Keratoconus (KC) is a progressive, non inflammatory, bilateral (but usually asymmetrical) ectatic corneal disease, characterized by paraxial stromal thinning and weakening that leads to corneal surface distortion (Figure 1). As cornea is the part of the eye responsible for refraction of most of the light entering, the distortion of its shape ultimately leads to distorting vision. In addition vision may also be impaired as a result of swelling and scarring of corneal tissue. Keratoconus usually occurs in the second decade of life and affects both genders and all ethnicities. The estimated prevalence in the general population is 54 per 100,000. 1

Figure 1: Keratoconus

Ocular signs and symptoms of keratoconus vary depending on disease severity. Early forms normally go unnoticed unless corneal topography is performed. Disease progression is manifested with a loss of visual acuity which cannot be compensated for with spectacles. Classification of keratoconus is based on morphology, disease evolution; ocular signs and index based systems. 1 Management varies depending on disease severity. Incipient cases are managed with spectacles, mild to moderate cases with contact lenses and severe cases can be treated with Keratoplasty. 1

The term “Keratoconus” derives from the Greek words Kerato (cornea) and Konos (cone). 1,2 Early reference to keratoconus was made by Mauchart in 1748 and by Taylor in 1766, but the condition was first adequately described and distinguished from other corneal ectasia by British physician John Nottingham in 1854. 2,3 Nottingham in his classical treatise on keratoconus mentioned that “... a candle, when looked at, appears like a number of lights, confusedly running into one another”. 2,3 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. By 1869, when the pioneering Swiss ophthalmologist Johann Horner wrote a thesis entitled “ On the treatment of keratoconus” , the disorder had acquired its current name. 2 The treatment of keratoconus at that time consisted of cauterizing the conical area with silver nitrate and the instillation of miotics accompanied by a pressure dressing. In the early months of 1888, a French ophthalmologist, Eugene Kalt, began work on a crude glass shell designed to “compress the steep conical apex thereby correcting the condition.” This was the first known application of a contact lens for the correction of keratoconus (Figure 2).

Figure 2: Eugene Kalt, MD, first to propose the use of a contact lens for keratoconus

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. 2

Keratoconus occurs with approximately equal gender distribution in every region and every ethnicity throughout the world. Many studies have been conducted to estimate the incidence and prevalence of the condition, and, although the incidence varies somewhat from country to country, a 1986 population-based study in the US indicated that approximately 5 in 10,000 people have keratoconus. Studies from various other areas of the world have reported prevalence from a high of 1 in 250 to 1 in 2000 population. 3 The prevalence in India would vary from 1 in 2000 to 1 in 4000 population. 3 An early onset and increased severity of keratoconus was found in recent studies in ethnic (Asian) groups. This may be related to a combination of genetic and/or environmental factors. However it also indicates that in non-western countries the prevalence of Keratoconus could be much higher (4.4 times). 3

Several factors can predispose to developing keratoconus, including:

• Wearing ill-fitting hard contact lenses: If the contact lenses haven't been fitted properly, the constant pressure or continual injury they cause can lead to keratoconus.
• Certain inherited diseases: The risk of developing keratoconus is higher in case an individual has certain conditions, such as Down syndrome or certain retinal diseases.
• Family history of keratoconus: Most people with keratoconus have no family history of the disease, but researchers have found that in some cases there may be a family connection.

The exact etiology of keratoconus is unknown and it is most likely multifactorial.

1. Several studies have reported a strong association between eye rubbing and the development of keratoconus. This association may be due to the activation of wound healing processes and signaling pathways secondary to mechanical epithelial trauma and also direct rubbing-related mechanical trauma to the keratocytes and increased hydrostatic pressure in the eye. 5
2. Contact lens wear is another form of corneal micro trauma associated with keratoconus. 5
3. Genetics: Inheritance is also associated with keratoconus. Between 6%-18% of patients with keratoconus have a history of familial disease, several studies suggest that KC is a complex genetic disease. 6

Family, twins and genetic studies have been conducted in an attempt to further understand the genetic nature of keratoconus:

I] Family studies : Studies carried out before corneal topography techniques became commercially available reported that 6–8% of subjects with keratoconus had close relatives affected by the disease. 1 However, studies assisted by corneal topography have shown that up to 50% of subjects with keratoconus have at least one close relative affected by the disease. A recent study estimated that relatives of keratoconics have a risk 15–67 times higher of developing keratoconus than those who do not have relatives with keratoconus. 7 An autosomal dominant mode of inheritance with variable expression has been suggested.

II] Twin studies: Till date 19 pairs of monozygotic twins affected with keratoconus have been described. In most cases, both twins were affected, although with different or similar levels of severity, which suggests a strong genetic component of disease development, perhaps also combined with environmental factors.

