Keratoconus

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Keratoconus
The "conical cornea" that is characteristic of keratoconus
ICD-10 H18.6
ICD-9 371.6
OMIM 148300
DiseasesDB 7158
MedlinePlus 001013
eMedicine oph/104 

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]


Overview

Keratoconus (from Greek: kerato- horn, cornea; and konos cone), is a degenerative non-inflammatory 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. Keratoconus is the most common dystrophy of the cornea, affecting around one person in a thousand, and it seems to occur in populations throughout the world, although some ethnic groups experience a greater prevalence than others. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties.

Keratoconus is a little-understood disease with an uncertain cause, and its progression following diagnosis is unpredictable. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. In most cases, corrective lenses are effective enough to allow the patient to continue to drive legally and likewise function normally. Further progression of the disease may require surgery including transplantation of the cornea. Despite its uncertainties, keratoconus can be successfully managed with a variety of clinical and surgical techniques, and often with little or no impairment to the patient's quality of life.

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,[1] 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.[1] 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.[2] 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.[3] 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,[4] the disorder had acquired its current name. The treatment at that time, endorsed by the leading German ophthalmologist Albrecht von Gräfe, 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.[1] 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.[5] 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.

Features

Symptoms

A simulation of the multiple images seen by a person with keratoconus.
"... a candle, when looked at, appears like a number of lights, confusedly running into one another" — Nottingham[2]

People with early keratoconus typically notice a minor blurring of their vision and come to their clinician seeking corrective lenses for reading or driving.[6][7] 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. Some develop photophobia (sensitivity to bright light), eye strain from squinting in order to read, or itching in the eye.[6] There is however 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.

Signs and diagnosis

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,[8] with detection of irregular astigmatism suggesting a possibility of keratoconus. Severe cases can exceed the instrument's measuring ability.[7] 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.[9][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.[10] 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.[11] 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.[7] Similarly, around 50% of subjects exhibit Vogt's striae, fine stress lines within the cornea caused by stretching and thinning.[11] The striae temporarily disappear while slight pressure is applied to the eyeball.[7] 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.[6] Other clinical signs of keratoconus will normally have presented themselves long before Munson's sign becomes apparent,[12] and so this finding, though a classic sign of the disease, tends not to be of primary diagnostic importance.

Corneal topogram of a keratoconic eye

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.[1] 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.[13]

Once keratoconus has been diagnosed, its degree may be classified by several metrics:[14]

  • 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.[14]

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,[15][16] but some reports place the figure as high as 1 in 500.[17] The inconsistency may be due to variations in diagnostic criteria,[7] with some cases of severe astigmatism interpreted as those of keratoconus, and vice versa.[12] A long-term study found a mean incidence rate of 2.0 new cases per 100,000 population per year.[16] It is suggested that males and females, and all ethnicities appear equally susceptible, though some recent studies have cast doubt upon this,[18] suggesting a higher prevalence amongst females; the literature however varying as to its extent. Also, a study carried out in the UK[19] suggests that people of an 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[16] (affecting both eyes) although the distortion is usually asymmetric and is rarely completely identical in both corneas.[7] 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.[12] 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.

Prognosis

Patients with keratoconus typically present initially with mild astigmatism, commonly at the onset of puberty, and are diagnosed as having the disease by the late teenage years or early 20s. In rare cases keratoconus can occur in children or not present until later adulthood.[7] A diagnosis of the disease at an early age may indicate a greater risk of severity in later life.[1][20] 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 become 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. Most commonly, keratoconus progresses for a period of ten to twenty years[12] before the course of the disease generally ceases.

Corneal hydrops

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.[21] 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.[21] Very occasionally, in extreme cases, the cornea thins to the point that a partial rupture occurs, resulting in a small, bead-like swelling on the cornea that has been filled with fluid. When this occurs, a corneal transplant can become urgently necessary to avoid complete rupture and resulting loss of the eye.[21]

Pathophysiology and cause

Despite considerable research, the etiology of keratoconus remains somewhat of a mystery.[1] A number of 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.[22][23] Once initiated, the disease normally develops by progressive dissolution of Bowman's layer,[7] 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.[24]

A number of studies have indicated that keratoconic corneas show signs of increased activity by proteases,[22] a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors.[25] 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.[26] 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.

