Management of Keratoconus: Recent Trends - DJO

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better understanding of the disease and its progression. ... Intrastromal corneal ring segments; DALK: Deep anterior lamellar keratoplasty; CXL: Corneal collagen cross-linking; IOL: .... Aquaport (a central hole of size 0.36 mm) eliminating the.

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Management of Keratoconus: Recent Trends Vikas Veerwal, Pooja Jain, J L Goyal, Ritu Arora, Ankit Malhotra Guru Nanak Eye Centre, Maulana Azad Medical College, Maharaja Ranjit Singh Marg, New Delhi

the world.2,3 Currently, techniques for the management of KC can be classified into 3 types: Corneal strengthening techniques, Optical optimization techniques and Combined techniques.4 The use of Intracorneal ring segments (ICRS), excimer laser , phakic intraocular lenses (IOLs) and evolvement of DALK techniques have all made significant contributions in providing effective treatment for all stages of KC. Although techniques have been developed to treat thinner or steeper corneas,5 corneas thinner than 400µm or steeper than 58D may not be eligible for UV cross-linking. The new technique of Bowman Layer Transplantation has been the latest addition in the armamentarium to tackle advanced KC. Treatment of KC needs to be individualized. Multiple criteria to consider the more suitable technique or treatment for any patient include refraction, age, degree of thinning, irregular astigmatism, and presence or absence of scarring. A practical approach to a patient of KC has been described by means of a flow chart in (Figure 1).6

Abstract Keratoconus (KC) is a bilateral, progressive disease characterised by corneal thinning, ectasia, variable degree of irregular astigmatism and resultant mild to severe reduction in visual acuity. Multiple advances in corneal imaging and topographic mapping have led to a better understanding of the disease and its progression. Traditionally, use of spectacles and rigid contact lenses has been the primary mode of treatment in early KC, while keratoplasty has been the treatment of choice in advanced cases. However, development of an array of therapeutic options over the last decade has revolutionized the approach to this disease. The preferred treatment for progressive KC has shown a paradigm shift from contact lens fitting for as long as tolerated, followed by Penetrating Keratoplasty (PK) or Deep Anterior Lamellar Keratoplasty (DALK), to Ultraviolet-A (UV-A) induced collagen cross-linking (CXL) to stabilize corneal ectasia in the long term. Recently, use of Intrastromal Corneal Ring Segments (ICRS), Phakic IOLs, application of excimer laser and use of combination techniques have all made significant contribution in providing options for effective management of different stages of this disease. Bowman layer (BL) transplantation is a new technique that has recently been introduced as an alternative to PK/ DALK in eyes with advanced KC, unsuitable for either UV-CXL or ICRS. By means of this article, we aim to provide a summary of these recent trends in therapeutic options for the optimal management of keratoconus.

Corneal collagen cross-linking (CXL) with Riboflavin

CXL aims to improve the intrinsic biomechanical characteristics of corneal stroma in order to stabilise progressive KC. The current technique involves the use of riboflavin (vitamin B2), which is exposed to a measured dose of longer wavelength UV-A radiation (370nm) at 3 mW/cm2 (5.4 J/cm2). Riboflavin acts as a photosensitiser as well as absorbs UV radiation to limit the depth of the treatment effect. Free radicals produced by photosensitising process catalyse a reaction resulting in formation of covalent bonds between the collagen molecules and microfibrils.7,8 The induction of molecular crosslinks appears to increase corneal stability and thus slows the progression of the disease. The accepted criteria to perform a corneal crosslinking include patients with topographic evidence of KC progression, corneal thickness > 400µm and KC without deep stromal scarring or history of corneal hydrops.9

Keywords: keratoconus, collagen cross-linking, bowman layer transplantation, ICRS, phakic IOLs, DALK, excimer laser.

Keratoconus (KC) is a bilateral, asymmetric, progressive, non-inflammatory condition resulting from biomechanical instability of the cornea. The cornea assumes a conical shape because of thinning and protrusion causing a variable degree of irregular astigmatism and myopia resulting in mild to marked impairment of visual function.1 While Amsler-Krumeich scale is still the most widely used method to classify KC, with the increasing availability and usage of elevation based slit scanning topographic mapping as well as Scheimpflug imaging of cornea by Orbscan and Pentacam, Amsler-Krumeich scale is becoming outdated in the practical decision making for management of KC. Indices and classifications based on Orbscan and Pentacam are increasingly being used by ophthalmologists all over

Newer CXL Protocols

The originally developed Dresden Protocol is still most widely used, however, a number of variations to reduce the duration of treatment and to apply CXL in corneas thinner than 400µm have been tried.