Other studies have assessed the mode of transmission in keratoconus disease. A study in an 18-year-old monozygotic keratoconus twin, their 8-year-old sister and parents, who have not been diagnosed with keratoconus, suggests the possibility of a recessive mode of inheritance, although it is possible the sister could develop the disease over time. 8

III] Genetic analyses: Linkage studies carried out in families affected with keratoconus to identify the genetic regions (Loci) have reported genetic susceptibility to the disease. Héon et al. identified four mutations of the VSX1 gene (i.e., R166W, L159M, D144E and H244R) in different keratoconics patients. 9 Bisceglia et al. also found four mutations of the VSX1 gene (i.e., D144R, G160D, P247R and L17P) in 7 out of 80 keratoconus subjects assessed. 10

4. Apart from the above mentioned causes, several biochemical theories for keratoconus development have also been proposed to support the hypothesis that corneal thinning occurs as a result of the loss of corneal structural components. Määttä et al. found differences in collagen types XIII, XV and XVIII between normal and keratoconic corneas, leading to the suggestion that these differences might play an active role in the wound healing process observed between normal and keratoconics corneas. 1 The excessive degradation of the corneal stroma commonly observed in keratoconus might be the result of proteolytic enzyme activity that can be initiated by an increased level of proteases and other catabolic enzymes, or decreased levels of proteinase inhibitors such as a2-macroglobulin and a1-antiprotease. It has also been found that keratocytes in keratoconus have four times greater numbers of Interleukin-1 receptors compared to normal subjects.

Proinflammatory markers Interleukin-6, ICAM-1 and VCAM-1 are over expressed by 2–40 times, whereas anti-inflammatory marker Interleukin-10 is under expressed by 8 times in keratoconic patients who wear contact lenses compared to normal myopic subjects. 11 This suggests that contact lens wear might be a precursor for ectasia development. Interleukin- 6 cytokine is over expressed in early forms of keratoconus, which supports the development of chronic inflammatory events in the pathogenesis cascade of the disease.

5. The Environment and Keratoconus: Although it is generally believed that keratoconus has a genetic component, there are increasing data that suggest the environment might also play a role in the development of the condition. Research has discovered that corneas with keratoconus have been exposed to a number of factors that can produce reactive oxygen species (i.e., free radicals). These include ultraviolet light, atopy, mechanical eye rubbing, and poorly fitted contact lenses. They propose that susceptible corneas exhibit an inability to process reactive oxygen species because they lack the necessary protective enzymes (e.g., ALDH3 and superoxide dismutase). The reactive oxygen species result in an accumulation of toxic byproducts such as MDA and peroxynitrites that can damage corneal proteins and trigger a cascade of events that disrupt the cornea's cellular structure and function (Figure 3).

Figure 3: Oxidative damage resulting in Keratoconus

This can result in corneal thinning, scarring, and apoptosis (Figure 4).

Figure 4: Reactive oxygen species within the keratoconus cornea result in an accumulation of toxic by-products that can trigger cornea thinning, scarring, and apoptosis .

Protective steps to reduce oxidative damage and potentially prevent keratoconic development include: (1) the use of ultraviolet filters; (2) improvement of ocular comfort with the use of non steroidal anti-inflammatory medications; (3) the use of preservative-free artificial tears and allergy medications and; (4) improved contact lens fit to minimize corneal micro trauma.

Keratoconus can involve each layer of the cornea. The corneal epithelial cells may be enlarged and elongated. Early degeneration of basal epithelial cells can be followed by disruption of the basement membrane. This disruption results in the growth of epithelium posterior to the Bowman's layer and collagen anterior to the epithelium, forming typical Z-shaped interruptions or breaks in the Bowman's layer. Scarring of the Bowman's layer and the anterior stroma are common and present histopathologically with collagen fragmentation, fibrillation and fibroblastic activity. The stroma has normal-sized collagen fibers but low numbers of collagen lamellae, which results in stromal thinning. Endothelial cell pleomorphism and polymegathism may also be manifested. With increasing severity and duration increase, greater change and damage occurs at the base of the cone than at the apex.

Symptoms

Keratoconus often manifests during the late teens or early twenties, then progresses slowly for the next decade or two as the cornea scars and becomes more elongated. 5, 12 Patients with keratoconus complain of progressive visual blur and distortion secondary to myopia and high astigmatism. Photophobia, glare and monocular diplopia are also presenting symptoms. (Figure 5A, B, C and D) 5, 12

Figure 5A: Visual blur and distortion, 5B: Photophobia, 5C: glare, 5D: monocular diplopia

Signs:
Disease progression is manifested by a significant loss of visual acuity which cannot be compensated for with spectacles. A scissors reflex during retinoscopy is a very early sign. 1, 5 The Charleux oil drops that is observed by backlighting the mydriatic pupil also poses a warning sign. 1, 5 Corneal thinning, where the thinnest part of the cornea is normally located outside the visual axis, is also a common sign preceding ectasia.

