-clinical-trials.html
^ Spoerl E, Wollensak G, Dittert DD, Seiler T (2004). "Thermomechanical behavior of collagen-cross-linked porcine cornea". Ophthalmologica. 218 (2): 136–40. doi:10.1159/000076150. PMID 15004504.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Kanellopolous, A (September 2009). "Comparison of Sequential vs Same-day Simultaneous Collagen Cross-linking and Topography-guided PRK for Treatment of Keratoconus" (PDF). Journal of Refractive Surgery.
^ Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR (2008). "A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results". Journal of Refractive Surgery. 24 (7): S720–5. PMID 18811118. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Hasson, Matt (January 25, 2008). "FDA backs launch of collagen cross-linking clinical trials". Ocular Surgery News. Retrieved 2008-02-26.
^ ^a ^b http://www.news-medical.net/news/20100317/Avedro-to-acquire-Corneal-Collagen-Crosslinking-Phase-III-study-rights-from-Peschke-Meditrade.aspx
^ http://clinicaltrials.gov/ct2/show/NCT00674661?term=avedro&rank=3
^ http://clinicaltrials.gov/ct2/show/NCT00647699?term=avedro&rank=4
^ Chan CC, Sharma M, Wachler BS (2007). "Effect of inferior-segment Intacs with and without C3-R on keratoconus". Journal of Cataract and Refractive Surgery. 33 (1): 75–80. doi:10.1016/j.jcrs.2006.09.012. PMID 17189797. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ http://bmctoday.net/crstodayeurope/pdfs/euro0310_rs_keraflex.pdf
^ http://www.modernmedicine.com/modernmedicine/ModernMedicine+Now/Thermo-biomechanical-system-gets-CE-mark/ArticleStandard/Article/detail/668958?contextCategoryId=40207&ref=25
^ Tan, D.; Por, Y-M. (July 2007). "Current treatment options for corneal ectasia". Current Opinion in Ophthalmology. 18 (4): 279–283. doi:10.1097/ICU.0b013e3281a7ecaa. PMID 17568202.
^ http://www.oteurope.com/ophthalmologytimeseurope/Cornea/Keratoconus-approach-is-promising/ArticleStandard/Article/detail/672226?contextCategoryId=33158
^ Jabbur NS, Stark WJ, Green WR (2001). "Corneal ectasia after laser-assisted in situ keratomileusis". Archives of Ophthalmology. 119 (11): 1714–6. PMID 11709027. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Colin J, Velou S (2003). "Current surgical options for keratoconus". Journal of Cataract and Refractive Surgery. 29 (2): 379–86. doi:10.1016/S0886-3350(02)01968-5. PMID 12648653. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Bergmanson JP, Farmer EJ (1999). "A return to primitive practice? Radial keratotomy revisited". Contact Lens & Anterior Eye. 22 (1): 2–10. doi:10.1016/S1367-0484(99)80024-1. PMID 16303397.
^ ^a ^b Lombardi M, Abbondanza M (1997). "Asymmetric radial keratotomy for the correction of keratoconus". Journal of Refractive Surgery. 13 (3): 302–7. PMID 9183763.
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^ Davis, L (1997). "Keratoconus: Current understanding of diagnosis and management". Clinical Eye and Vision Care. 9: 13. doi:10.1016/S0953-4431(96)00201-9.
^ ^a ^b Grewal S, Laibson PR, Cohen EJ, Rapuano CJ (1999). "Acute hydrops in the corneal ectasias: associated factors and outcomes". Transactions of the American Ophthalmological Society. 97: 187–98, discussion 198–203. PMC 1298260. PMID 10703124.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ US National Eye Institute, Facts About The Cornea and Corneal Disease Keratoconus. Accessed 12 Feb 2006.
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External links

Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study
Facts About the Cornea and Corneal Disease The National Eye Institute (NEI)
KCVision What people with keratoconus see (images)
Keratoconus Experience - Views of a Patients Eye
The Global Keratoconus Foundation
Keratoconus Australia
National Keratoconus Foundation (US)
Information from Keratoconus Self Help and Support Group (UK)
Experiences Symptoms and Progressions from patients view (PeerMade.info IN)
Nederlandstalige Lotgenoten Keratoconus (NL)
Keratoconus and Corneal Transplantation - An Educated Patient's Journey (US)

Template:Link FA Template:Link GA

[nottingham-1] Nottingham J. Practical observations on conical cornea: and on the short sight, and other defects of vision connected with it. London: J. Churchill, 1854.

