Essay: Keratoconus

Keratoconus is a corneal ectasia characterized by progressive corneal thinning and apical protrusion. It is reported to have bilateral involvement in 90% individuals with asymmetric presentation. Its incidence is reported as  1 in 2000 in general popuation.(1) It typically presents at puberty with visual symptoms of irregular astigmatism and high myopia. Keratoconus occurs in all indigenous groups with no male or female predisposition.(2)
ETIOLOGY AND PATHOGENESIS
The etiological factors can be divided into biochemical, genetic and environmental.
Many biochemical theories hypothesized that corneal thinning occurs because of loss of corneal structural components. These changes might be due to anomalous free radicals and superoxides processing, increased aldehydes and peroxynitrates, abnormal healing and fibrosis of damaged cells.(3) Shetty R et al reported increased levels of cytokines such as Interleukin-6, Tumour necrosis factor-α, MMP-9  in the tear fluid and up regulation  at mRNA level in epithelium of  keratoconus patient.(4) Shetty R et al also reported reduction in  LOX transcript levels in epithelium and LOX levels in tear fluid correlating with disease severity.(5)
The  inheritance pattern can be sporadic , autosomal dominant with reduced penetrance or autosomal recessive among which sporadic pattern is more  common.(6)The genes involved in pathogenesis of keratoconus are VSX1,SOD1, RAB3GAP1, ZEB1,TGFB1 and FLG.(7) The  first degree relatives of keratoconics have 15–67 times greater risk of  developing keratoconus.(8)
The genetic predilection  requires an additional  environmental event for example;  rubbing of eyes  to elicit the progression  in keratoconus.(9) The microtrauma caused by eye rubbing elevates levels of matrix metalloproteinases and inflammatory mediators which contribute to progression of keratoconus. Excessive sunlight exposure leads to oxidative damage by reactive oxygen species to keratoconic corneas.(10)Bawazeer et al reported indirect association of atopy due to itching which leads to eye rubbing.(11)
Keratoconus can be  associated with Leber’s congenital amaurosis, Down syndrome, hard contact lens wear, connective tissue disorders, positive family history of the disorder, Monosomia X, Retinitis pigmentosa, Marfan syndrome (2) and  mitral valve prolapse.(12)
HISTOPATHOLOGY
The classical triad of  histopathologic features found in keratoconus includes thinning of the corneal stroma, breaks in Bowman’slayer, and deposition of iron in the basal layers of the corneal epithelium.(2)
CLINICAL FEATURES
Keratoconus is a progressive disorder ultimately affecting both eyes, although only one eye may be affected initially. The ocular symptoms and signs of keratoconus vary depending on severity of the disease. Keratoconus patients may present with blurring or distortion in vision due to glare, halos and frequent change in glasses. As the disease advances, significant vision loss occurs due to irregular astigmatism, myopia and corneal scarring. (2)
SIGNS OF KERATOCONUS (2)
EXTERNAL SIGNS
Munson’s sign: V-shaped conformation of the lower lid in downgaze seen in advanced keratoconus.
Rizzuti’s sign: Conical reflection on nasal cornea when a penlight is shone from the temporal side.
SLIT LAMP FINDINGS
Corneal protrusion
Stromal thinning: Centrally or paracentrally, most commonly inferiorly or inferotemporally
Fleischer ring : Yellow Brown to olive green ring of hemosiderin which may or may not surround the base of cone seen best with cobalt blue.
Vogt’s striae: Small brush like vertical  lines in deep layers of stroma and descemet’s membrane along the axis of cone which  disappear on digital  pressure.
Enlarged corneal nerves
Scarring: Epithelial or subepithelial
Acute hydrops: This occurs due to descemet’s membrane breaks with stromal imbibition of aqueous through these breaks. The oedema regresses gradually within weeks or months with resolution of the redness and pain ultimately resulting into corneal scarring.