In moderate and advance cases of keratoconus, a hemosiderin arc or circle line, commonly known as Fleischer's ring, is frequently seen around the cone base. 1,6,13,14 This line has been suggested to be an accumulation of iron deposits from the tear film onto the cornea as a result of severe corneal curvature changes induced by the disease and/or due to modification of the normal epithelial slide process (Figure 6).

Figure 6: Fleisher's ring (black arrows) is evident on the surface of the cornea

Another characteristic sign is the presence of Vogt's striae ( Figure 7 ), which are fine vertical lines produced by compression of Descemet's membrane, which tend to disappear when physical pressure is exerted on the cornea digitally or by gas permeable contact lens wear. 1,5,13

Figure 7: Vogt's Striae sign. Vertical lines in Descemet's membrane are noted.

The increased visibility of corneal nerves (Figure 8) and observation of superficial and deep corneal opacities (Figure 9) are also common signs, which can be present at different severity stages of the disease. 1,5,13

Figure 8: Increased visibility of corneal nerves in a keratoconus

Figure 9: Significant corneal scarring induced by contact lens wear

Munson's sign, (Figure 10) a V-shape deformation of the lower eyelid when the eye is in downward position, and Rizzuti's sign, (Figure 11) a bright reflection of the nasal area of the limbus when light is directed to the temporal limbal area, are signs frequently observed in advanced stages. 1,5,13 Breaks in Descemet's membrane have been described in severe keratoconus, causing acute stromal oedema, known as Hydrops, (Figure 12) sudden vision loss and significant pain. 1,5,13

Figure 10: Munson's sign

Figure 11: Rizzuti's sign

Figure 12: Hydrops in Keratoconus

Keratoconus is classified based on morphology, disease evolution, ocular signs and index-based systems.

I] Morphology: Classically, keratoconus has been classified into:

Nipple- the cone has a diameter ≤ 5mm, round morphology and is located in the central or paracentral cornea, more commonly in the infero-nasal corneal quadrant. Correction with contact lenses is normally relatively easy.

Oval- The cone has a diameter > 5mm and a paracentral to peripheral location, more commonly in the infero-temporal corneal quadrant. Contact lens correction is more difficult.

Keratoglobus - The cone is located throughout 75% of the cornea. Contact lens correction is a difficult challenge, except in very limited cases.

II] Disease evolution
The first keratoconus classification based on disease evolution was proposed by Amsler, who classified the disease in four different severity stages, similar to that reported by Hom and Bruce (Table 1).

Table 1: Keratoconus classification based on disease evolution

VA, visual acuity; D, diopters

STAGE	DESCRIPTION
1	Fruste or subclinical form; diagnosed by corneal topography; ~ 6/6VA achievable with spectacle correction.
2	Early form; mild corneal thinning; corneal scarring absent.
3	Moderate form; corneal scarring and opacities absent; Vogt's striae; Fleischer's ring; <6/6VA with spectacle correction, but ~ 6/6VA with contact lens correction; irregular astigmatism between 2.00–8.00 D; significant corneal thinning.
4	Severe form; corneal steepening >55.00 D; corneal scarring, <6/7.5VA with contact lens correction; severe corneal thinning and Munson's sign.

III] Index-based systems
Disease detection, even at early stages, has become increasingly important particularly in an attempt to prevent iatrogenic ectasia formation – the lost of corneal shape – which has been widely documented in patients with subclinical forms of keratoconus who have undergone refractive surgery procedures. For this reason, several index-based classification methods build on corneal topography systems for grading the severity of keratoconus have been developed (Table 2). 1

Table 2: Index-based systems for keratoconus detection

(A higher value than the point of cut value suggests the presence of keratoconus)  

Author	Index	Point of cut	Description
Rabinowitz/Mc Donnel	K Value   I-S Value	47.2   1.4	Diagnosis is performed based on the central keratometry and the inferior–superior asymmetry in keratometric power
Maeda/Klyce	KPI   KCI%	0.23   0%	KPI is derived from eight quantitative videokeratography indexes. KCI% is derived from KPI and other four indexes.
Smolek/Klyce	KSI	0.25	Keratoconus detection and the level of severity is assessed using an artificial intelligent system.
Schwiegerling/Greivenkamp	Z3	0.00233	Diagnosis is performed based in videokeratoscopic height data decomposed into orthogonal Zernike polynomials.
Rabinowitz/Rasheed	KISA%	100%	Diagnosis is derived from K value, I-S value, AST and SRAX.
Mc Mahon et al.	KSS	0.5	Diagnosis is performed based on slit-lamp findings, corneal topography, corneal power and higher order first corneal surface wavefront root mean square error.
Mahmoud et al.	CLMI	>0.45	Diagnosis based in detecting the presence or absence of keratoconic patterns and determining the location and magnitude of the curvature of the cone.

Recently, two relatively new optical instruments for assessing different characteristics of the anterior eye have included built-in software for the detection and monitoring of keratoconus disease: the Pentacam and the Ocular Response Analyzer.