[feder-2] Feder R, Kshettry P (2005). "Non-inflammatory Ectactic Disorders, Chapter 78". In Krachmer J (ed.). Cornea. Mosby. ISBN 0-323-02315-0. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)

[epstein-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Epstein A (2000). "Keratoconus and related disorders" (PDF). North Shore Contact Lens. Retrieved 2007-09-08.

[pmid17553566-4] Pantanelli S, MacRae S, Jeong TM, Yoon G (2007). "Characterizing the wave aberration in eyes with keratoconus or penetrating keratoplasty using a high-dynamic range wavefront sensor". Ophthalmology. 114 (11): 2013–21. doi:10.1016/j.ophtha.2007.01.008. PMID 17553566. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[pmid19029032-5] Nakagawa T, Maeda N, Kosaki R; et al. (2009). "Higher-order aberrations due to the posterior corneal surface in patients with keratoconus". Investigative Ophthalmology & Visual Science. 50 (6): 2660–5. doi:10.1167/iovs.08-2754. PMID 19029032. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[6] Nordan LT (1997). "Keratoconus: diagnosis and treatment". International Ophthalmology Clinics. 37 (1): 51–63. doi:10.1097/00004397-199703710-00005. PMID 9101345.

[7] Zadnik K (1997). The ocular examination : measurements and findings. Philadelphia: W.B. Saunders. ISBN 0-7216-5209-3. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)

[rabonitz-8] Rabonitz Y (2004). "Ectatic Disorders of the Cornea". In Foster C; et al. (eds.). The Cornea (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 889–911. ISBN 0-7817-4206-4. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help); Explicit use of et al. in: |editor= (help)

[Edrington-9] Edrington TB, Zadnik K, Barr JT (1995). "Keratoconus". Optometry Clinics. 4 (3): 65–73. PMID 7767020.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Krachmer-10] ^ ^a ^b ^c ^d ^e ^f Krachmer JH, Feder RS, Belin MW (1984). "Keratoconus and related noninflammatory corneal thinning disorders". Survey of Ophthalmology. 28 (4): 293–322. doi:10.1016/0039-6257(84)90094-8. PMID 6230745.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[puco-11] ^ ^a ^b ^c ^d ^e ^f ^g Caroline P, Andre M, Kinoshita B, and Choo, J. "Etiology, Diagnosis, and Management of Keratoconus: New Thoughts and New Understandings". Pacific University College of Optometry. Retrieved 2008-12-15.{{cite web}}: CS1 maint: multiple names: authors list (link)

[12] Maguire LJ, Bourne WM (1989). "Corneal topography of early keratoconus". American Journal of Ophthalmology. 108 (2): 107–12. PMID 2757091. {{cite journal}}: Unknown parameter |month= ignored (help)

[Gupta-13] Gupta D. "Keratoconus: A clinical update" (PDF). Archived from the original (PDF) on May 15, 2006. Retrieved 2006-03-26. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[grayson-14] ^ ^a ^b ^c ^d ^e ^f Arffa R (1997). Grayson's Diseases of the Cornea. Chap. 17. Mosby. pp. 452–454. ISBN 0-8151-3654-4. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)

[nkcf-15] Brown D. National Keratoconus Foundation: Research Overview. http://www.nkcf.org. Accessed 12 Feb 2006.