 
RETROILLUMINATION TECHNIQUES
Retinoscopy: Scissoring of the reflex
Direct opthalmoscopy: The “Charleux” oil droplet sign
KERATOMETRIC SIGNS
Steep cornea
Malalignment, distortion, malpositioning, malfocussing, malshaping, malsizing, pulsation of mires with lack of mire parallellism.(2)
IMAGING
The corneal topography is sensitive to subtle changes in cornea prior to the arrival of clinical symptoms and  signs.(13) In videokeratography, systems relied on  Placido disc imaging show  zone of increased corneal power surrounded by zones of decreasing corneal power, inferior-superior asymmetry in corneal power, and skewing of the steepest radial axes above and below the horizontal meridian which point towards irregular astigmatism.(14) Usually, keratoconus  have an asymmetric bow tie arrangement unlike the symmetric pattern  elicited  in obviously occurring astigmatism.(15)Corneal measurement by Placido disc imaging is  restricted  to anterior corneal surface.(16)
The Orbscan (Bausch and Lomb, Rochester, NY, USA) utilizes slit scanning technology to provide wide-field pachymetry,anterior and posterior elevation and  keratometry maps . The Orbscan II combines slit scanning with Placido-based Topography  to provide  maximum posterior elevation compared with the best fit sphere (BFS), irregularity in the central 3mm, 5mm zones and  pachymetry which is more sensitive. (14)
The Pentacam, Galilei and Sirius use the Scheimpflug principle to provide three-dimensional mapping of the cor¬nea, direct measurement of anterior and posterior corneal surfaces, pachymetry, anterior chamber angle characterization , lens thickness and lens opacification .(14)
Aberrometry uses wavefront sensing, which is a technique of measuring the complete refractive status, including irregular astigmatism of an optical system. The shape of the wavefront can be analyzed by expanding it into sets of Zernike polynomials. The Zernike polynomials are a combination of independent trigonometric functions that are appropriate for describing the wavefront aberrations because of their orthogonality.(17)
CLASSIFICATION OF KERATOCONUS
Keratoconus can be classified based on cone morphology, keratometry readings and pattern of corneal topography. Morphologically cones can be of nipple type, oval type and globus type. Classification by topography is according to elevation map, thickness map and curvature map.
Classification based on severity of curvature
Mild <45 D in both meridians
Moderate 45-52 D in both meridians
Advanced >52 D in both meridians
Severe >62 D in both meridians
Table 1 : AmslerKrumeich Classification(18)
stage 1 stage 2 stage 3 stage 4
Myopia and astigmatism < 5D 5-8 D >8 D not measurable
Mean central K readings <48 D 48-53D 54-55 D >55D
Corneal thickness (µm) >500 >400 300-400 <200
Scarring no no no central scarring
DIFFERENTIAL DIAGNOSIS:
A. Corneal ectatic disorders like pellucid marginal degeneration and keratoglobus.
B. Post-traumatic corneal ectacia or protrusion of the cornea subsequent to corneal thinning from ulceration
SPECTACLE AND CONTACT LENSES:
In very early stages spectacles and soft contact lenses with toric design  are used but  these do not correct irregular astigmatism. Patients with advanced keratoconus are managed by rigid gas permeable  lenses among which single  base curve  contact lenses are most commonly used.In advanced keratoconus, multicurve lenses like Soper lenses ,Mcguire lenses  and  Rose K lenses; Hybrid lenses and Wave custom designed contact lenses are used.(20).Scleral lenses are  prescribed for irregular corneas of severe keratoconus(21)
CORNEAL COLLAGEN CROSS LINKING:
Keratoconus leads to specific biomechanical alterations in cornea but cause is exactly not known. Immune histochemical analysis  and biochemical studies show enzymatic alterations with increased expression of  proteolytic enzymes and decreased concentration of protease inhibitors.(22) The biomechanical abnormality is related to collagen frame work, collagen compound and bonding with collagen fibrils.
Corneal collagen cross linking is an effective therapeutic option to halt the progression  of  keratoconus.(23)The UV-A light induced production of oxygen radicals leads to development of strong chemical bonds between collagen fibrils which strengthens  the cornea. The Cross linking procedure increases biomechanical strength of  cornea up to 330%.(24)
According to Dresden protocol , cornea is treated by application of riboflavin (vitamin B2) 0.1% solution (10 mg riboflavin-5-phosphate in 10 ml dextran 20% solution) for 30 min (induction time) which is followed by UVA radiation of 370 nm wave- length and an irradiance (exposure dose rate) of 3 mW/cm2 for 30 min to  deliver total  radiant exposure (total dose) of 5.4 J/cm2.(25)