The Pentacam instrument, which is based on the Scheimpflug working principle, takes 12–50 images of the cornea at different angles using a rotating camera (Fig. 13). This method evaluates disease severity and progression based on changes in corneal volume and anterior chamber angle, depth and volume. The Ocular Response Analyzer allows keratoconus diagnosis and classification by assessing corneal hysteresis and resistance.

Figure 13: Scheimpflug image in severe keratoconus

Significant corneal thinning is appreciated in the central cornea

Histopathology 1, 13

The hallmark of keratoconus is thinning of the central stroma (Figure 14). Changes in focal disruptions of the epithelial basement membrane and Bowman's layer are initial indicators of keratoconus.

Figure 14: Thinning Of the Central Stroma (Arrows)

A bisected cornea is shown in figure 15. The Prussian blue stain (Perls test) detects iron depositions in the basal epithelial layers (Figure 16).

Figure 15: A bisected cornea is taken at the dissecting microscope with the cornea placed on edge. Here a brown ring called Fleisher's ring (black arrows). At the very edge of the specimen (black arrow 1) the brown (oxidized iron) can be seen deposited within the epithelium. The white arrows show Descemet's membrane; the central cornea (left side of photo) is thinner than the peripheral portion of the cornea.

The earliest abnormalities of keratoconus (Figure 17) occur in the epithelial basement membrane and Bowman's layer. The basement membrane may be disrupted (arrow 6) and duplicated. Bowman's layer (arrow 3) is disrupted (arrow 4) and fibrous tissue is interposed between the epithelial basement membrane and Bowman' layer (arrows 5). There is also stromal scarring. The endothelium is not significantly attenuated and the Descemet's membrane is thin (the patient is young).

Figure 17: The earliest abnormalities of keratoconus

Laboratory Studies 14

• No laboratory workup is necessary in keratoconus (KC).
• Careful refraction, keratometry, videokeratography, and slit lamp biomicroscopy and rigid gas permeable (GP) contact lens application allows detection of keratoconus.

 Imaging Studies 13, 14

• Corneal Topography: Corneal topography is a very useful aid in the diagnosis of keratoconus, especially in the absence of clinical signs. Caution, must, however, still be exercised as dry-eyed patients with aqueous tear deficiency and chronic drying of the ocular surface can exhibit changes similar to those seen in keratoconus; that is, inferior corneal steepening and high astigmatism.
• Computer-assisted videokeratography and diagnostic use of rigid contact lenses (CLs) are sometimes required, especially when the typical biomicroscopy signs of Vogt striae and Fleischer ring are absent. Several quantitative indices are available using computer-assisted videokeratography information to screen for keratoconic corneal shape factors. The two most commonly known indices are those of Rabinowitz and Maeda/Klyce (Refer to Table 2).
• The Rabinowitz diagnostic criterion consists of 3 videokeratography derived indices, which, when abnormal in value, indicates keratoconus. These indices are as follows:
  • K value quantifies the central steepening of the cornea that occurs in keratoconus. A value of 47.20 D or greater is suggestive of keratoconus.
  • I-S value quantifies the inferior versus superior corneal dioptric asymmetry that occurs in keratoconus. A value of 1.4 D or greater is suggestive of keratoconus.
  • KISA% incorporates the K and I-S values with a measure quantifying regular and irregular astigmatism into one index. This index is highly sensitive and specific in separating normal from keratoconic corneas. A value of greater than 100% is highly suggestive of frank keratoconus, and the range from 60-100% represents keratoconus suspects.
• On the other hand, Maeda et al designed an alternative computer expert program, based on linear discriminant analysis of 8 indices drawn from the corneal map and a binary decision tree. The program assigns the topographical map a quantitative percentage score of the severity of keratoconus called the KCI%. A value of greater than zero is believed to be suggestive of keratoconus.
• Studies of corneal optics by wavefront analysis also suggest keratoconus induces higher order abberations (root mean square [RMS]), especially coma (figure 18).

Figure 18: Coma

•  Procedures

• Keratometry
• Images of the keratometry mires are commonly steep, highly astigmatic, irregular, and often appear egg-shaped (rather than circular or oval) in keratoconus.
• Some patients with keratoconus do not exhibit these signs.
• Videokeratography
• This commonly shows inferior corneal steepening in keratoconus, although a small percentage of patients with keratoconus show central astigmatic changes.
• An even smaller number show superior peripheral steepening. Pellucid marginal degeneration (PMD) typically shows an inferior lobster claw like map due to against-the-rule astigmatism.

Several topographic devices provide additional information through various features. For example, the Orbscan provides data on anterior and posterior elevation and best-fit sphere and a corneal pachymetry map and can be used as a tool for screening keratoconus suspects (Figure 19). A recently introduced imaging device that provides accurate measurement of corneal power, elevation and pachymetry is the Pentacam. This device uses a rotating Scheimpflug camera. The Scheimpflug system determines net corneal power, elevation maps, anterior chamber depth and corneal wavefront. It is also an excellent method to detect form fruste keratoconus and keratoconus suspects by calculating the corneal thickness spatial profile and corneal volume distribution.