[16] Edwards M, McGhee CN, Dean S (2001). "The genetics of keratoconus". Clinical & Experimental Ophthalmology. 29 (6): 345–51. doi:10.1046/j.1442-9071.2001.d01-16.x. PMID 11778802. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[17] Zadnik K, Barr JT, Edrington TB; et al. (1998). "Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study". Investigative Ophthalmology & Visual Science. 39 (13): 2537–46. PMID 9856763. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Merin-18] Merin S (2005). Inherited Eye Disorders: Diagnosis and Management. Boca Raton: Taylor & Francis. ISBN 1-57444-839-0. {{cite book}}: Cite has empty unknown parameters: |coauthors= and |month= (help)

[19] Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, Willoughby CE (2011). "Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract". The American Journal of Human Genetics. doi:10.1016/j.ajhg.2011.09.014. Retrieved 14/10/2011. {{cite journal}}: Check date values in: |accessdate= (help)CS1 maint: multiple names: authors list (link)

[20] Rabinowitz YS (1998). "Keratoconus". Survey of Ophthalmology. 42 (4): 297–319. doi:10.1016/S0039-6257(97)00119-7. PMID 9493273.

[21] Koenig SB (2008). "Bilateral recurrent self-induced keratoconus". Eye & Contact Lens. 34 (6): 343–4. doi:10.1097/ICL.0b013e31818c25eb. PMID 18997547. {{cite journal}}: Unknown parameter |month= ignored (help)

[22] McMonnies CW, Boneham GC (2003). "Keratoconus, allergy, itch, eye-rubbing and hand-dominance". Clinical & Experimental Optometry. 86 (6): 376–84. doi:10.1111/j.1444-0938.2003.tb03082.x. PMID 14632614. {{cite journal}}: Unknown parameter |month= ignored (help)

[23] Bawazeer AM, Hodge WG, Lorimer B (2000). "Atopy and keratoconus: a multivariate analysis". The British Journal of Ophthalmology. 84 (8): 834–6. doi:10.1136/bjo.84.8.834. PMC 1723585. PMID 10906086. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[24] Jafri B, Lichter H, Stulting RD (2004). "Asymmetric keratoconus attributed to eye rubbing". Cornea. 23 (6): 560–4. doi:10.1097/01.ico.0000121711.58571.8d. PMID 15256993. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[25] Ioannidis AS, Speedwell L, Nischal KK (2005). "Unilateral keratoconus in a child with chronic and persistent eye rubbing". American Journal of Ophthalmology. 139 (2): 356–7. doi:10.1016/j.ajo.2004.07.044. PMID 15734005. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[26] Lindsay RG, Bruce AS, Gutteridge IF (2000). "Keratoconus associated with continual eye rubbing due to punctal agenesis". Cornea. 19 (4): 567–9. doi:10.1097/00003226-200007000-00034. PMID 10928781. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[27] McLeod SD, Kisla TA, Caro NC, McMahon TT (2000). "Iatrogenic keratoconus: corneal ectasia following laser in situ keratomileusis for myopia". Archives of Ophthalmology. 118 (2): 282–4. PMID 10676799. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[28] Barr JT, Wilson BS, Gordon MO; et al. (2006). "Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study". Cornea. 25 (1): 16–25. doi:10.1097/01.ico.0000164831.87593.08. PMID 16331035. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Spoerl1-29] Spoerl E, Wollensak G, Seiler T (2004). "Increased resistance of crosslinked cornea against enzymatic digestion". Current Eye Research. 29 (1): 35–40. doi:10.1080/02713680490513182. PMID 15370365. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[30] Gondhowiardjo TD, van Haeringen NJ, Völker-Dieben HJ; et al. (1993). "Analysis of corneal aldehyde dehydrogenase patterns in pathologic corneas". Cornea. 12 (2): 146–54. doi:10.1097/00003226-199303000-00010. PMID 8500322. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[pmid18650659-31] Lema I, Durán JA, Ruiz C, Díez-Feijoo E, Acera A, Merayo J (2008). "Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects". Cornea. 27 (7): 758–63. doi:10.1097/ICO.0b013e31816a3591. PMID 18650659. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[32] "Corneal Dystrophies (including Keratoconus)". Eye Info. RNIB. Retrieved 20 January 2009.