The Bunsen-Roscoe law of reciprocity states that a photochemical effect should be comparable as long as total fluence remains constant, so the amount of corneal strengthening derived from cross-linking is energy dependent and not power dependent. The Accelerated crosslinking(KXL) is similar to the standard riboflavin/UV cross-linking (CXL) procedure, except that the induction time and UV exposure time are significantly reduced and the UV irradiance is increased. After induction time of 10 minutes, cornea is exposed to UVA radiation of 370 nm with  an irradiance (exposure dose rate)  of 9 mW/cm2 for 10 minutes or 18 mW/cm2 for 5 minutes or 27 mw/cm2 for 3 minutes to achieve a total radiant exposure (total dose) of 5.4 J/cm2.(26)
The UVA dose absorbed in the anterior part of the stroma is same in accelerated and standard protocol thus providing same crosslinking effect in both protocols. Due to shorter induction time the posterior cornea has less absorbed UVA dose in accelerated protocol which implies safer dose of UVA/riboflavin close to endothelium in accelerated protocol.(26)
UV-A exposure in accelerated collagen cross linking is comparable to the UV-A exposure in the outdoor environment. Normally most of UV- A energy, about 95-99% is absorbed by the cornea and lens, and only 1% or less reaches the retina in the 350-380 nm spectral zone. Cornea and its absorbed riboflavin attenuate much of the incident UV-A radiant energy during the procedure, so the scope for direct damage of ocular structures is negligible during the accelerated cross-linking procedure.(26)
Table 2 – Summary of the Avedro Procedures(26)
Treatment Procedure Total UVA Radiant
Exposure [J/cm2] Total UVA Dose
Absorbed by
Riboflavin [J/cm2]
Riboflavin
Concentration Presoak
Time
[min] UV Lamp
Irradiance
[W/cm2] Time UV
Lamp on
[min] Surface
under
epithelium Endothelium (300μm) Surface Endothelium
(300μm)
0.10% 10 17 7.05 6.4 0.75 0.58 0.017
When crosslinking is combined with procedures like Phototherapeutic keratectomy (PTK), Photorefractive keratectomy (PRK) and intrastromal corneal ring segments accelerated technique is more efficient due to better patient comfort and faster visual recovery.(27)
EXCIMER LASER FOR KERATOCONUS:
Accelerated crosslinking (KXL)  procedure  alone is capable of corneal stabilization, but  it does not address the problem of  irregular astigmatism . So combination of KXL with other procedures like Phototherapeutic Keratectomy (PTK), Photo astigmatic refractive  Keratectomy (PRK) and Wavefront guided ablation are intended to reduce the irregular astigmatism.
The combination of PRK and KXL uses excimer laser to ablate the stroma to reduce the irregular astigmatism. (28) Athens protocol involves excimer laser epithelial de¬bridement (50 μm), partial (maximum ablation 80 μm) topography-guided excimer laser stromal ablation (PRK) followed by accelerated collagen cross linking (10 mW/cm2 for 8 minutes) performed with the Avedro KXL system. (29) PRK with KXL is not useful in advanced  keratoconus due to corneal thickness limitations.(30)
The combination of KXL with Transepithelial PTK (t-PTK) uses an excimer laser ablation to remove the epithelium. In keratoconic eyes the epithelium is thinner (<50 µm) over cone apex than other areas.(31)(32) Due to this keratoconic epithelial pattern, transepithelial PTK (ablation depth of 50 µm) not only removes corneal epithelium but also small amount of anterior stromal tissue on the cone apex (areas with epithelial thickness <50 µm) which regularize the anterior corneal surface. In Cretan protocol, transepithelial PTK ablation (50µm) of 6.5 -7.0 mm zone is done and then this area is enlarged by scrapping at an intended zone of 8 -9 mm. This is followed by standard collagen cross linking (3 mW/cm2 for 30 minutes). (30)
INTRASTROMAL CORNEAL RING SEGMENTS:
Intrastromal corneal ring segments are placed at a depth of two thirds of corneal thickness by a  small radial incision into a track created within corneal stroma. They flatten the central cornea by an arc-shortening effect on the corneal lamellae structure. Two main types of intrastromal rings available are Intacs and Ferrara Rings.(33)
KERATOPLASTY
Approximately 10-25% of cases of keratoconus will progress to a point where vision correction is no longer possible. Penetrating keratoplasty is the most frequently performed surgical procedure for ectatic corneas. In keratoconus, conventional penetrating keratoplasty has good long-term outcome with graft survival of  90% up to 13.8 years and good visual outcomes with 73.2% achieving BCVA over 20/40.(34)
The deep anterior lamellar keratoplasty (DALK) aims at removing all or near total stroma upto  descemet’s membrane. As it is mostly an extra ocular procedure and it  also preserves the host’s descemet’s membrane and  endothelium there is no risk of endothelial rejection.(35)
In femtosecond-assisted keratoplasty (FSALK) femtosecond laser allows an incision to be of desired shape and it can easily match donor and recipient dimensions. Eyes with prior scarring and loss of anterior stromal tissue benefit more from femtosecond laser-assisted grafts as it restores a more normal peripheral corneal topography and thickness in such eyes.(36)
Tuck in lamellar keratoplasty involves a central lamellar keratoplasty with intra stromal tucking of peripheral edge. (37)