Figure 19: Orbscan

Keratoconus has been associated with atopy, asthma and eye rubbing. 6, 15 Other conditions in which keratoconus has been noted include ocular rosacea, cone-rod dystrophy, and corneal granular dystrophy as well as a case of early onset of ectasia following laser in situ keratomileusis (LASIK). Keratoconus has also been linked with systemic conditions such as Leber's congenital amaurosis, Down's syndrome, and mitral valve prolapse. 6, 15

Other Problems to Be Considered 14

• Other causes of irregular oblique astigmatism, imprecise variable subjective refractions and non-inflammatory central corneal scarring, such as corneal surgery, healed infections, and trauma should be considered while detecting keratoconus.
• Stromal striations similar to Vogt striae occur when corneas swell (rather than thin) from either hypoxia (associated with wear of contact lenses) or with early Fuchs corneal dystrophy.
• Iron depositions in the basal epithelium (similar to a Fleischer ring) occur in any area of relative depression in the corneal surface in association with pterygium, surgical scars, and central depressions from refractive surgery.
• Pellucid marginal degeneration (PMD) is often considered a variant of keratoconus (KC), in which corneal thinning occurs about a millimeter above the inferior limbus, resulting in advanced against-the-rule corneal astigmatism that may be observed by keratometry or videokeratography.
• Terrien marginal corneal degeneration is a mildly inflammatory disease, usually of the superior limbus, which can also induce irregular against-the-rule astigmatism and corneal thinning (often with vascularization and lipid deposits).
• Keratoglobus (KG) is an extremely rare corneal disease in which the entire cornea, from limbus to limbus, thins, sometimes to the point where spontaneous perforation becomes possible. KG is probably unrelated to keratoconus.
• Posterior keratoconus is another extremely rare disease in which the posterior corneal surface suffers a loss of substance. This condition is probably unrelated to keratoconus.

A relatively new and powerful means to determine the effect a disease has upon an affected individual is to measure the quality of their life. The CLEK Study measured this through the course of the 8 year study. The National Eye Institute (a branch of the National Institutes of Health) developed a vision specific quality of life instrument to assess how different eye diseases affect their victims. This instrument is called the NEI VFQ. In people with keratoconus, NEI VFQ scores were quite low indicating that keratoconus has a profound effect. In particular, pain scores were notably troublesome, even when compared to non-diseased rigid gas permeable lens wearers. 6

Keratoconus management varies depending on the disease severity. Traditionally, incipient cases are managed with spectacles, mild to moderate cases with contact lenses, and severe cases can be treated with keratoplasty. Other surgical treatment options include intra-corneal rings segments, corneal cross-linking, laser procedures (i.e., photorefractive keratectomy, phototherapeutic keratectomy, LASIK) intra-ocular lens implants or a combination of these.

Spectacles
Spectacles are normally used in early cases of keratoconus only. As the disease progresses, irregular astigmatism develops and adequate visual acuity cannot be achieved with this type of visual correction.

Contact lenses
Contact lens wear has represented the most common and successful treatment option for early to moderate cases of keratoconus. Although contact lenses for keratoconus are manufactured with hydrogel, silicone hydrogel, gas permeable and hybrid (i.e., rigid centre and soft skirt) materials, gas permeable contact lenses remain the most commonly used contact lens type as high levels of irregular astigmatism cannot normally be corrected with other contact lens types.

Rigid gas permeable lenses
Rigid gas permeable (RGP) corneal lenses are the lenses of first choice for correcting the irregular astigmatism which occurs as the cornea changes shape. The aim is to provide the best vision possible with the maximum comfort so that the lenses can be worn for a long period of time. Keratoconic patients tend to have long wearing times and usually become long term lens wearers.

Three fitting strategies of gas permeable contact lenses, including apical clearance, apical touch and three-point touch, have been traditionally used for keratoconus fitting.

Apical clearance provides lens support and bearing directed off the apex and onto the paracentral cornea, with clearance (vaulting) of the apex of the cornea; however, this strategy is no longer in current use as it has been associated with poor visual acuity and cone progression control.

The apical touch fitting technique is characterized by providing primary lens support on the apex of the cornea, in which the central optic zone of the lens actually touches or “bears on” the central cornea (Figure 20). This technique provides good visual acuity and keratoconus progression control; however, an increase in corneal scarring has also been documented.

The three-point touch fitting technique, perhaps the most popular, allows the contact lens to bear at several points on the cornea, including a light touch on the apex and a heavier touch on the paracentral cornea (Fig. 20) . This technique has also been associated with good visual acuity and keratoconus progression control.

Figure 20: Fluorescein patterns of two different gas permeable contact lens fittings in keratoconus. The figure on the left shows a flat fitting with a significant touch of the lens on the central cornea.

The figure on the right shows a three-point-touch fitting with slight central touch and peripheral bearing on the cornea.