A genetic predisposition to keratoconus has been observed,[27] with the disease running in certain families,[28] and incidences reported of concordance in identical twins.[10] 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,[1] and studies have obtained estimates ranging between 6% and 19%.[29] A responsible gene has not been identified: two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q.[29] However, most genetic studies agree on an autosomal dominant model of inheritance.[6] Keratoconus is also diagnosed more often in people with Down syndrome, though the reasons for this link have not yet been determined.[30] 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 may contribute to the progression of keratoconus, and that patients should be discouraged from the practice.[31][32][33][34][35]

Treatment

Contact lenses

Main article: Contact lens

In early stages of keratoconus, spectacles can suffice to correct for the mild astigmatism. As the condition progresses, spectacles may no longer provide the patient with a satisfactory degree of visual acuity, and most clinical practitioners will move to managing the condition with contact lenses.

Rigid gas permeable lens for keratoconus

In keratoconic patients, 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[22] and the fitter will endeavour to produce a lens with the optimal contact, stability and steepness. Some trial-and-error fitting may prove necessary.[12]

Traditionally, contact lenses for keratoconus have been the 'hard' or rigid gas-permeable variety, although manufacturers have also produced specialized 'soft' or hydrophilic 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. Soft or hybrid lenses do not however prove effective for every patient.[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

Main article: Cornea transplant
Corneal transplant for keratoconus, approximately 1 week after surgery. Multiple light reflections indicate folds in the cornea which later resolved.

Between 10% and 25% of cases of keratoconus[23][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.[23] 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 a require 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.

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 is retained, giving some additional structural integrity to the post-graft cornea.[44] Because a graft rejection usually begins in the endothelium, the chance of a rejection episode is greatly reduced. 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.[44]

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.[22] 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. It may however be seen as an option in a number of cases, particularly for young patients.[45]

Corneal ring segment inserts

Main article: Intrastromal corneal ring segments
A pair of Intacs 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.[46] 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.[46]

The two principal types of intrastromal rings available are known by the trade names of Intacs and Ferrara rings. Intacs are flatter and less centrally placed than the prismatic Ferrara rings. Intacs 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.[47] Ferrara rings await FDA approval for keratoconus. A development on the concept involves the injection of a transparent synthetic gel into a channel bored through the stroma. As the gel polymerises, it stiffens and takes on similar properties to the pre-formed rings.[48]

Clinical studies on the effectiveness of intrastromal rings on keratoconus are in their early stages, and results have so far been generally encouraging,[49][50] 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.[50] 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.[51] 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.[52]

Radial keratotomy

Main article: 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.[53]

For similar reasons, radial keratotomy has also generally not been used for keratoconic patients.[54][55] However, an Italian clinic has reported some success with a modified asymmetric radial keratotomy procedure,[56] 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.[56]

Corneal Collagen Crosslinking with Riboflavin (C3-R)

A innovative treatment which has shown early success is Corneal Collagen Crosslinking with Riboflavin (C3-R), which involves a one-time application of riboflavin eye drops to the eye.[25][57] The riboflavin, when activated by approximately 30 minutes illumination with UV-A light, augments the collagen cross-links within the stroma and so recovers some of the cornea's mechanical strength. C3-R, developed at the Technische Universität Dresden and the Boxer Wachler Vision Institute[58], has been shown to slow or arrest the progression of keratoconus, and in some cases even reverse it, particularly when applied in combination with intracorneal ring segments. A recent study showed that when C3-R was combined with Intacs, twice as much improvement occurred compared to Intacs alone.[59]

Clinical trials are continuing, and while relatively few procedures have been performed, the technique is showing promise in treating early cases of the disease.[60] Corrective lenses may still be required after the treatment but it is hoped that it could limit further deterioration in the patient's vision and reduce the case for keratoplasty.