[33] Rubinstein MP, Sud S (1999). "The use of hybrid lenses in management of the irregular cornea". Contact Lens & Anterior Eye. 22 (3): 87–90. doi:10.1016/S1367-0484(99)80044-7. PMID 16303411.

[34] "SoftPerm Hybrid Contact Lenses Discountinued=".

[35] Davis Robert, Eiden Barry. Hybrid Contact Lens Management. Contact Lens Spectrum: [1].

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@@ Line 114: / Line 114: @@
 ==== Corneal collagen crosslinking with riboflavin ====
+{{time-context}}
 [[File:Intraoperative pachymetric-guided corneal epithelium removal during corneal collagen cross linking in patient with post-LASIK corneal ectasia and inferior corneal thinning.jpg|240px|thumb|Removed [[corneal epithelium]] during CCR operation on an eye with post-[[LASIK]] complication. From Kymionis et al., 2009.<ref name="Kymionis09">{{cite journal |author=Kymionis GD, Diakonis VF, Coskunseven E, Jankov M, Yoo SH, Pallikaris IG |title=Customized pachymetric guided epithelial debridement for corneal collagen cross linking |journal=BMC Ophthalmology |volume=9|pages=10 |year=2009 |pmid=19715585 |pmc=2744909 |doi=10.1186/1471-2415-9-10}}</ref>]]
 A treatment developed at the [[Technische Universität Dresden]], and which has shown early success is Corneal Collagen Crosslinking with Riboflavin, also known as CXL, CCR, CCL and KXL.<ref>http://www.nkcf.org/research/research-update/139-kxl-clinical-trials.html</ref> A one-time application of [[riboflavin]] solution is administered to the eye and is activated by illumination with [[UV-A]] light for approximately 30 minutes.<ref name="Spoerl1"/><ref>{{cite journal |author=Spoerl E, Wollensak G, Dittert DD, Seiler T |title=Thermomechanical behavior of collagen-cross-linked porcine cornea |journal=Ophthalmologica |volume=218 |issue=2 |pages=136–40 |year=2004 |pmid=15004504 |doi=10.1159/000076150}}</ref> The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. The corneal epithelial layer is generally removed in order to increase penetration of the riboflavin into the [[Stroma of cornea|stroma]].
-[[Clinical trial]]s are ongoing, but [[crosslinking]] is seeing increasing adoption by the ophthalmological community, and has shown success in retarding or stopping progression of the disease.<ref name="lasikmd">{{cite news | first=A | last=Kanellopolous|title= Comparison of Sequential vs Same-day Simultaneous Collagen Cross-linking and Topography-guided PRK for Treatment of Keratoconus | date=September 2009 | publisher=Journal of Refractive Surgery | url= http://www.lasikmd.com/pdf/resources/Sequential-vs-simultaneous-CXL-and-PRK-Kannelopoulos-JRS-Sept2009.pdf}}</ref> Early results from an Australian study are very promising in reporting stabilization in all treated eyes, and a slight correction in visual acuity in most patients.<ref name="cxr-results">{{cite journal |author=Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR |title=A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results |journal=Journal of Refractive Surgery |volume=24 |issue=7 |pages=S720–5 |year=2008 |month=September |pmid=18811118}}</ref> The procedure, with epithelium removed, is approved for use throughout Europe, and commenced clinical trials in the USA in 2008.<ref>
+[[Clinical trial]]s are ongoing,{{when}} but [[crosslinking]] is seeing increasing adoption by the ophthalmological community, and has shown success in retarding or stopping progression of the disease.<ref name="lasikmd">{{cite news | first=A | last=Kanellopolous|title= Comparison of Sequential vs Same-day Simultaneous Collagen Cross-linking and Topography-guided PRK for Treatment of Keratoconus | date=September 2009 | publisher=Journal of Refractive Surgery | url= http://www.lasikmd.com/pdf/resources/Sequential-vs-simultaneous-CXL-and-PRK-Kannelopoulos-JRS-Sept2009.pdf}}</ref> Early results from an Australian study are very promising in reporting stabilization in all treated eyes, and a slight correction in visual acuity in most patients.