Piggy back systems, consisting on the fitting a gas permeable on top of a soft contact lens, have also been used for keratoconus management. The soft contact lens is used to improve wearing comfort and provide a more regular area for the gas permeable contact lenses to sit, whereas the gas permeable contact lens is primarily used for providing adequate visual acuity (Fig. 21). The use of high oxygen permeability soft (i.e., silicone hydrogel) and gas permeable contact lenses is highly recommended for keratoconus management as these corneas are well known to be compromised.

Figure 21: Piggy-Back fitting in keratoconus

Hybrid contact lenses, such as SoftPerm, Solotica and more recently, Synergeyes have also been used with relative success in keratoconus management. However, these lenses have not been widely accepted as the current designs, because they are generally more expensive than gas permeable lenses, do not normally provide improved visual correction and wearing comfort in comparison with gas permeable contact lenses.

Surgical Procedures
Current surgical options are multiple and varied, and include:

•  Corneal transplantation

• Penetrating keratoplasty
• Deep anterior lamellar keratoplasty
• Epikeratophakia

•  Intra-corneal ring segment insert

• Intacs
• Ferrara Rings

•  UVA / riboflavin corneal cross linkage (CR3)

•  Thermokeratoplasty

•  Lenticular refractive surgery

• Refractive lens exchange with toric intraocular lenses
• Toric phakic intraocular lenses

•  Contraindications to surgery in individuals with preexisting sub-clinical or overt keratoconus

• Astigmatic and radial keratotomies
• Refractive laser surgery

Penetrating keratoplasty (PKP): It is perhaps the most commonly used surgical option for advanced cases of keratoconus which cannot be successfully managed with contact lenses, but its use is limited to a relatively low number of cases. Reported risk factors for progression to PKP include young age of presentation (less than 20) and keratometry measurements >55 diopters. In this technique the entire thickness of the cornea is removed and replaced by transparent corneal tissue. Visual recovery takes several weeks / months, with full stabilization not occurring until a year, after which time the sutures can be removed. PKP in keratoconus in comparison to other indications is considered low risk in terms of graft rejection, graft survival and postoperative complications. The outcomes of PKP for keratoconus are generally very good. Published series report average final best spectacle corrected visual acuities (BSCVA) of 20/25-20/32 with 73-91% of eyes achieving 20/40 or better. 16 Long-term studies have documented five and 10-year graft survival rates of over 90% in primary transplants. 16

Deep Anterior Lamellar Keratoplasty (DALK): In keratoconic eyes the corneal endothelium is usually intact, with good cell counts even after cases of acute hydrops. While corneal stromal rejection episodes can occur, host keratocytes migrate and replace donor keratocytes and most rejection episodes after 12 months are endothelial in origin. For such reasons, there has been a recent trend to perform lamellar keratoplasty (LK) and in particular deep anterior lamellar keratoplasty (DALK) in keratoconic eyes. DALK involves removing the pathological stroma down to Descemet's membrane and transplanting a full thickness donor button devoid of endothelium and Descemet's membrane. This technique has shown to result in less host endothelial cell loss, less postoperative intraocular pressure problems, a reduction in rejection episodes and, in some series a reduction of induced astigmatism compared to PKP. Published series indicate that 80- 100% of eyes achieve a BSCVA of 20/40 or better. There appears to be a postoperative endothelial cell loss of approximately 10% during the first six months, which is 50% less than that seen after PKP followed by a physiological rate of cell loss (1-2% per annum) in contrast to PKP, where an accelerated continuing loss has been reported (4% per annum). 15 However, eyes undergoing PKP are more likely to achieve 6/6 (20/20) vision than those undergoing DALK.

Lamellar keratoplasty is likely to become the surgical intervention of choice in keratoconus providing an effective, technically easy to perform, outpatient, local anesthetic procedure with fairly rapid visual recovery, excellent visual outcomes and long-term graft survival and stability.

Epikeratophakia: It was first described by Kaufman in 1980. It involves removing the corneal epithelium from the host and then sewing onto the corneal stromal bed a previously cryolathed lenticule of donor cornea. The procedure has generally resulted in less favorable outcomes than PKP with reports of failure of re-epithelialisation, poor BSCVA, stromal and lenticule inflammation and opacification and interface haze.

Intra-corneal ring segment inserts (Intacs and Ferrara Rings): The development of intra-corneal ring segments has provided a surgical alternative to corneal transplantation in some eyes with keratoconus (Figure 22). This technology has been available for over 10 years and was initially developed for the correction of low degrees of myopia, up to -3.0 diopters, with some success. The technique consist of the implantation of one or two polymethyl methacrylate segments in the corneal stroma to reshape its abnormal shape in an attempt to improve visual acuity, contact lens tolerance and prevent or, at least, delay the need for corneal graft. It is commonly used to treat mild to moderate cases of keratoconus, as normal corneal transparency and a minimum corneal thickness of 450µm at the site of the incision are required.