Related disorders

Several other non-inflammatory eye disorders, generally rarer than keratoconus, also cause thinning of the cornea:[12]

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.[22]
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.[10]
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.[22]

See also

References

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  2. ↑ 2.0 2.1 Nottingham J. Practical observations on conical cornea: and on the short sight, and other defects of vision connected with it. London: J. Churchill, 1854.
  3. ↑ Bowman W, On conical cornea and its treatment by operation. Ophthalmic Hosp Rep and J R Lond Ophthalmic Hosp. 1859;9:157.
  4. ↑ Horner JF, Zur Behandlung des Keratoconus. Klinische Monatsblätter für Augenheilkunde. 1869.
  5. ↑ Kalt E, reported by Panas P, translated by Pearson R. Kalt, keratoconus and the contact lens. (1888). Bull Aced Med, 19, 400 Optom Vis Sci; (1989) 66, 643 PMID 2677884
  6. ↑ 6.0 6.1 6.2 6.3 Feder R, Kshettry P (2005). "Non-inflammatory Ectactic Disorders, Chapter 78". In Krachmer J. Cornea. Mosby. ISBN 0-3230-2315-0.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Epstein A (2000). "Keratoconus and related disorders" (PDF). North Shore Contact Lens. Retrieved 2007-09-08.
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  10. ↑ 10.0 10.1 10.2 Rabonitz Y (2004). "Ectatic Disorders of the Cornea". In Foster C; et al. The Cornea (4th Ed. ed.). pp. pp889&ndash, 911. ISBN 0-7817-4206-4.
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  20. ↑ Davis LJ. Keratoconus: Current understanding of diagnosis and management. Clin Eye Vis Care 9(I): 13–22, 1997.doi:10.1016/S0953-4431(96)00201-9
  21. ↑ 21.0 21.1 21.2 Grewal S, Laibson PR, Cohen EJ, Rapuano CJ. Acute hydrops in the corneal ectasias: associated factors and outcomes. Trans Am Ophthalmol Soc. 1999;97:187–98; PMID 10703124
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 Arffa R (1997). Grayson's Diseases of the Cornea. Chap. 17. Mosby. pp. 452&ndash, 454. ISBN 0-8151-3654-4.
  23. ↑ 23.0 23.1 23.2 Brown D. National Keratoconus Foundation: Research Overview. http://www.nkcf.org. Accessed 12 Feb 2006.
  24. ↑ Barr JT, Wilson BS, Gordon MO, Rah MJ, Riley C, Kollbaum PS, Zadnik K; CLEK Study Group. Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. Cornea. 2006 Jan;25(1):16–25. PMID 16331035
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  32. ↑ Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol. 2000 Aug;84(8):834-6. PMID 10906086
  33. ↑ Jafri B, Lichter H, Stulting RD. Asymmetric keratoconus attributed to eye rubbing. Cornea. 2004 Aug;23(6):560-4. PMID 15256993
  34. ↑ Ioannidis AS, Speedwell L, Nischal KK. Unilateral keratoconus in a child with chronic and persistent eye rubbing. Am J Ophthalmol. 2005 Feb;139(2):356-7. PMID 15734005
  35. ↑ Lindsay RG, Bruce AS, Gutteridge IF. Keratoconus associated with continual eye rubbing due to punctal agenesis. Cornea. 2000 Jul;19(4):567-9. PMID 10928781
  36. ↑ Rubinstein MP, Sud S. The use of hybrid lenses in management of the irregular cornea. Cont Lens Anterior Eye. 1999;22(3):87–90. PMID 16303411
  37. ↑ Yeung K, Eghbali F, Weissman BA. "Clinical experience with piggyback contact lens systems on keratoconic eyes." J Am Optom Assoc. 1995 Sep;66(9):539-43. PMID 7490414.
  38. ↑ Pullum KW, Buckley RJ. A study of 530 patients referred for rigid gas permeable scleral contact lens assessment. Cornea. 1997 Nov;16(6):612-22. PMID 9395869
  39. ↑ Schirmbeck T, Paula JS, Martin LF, Crosio Filho H, Romao E. Efficacy and low cost in keratoconus treatment with rigid gas-permeable contact lens. Arq Bras Oftalmol. 2005 Mar-Apr;68(2):219-22. Epub 2005 May 18. PMID 15905944