<ref name="cxr-results">{{cite journal |author=Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR |title=A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results |journal=Journal of Refractive Surgery |volume=24 |issue=7 |pages=S720–5 |year=2008 |month=September |pmid=18811118}}</ref> The procedure, with epithelium removed, is approved for use throughout Europe, and commenced clinical trials in the USA in 2008.<ref>
-{{cite web |url= http://www.osnsupersite.com/view.asp?rid=25785|title= FDA backs launch of collagen cross-linking clinical trials|accessdate=2008-02-26 |last=Hasson |first= Matt|date= January 25, 2008|work=Ocular Surgery News|publisher=}}</ref> Over 300 patients have now been treated in the United States in those trials, which are composed of two randomized, controlled, multi-site clinical trials for the treatment of progressive keratoconus and post LASIK ectasia.<ref name="news-medical.net">http://www.news-medical.net/news/20100317/Avedro-to-acquire-Corneal-Collagen-Crosslinking-Phase-III-study-rights-from-Peschke-Meditrade.aspx</ref> Avedro Inc., the trial’s sponsor,<ref>http://clinicaltrials.gov/ct2/show/NCT00674661?term=avedro&rank=3</ref><ref>http://clinicaltrials.gov/ct2/show/NCT00647699?term=avedro&rank=4</ref> is closing the follow-up phase of the study and completing the necessary steps to file the results with the FDA.<ref name="news-medical.net"/>
+{{cite web |url= http://www.osnsupersite.com/view.asp?rid=25785|title= FDA backs launch of collagen cross-linking clinical trials|accessdate=2008-02-26 |last=Hasson |first= Matt|date= January 25, 2008|work=Ocular Surgery News|publisher=}}</ref> Over 300 patients have now{{when}} been treated in the United States in those trials, which are composed of two randomized, controlled, multi-site clinical trials for the treatment of progressive keratoconus and post LASIK ectasia.<ref name="news-medical.net">http://www.news-medical.net/news/20100317/Avedro-to-acquire-Corneal-Collagen-Crosslinking-Phase-III-study-rights-from-Peschke-Meditrade.aspx</ref> Avedro Inc., the trial’s sponsor,<ref>http://clinicaltrials.gov/ct2/show/NCT00674661?term=avedro&rank=3</ref><ref>http://clinicaltrials.gov/ct2/show/NCT00647699?term=avedro&rank=4</ref> is closing{{when}} the follow-up phase of the study and completing the necessary steps to file the results with the FDA.<ref name="news-medical.net"/>
 In some cases, collagen [[crosslinking]] may also be combined with other treatments to improve corneal asymmetry or optical refraction.  Successful treatment methods include corneal ring segment inserts (INTACS or Ferrara Rings),<ref>{{cite journal |author=Chan CC, Sharma M, Wachler BS |title=Effect of inferior-segment Intacs with and without C3-R on keratoconus |journal=Journal of Cataract and Refractive Surgery |volume=33 |issue=1 |pages=75–80 |year=2007 |month=January |pmid=17189797 |doi=10.1016/j.jcrs.2006.09.012}}</ref> Topography Guided Laser <ref name="lasikmd" /> or Keraflex.<ref>http://bmctoday.net/crstodayeurope/pdfs/euro0310_rs_keraflex.pdf</ref><ref>http://www.modernmedicine.com/modernmedicine/ModernMedicine+Now/Thermo-biomechanical-system-gets-CE-mark/ArticleStandard/Article/detail/668958?contextCategoryId=40207&ref=25</ref> Corrective lenses are normally required after these treatments but with smaller, more normalised prescriptions. Increased corneal symmetry allows for more comfortable contact lens wear, often of daily disposable lenses. These newer methods may have an important role in limiting deterioration of vision, increasing unaided/uncorrected vision and reducing the case for corneal transplantation.<ref>{{Cite journal