Two types of rings are available: Intacs which have a hexagonal cross-section and are placed more peripheral than Ferrara Rings which are triangular / prismatic in shape. Intacs were approved by the Food & Drug Administration in 1994 for low myopic corrections and extended to treatment of keratoconus in July 2004. 17 The rings are inserted into the posterior stroma (about 75% of corneal depth at the incision site) in a quick outpatient technique performed under topical anaesthesia. The circular intra-lamellar pockets for the rings are created either using a specially designed vacuum lamellar dissector or with the femtosecond laser. The exact mode of action of the rings is unknown. It is assumed that they push out against the ectatic curvature peripherally flattening the peak of the cone centrally and returning the cornea to a more spherical shape. High resolution ultrasonic studies have suggested an important role for the epithelium with hyperplastic changes adjacent to the segments having an important refractive effect. Results have generally been encouraging with most eyes achieving a flattening of the cone postoperatively accompanied by reduction in astigmatism, lessening of inferior versus superior keratometric differences and resultant improvements in best spectacle corrected and uncorrected visual acuities (UCVA).

Figure 22: Intra-stromal rings for treatment of keratoconus

Intra-corneal ring technology does not offer a cure for the condition but can very often produce a marked improvement in unaided and best corrected visual acuity and allow eyes to be corrected with spectacles and / or soft rather than rigid lenses.

UVA / riboflavin corneal cross linkage (CR3): Corneal collagen cross-linkage (CR3) using riboflavin (vitamin B2) / ultraviolet A (UVA) [370nm] light is a new therapeutic modality which may be the first available treatment to halt and stabilize the keratoconic process. It is a technique which aims to increase corneal rigidity and biomechanical stability. The procedure involves removing the corneal epithelium in a 6–7mm diameter central zone followed by riboflavin 0.1% solution application and corneal radiation with ultraviolet-A light at 370 nm. Ultraviolet- A light radiation activates riboflavin generating reactive oxygen species that induce covalent bonds between collagen fibrils in the corneal stroma (Figure 23). The irradiation level at the corneal endothelium, lens and retina is significantly smaller than the damage threshold. It has been recommended not to perform this technique in corneas thinner than 400µm as toxic reactions could take place in the corneal endothelium.

Figure 23: Corneal collagen cross-linkage

In laboratory studies riboflavin / UVA CR3 has been shown to improve stress-strain measurements, reduce the swelling rates and increase shrinkage temperature and the resistance against enzymatic degeneration of corneal stromal tissue. 1 , 15 An increase in the diameter of the collagen fibres following the procedure has been documented with most changes occurring in the anterior 200µm.Clinical studies have indicated stabilization of the keratoconic process in treated eyes with no evidence of progression with up to five years follow-up. In addition 70% of eyes have shown some slight regression of the ectasia by an average of two diopters. No long-term problems in terms of loss of transparency of the cornea or lens have occurred and endothelial counts have been unchanged postoperatively. Also, this technique has been successfully used in combination with other surgery techniques, such as corneal rings segments.

The use of corneal cross-linking, however, has been associated with a decrease in the number of keratocytes immediately after treatment, followed by a progressive recovery post-operatively reaching baseline levels six months after treatment, accompanied by an increase in the density of stromal fibres.

Thermokeratoplasty
Thermal therapy, a surgical technique consisting of the application of heat at the cone, gained some popularity in the mid-1970s; however, its wide use was abandoned as a result of its poor predictability and induced adverse effects such as corneal scars and opacities. Recently, the advent of laser and conductive keratoplasty technologies, have offered greater control for thermokeratoplasty in terms of temperature regulation and shrinkage depth. Published results have indicated encouraging results for the correction of low degrees of hyperopia of up to +1.50D and have led a number of investigators to re-consider using such techniques for keratoconus.

Refractive lens exchange (phakic / toric intraocular lenses)
Corneal surgery in keratoconus can be problematic, often requiring specialized equipment and being technically difficult to perform. In addition, corneal surgical techniques may be associated with further destabilization of the cornea and acceleration of the ectatic process as in the case of laser refractive and incisional surgery. If not addressing the correction of the irregular nature of the induced astigmatism in keratoconus, refractive lens exchange and toric phakic intraocular lens insertion may be of some benefit in correcting myopia and astigmatism in selected eyes with early / mild disease with good BSCVA. Published studies have reported significant improvements in unaided visual performance with good safety and efficacy indices both for refractive lens exchange and toric phakic intraocular lens insertion. Such treatment modalities are relatively easy to perform, with technologies that are widely available to the majority of ophthalmologists and may offer an alternative in selected contact lens intolerant keratoconic before considering keratoplasty. Further refinements in positioning and implantation of toric intraocular lenses and biometry techniques in these irregular eyes may allow the greater use of lenticular refractive techniques for the future management of some keratoconic patients.