  40. ↑ 40.0 40.1 Javadi MA, Motlagh BF, Jafarinasab MR, Rabbanikhah Z, Anissian A, Souri H, Yazdani S. Outcomes of penetrating keratoplasty in keratoconus. Cornea. 2005 Nov;24(8):941-6. PMID 16227837
  41. ↑ Mamalis N, Anderson CW, Kreisler KR, Lundergan MK, Olson RJ. Changing trends in the indications for penetrating keratoplasty. Arch Ophthalmol. 1992 Oct;110(10):1409–11. PMID 1417539
  42. ↑ Al-Mezaine H, Wagoner MD. Repeat penetrating keratoplasty: indications, graft survival, and visual outcome. Br J Ophthalmol. 2006 Mar;90(3):324-7. PMID 16488955
  43. ↑ Rubinfeld RS, Traboulsi EI, Arentsen JJ, Eagle RC Jr. Keratoconus after penetrating keratoplasty. Ophthalmic Surg. 1990 Jun;21(6):420-2. PMID 2381677
  44. ↑ 44.0 44.1 Sugita, Juntaru (1997), Advances in Corneal Research: Selected Transactions of the World Congress on the Cornea, IV, pp. pp163&ndash, 166
  45. ↑ Wagoner MD, Smith SD, Rademaker WJ, Mahmood MA. Penetrating keratoplasty vs. epikeratoplasty for the surgical treatment of keratoconus. J Refract Surg. 2001 Mar-Apr;17(2):138-46. PMID 11310764
  46. ↑ 46.0 46.1 Yanoff M, Duker J (2004). Ophthalmology (2nd Ed. ed.). Mosby. ISBN 0-323-01634-0.
  47. ↑ US FDA, New Humanitarian Device Approval INTACS® Prescription Inserts for Keratoconus - H040002
  48. ↑ Simon G, Parel JM, Lee W, Kervick GN. Gel injection adjustable keratoplasty. Graefes Arch Clin Exp Ophthalmol. 1991;229(5):418-24. PMID 1718824
  49. ↑ Ruckhofer J. Clinical and histological studies on the intrastromal corneal ring segments (ICRS®, Intacs®) Klin Monatsbl Augenheilkd. 2002 Aug;219(8):555-6. PMID 12353173
  50. ↑ 50.0 50.1 Miranda D, Sartori M, Francesconi C, Allemann N, Ferrara P, Campos M. Ferrara intrastromal corneal ring segments for severe keratoconus. J Refract Surg. 2003 Nov-Dec;19(6):645-53. PMID 14640429
  51. ↑ Boxer Wachler BS, Christie JP, Chandra NS, Chou B, Korn T, Nepomuceno R. Intacs for keratoconus. Ophthalmology 2003 May;110(5):1031-40. PMID: 12750109
  52. ↑ Sharma M, Boxer Wachler BS. Comparison of single-segment and double-segment Intacs for keratoconus and post-LASIK ectasia. Am J Ophthalmol. 2006 May;141(5):891-5. PMID 16546107
  53. ↑ Jabbur N.S., Stark W.J., Green W.R. Corneal ectasia after laser-assisted in situ keratomileusis. Arch. Ophthal. 119: 1714–1716, 2001. PMID 11709027
  54. ↑ Colin J, Velou S. Current surgical options for keratoconus., J Cataract Refract Surg. 2003 Feb;29(2):379-86. PMID 12648653
  55. ↑ Bergmanson JP, Farmer EJ. A return to primitive practice? Radial keratotomy revisited. Cont Lens Anterior Eye. 1999;22(1):2–10. PMID 16303397
  56. ↑ 56.0 56.1 Lombardi M, Abbondanza M Asymmetric radial keratotomy for the correction of keratoconus. J Refract Surg. 1997 May-Jun;13(3):302-7. PMID 9183763
  57. ↑ Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica. 2004 Mar-Apr;218(2):136-40. PMID 15004504
  58. ↑ Chan CCK, Sharma M, Boxer Wachler BS. The effect of inferior segment Intacs with and without corneal collagen crosslinking with riboflavin (C3-R) on keratoconus. J Cataract Refract Surg 2007;33:75-80. PMID 17189797
  59. ↑ Chan CCK, Sharma M, Boxer Wachler BS. The effect of inferior segment Intacs with and without corneal collagen crosslinking with riboflavin (C3-R) on keratoconus. J Cataract Refract Surg 2007;33:75-80. PMID 17189797
  60. ↑ Guttman, C (Nov 1, 2005). "Early keratoconus responds to corneal cross-linking: Italian study shows significant improvement in UCVA, BSCVA". Ophthalmology Times.

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