Keratoconus as a contraindication to corneal surgical procedures 15
Techniques such as laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK) and laser epithelial keratomileusis (LASEK) have been shown to be safe and effective for the correction of low to moderate degrees of myopia, hyperopia and astigmatism with millions of patients having been treated worldwide. However, one of the major contraindications to such surgeries appears to be the presence of overt and even sub-clinical (forme fruste) keratoconus. An association between the development and acceleration of corneal ectasia in such eyes and LASIK has been clearly established and overt and forme fruste keratoconus are an absolute contraindication to LASIK surgery. While a number of investigators have actually proposed excimer laser phototherapeutic keratectomy (PTK) and PRK procedures as possible treatment modalities for keratoconus, with encouraging reported results and good five year stability, two recent reports of corneal ectasia following PRK strongly suggest that such surface ablation procedures (PRK, LASEK and wide area PTK) are not advisable in these eyes and that keratoconus in all its forms should be regarded as a relative, if not an absolute, contraindication. While many surgical interventions for keratoconus are still at an evolving stage, the use of techniques which are additive (such as intacts), mechanically and chemically stabilize the cornea (riboflavin / UVA corneal collagen cross linkage), assumed to be neutral (conductive keratoplasty) or that replace the diseased corneal tissue (keratoplasty techniques) must be deemed preferable to procedures that remove tissue (excimer laser) and mechanically de-stabilize the cornea (astigmatic and radial keratotomies), particularly in a condition where the cornea is known to be thin, ectatic and mechanically unstable.

Medications
No direct pharmacological management of keratoconus (KC) is available, although nonsteroidal anti-inflammatory (NSAID), antihistamine, or mast cell stabilizing topical medications are occasionally helpful in controlling the often concomitant signs of ocular allergies, especially pruritus, that can lead to eye rubbing. Giant papillary conjunctivitis is common in patients who wear contact lenses for keratoconus, and should be treated with increased lens cleaning, topical mast cell stabilizers, antihistamines, and perhaps steroid drops the latter only after consideration of increased risk of cataract, glaucoma, and decreased ability to resist infection. Episodes of hydrops may require treatment with hyperosmotics to reduce corneal swelling or topical steroid drops to reduce inflammation. Topical antibiotics are used for suspected infection.

1. Mast cell stabilizers

These agents are used to manage signs and symptoms of long-term ocular allergies, which can lead to patient discomfort and increased vigorous eye rubbing.

Drug	Dosing
Sodium Cromoglycate 2%	1 drop 4-6 times a day
Sodium Cromoglycate 4%	1 drop 2 times a day

2. Antihistamines
These agents reduce symptoms of itching that can lead to eye rubbing, thereby decreasing eye rubbing both in duration and intensity.

Drug	Dosing
Azelastine 0.05%	One drop both eyes BID
Emedastine difumarate 0.05%	One drop both eyes QID
Epinastine HCL 0.05%	One drop both eyes BID
Ketotifen fumarate 0.025%	One drop both eyes BID
Olopatadine HCL 0.1%	One- two drop both eyes BID

 3. Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. They are used to manage ophthalmic inflammation of giant papillary conjunctivitis resulting from keratoconus and contact lens wear. E.g. Loteprednol etabonate

 4.  Hyperosmolar diuretics
These agents may reduce inflammation in cornea by creating an osmotic gradient across an intact blood barrier. E.g.: Sodium chloride 2% and 5%

 5.  Immunomodulators
These agents may have anti-inflammatory effects. E.g.: Cyclosporine

1. Advanced keratoconus rarely progresses to acute corneal hydrops (acute keratoconus), wherein breaks occur in the Descemet layer that lead to central stromal edema and secondary severe corneal scarring.
   • Patients report a sudden loss of vision and some ocular discomfort in one eye but usually not much pain or conjunctival injection.
   • Acute treatment of hydrops is palliative; many corneas flatten secondary to hydrops, and both visual acuity and contact lens application may rarely improve following such events.
   • If secondary scarring is severe, corneal transplantation (i.e., PKP) may be warranted.
2. Patients with keratoconus develop all complications of contact lens wear, especially abrasion and giant papillary conjunctivitis. Contact lens–related secondary giant papillary conjunctivitis may be treated with topical mast cell stabilizers, antihistamine, and, occasionally, steroid drops.

Keratoconus is the most common corneal ectasia. It usually appears in the second decade of the life and affects both genders and all ethnicities. The prevalence in the general population has been estimated to be approximately 54 per 100,000. The ocular symptoms and signs of keratoconus vary depending on disease severity. Despite the intensity of research activity over the last few decades into its etiology and pathogenesis, the cause(s) and possible mechanisms for development remain poorly understood. There have been several hypotheses proposed into the genetic, environmental, biomechanical and biochemical causes and mechanisms. Keratoconus treatment and management has improved substantially in recent times. While contact lens wear remains the most successful option for managing mild to moderate cases of keratoconus, new surgical options, such as corneal rings and cross-linking procedures, have been developed to treat moderate to severe cases. The substantial amount of research currently being conducted will allow further understanding of this disease.

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