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CXL with Hypo-osmolar Riboflavin

Hypo-osmolar riboflavin formulated with Dextran or Hydroxypropyl Methyl Cellulose has a low colloidal osmotic pressure (310mOsmol/L as compared to 402.7 mOsmol/L in isotonic riboflavin) and has been used to cause stromal swelling where stromal bed is less than 400µm thick. A variable degree of stromal swelling ranging from

DOI

http://dx.doi.org/10.7869/djo.134

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Figure 1 : Algorithm for management in a case of Keratoconus.6 PRK: Photorefractive keratectomy; PTK: Phototherapeutic keratectomy; ICRS: Intrastromal corneal ring segments; DALK: Deep anterior lamellar keratoplasty; CXL: Corneal collagen cross-linking; IOL: Intraocular lenses; PK: Penetrating keratoplasty.

36 to 105µm over periods ranging from 3 to 20 minutes is noted.10 For all iatrogenic thickened corneas, concern exists for its safety and efficacy. The response of CXL may be less because of the decreased concentration of collagen fibrils in a hydrated cornea.

Accelerated CXL

In order to accelerate the treatment process, which takes more than 1 hour with the standard protocol, variations with the goal to shorten time of treatment have been introduced. According to the Bunsen–Roscoe law of reciprocity, the effect of a photochemical reaction is directly proportional to the total irradiation dose, regardless of how the combination of time and intensity are distributed. When the duration of UV light exposure is reduced, intensity of treatment

has to be increased in order to maintain the appropriate fluence. Various accelerated CXL protocols available use an irradiation time of 10 min, 5 min or 3 min with UV-A fluence of 9, 18 or 30 mW/cm2, respectively.11,12 A study comparing accelerated and conventional CXL showed no difference at 1 year in visual acuity, maximum keratometry, anterior stromal keratocyte density and sub-basal nerve density or endothelial cell count.11,12

Trans-epithelial CXL

Due to post-operative pain and risk of complications that result from epithelial debridement, as well as the limitations of use of CXL in corneas thinner than 400 µm the concept of cross-linking with the epithelium remaining

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largely intact has been introduced. Varying techniques have been used to promote riboflavin absorption into the stroma keeping an intact epithelium. Methods using drops containing preservatives, such as benzalkonium chloride (BAC) pre-operatively to break the epithelial tight junctions, or use of riboflavin combined with EDTA, BAC and tris hydroxymethyl aminomethane to facilitate the penetration of riboflavin have been tried. In the clinical setting, various transepithelial riboflavin formulations using permeability enhancers show some penetration but not equal to standard protocol in comparative studies.13,14 Examination using anterior segment optical coherence tomography (AS-OCT) has demonstrated a dense line at 100 µm, which compares with the demarcation line seen at a depth of 320 to 340 µm in conventional collagen cross-linking. This suggests that the effect of transepithelial CXL may be more superficial. Various studies suggest a significantly lesser effect of transepithelial CXL compared to standard CXL with epithelial debridement.13-16

pyrrolidone) is used instead of riboflavin and the UVA irradiation stage only takes 30 seconds at 4.2 mW/cm2, rather than the conventional 30 minutes at 3 mW/cm2. Measurements of corneal stiffness using surface wave elastometry in ex vivo porcine eyes suggested that ‘flashlinking’ and conventional CXL may have a comparable effect.22 Iontophoresis: Recent reports suggest that iontophoresis may increase the efficiency of riboflavin penetration into the corneal stroma. Iontophoresis involves the use of a small electrical current to enhance the penetration of a drug across a tissue (including an intact corneal epithelium). Pre-clinical testing has demonstrated the efficacy of this method in increasing the mechanical rigidity of the cornea. Demarcation line using iontophoresis appears less pronounced than traditional epi-off CXL but still better than standard transepithelial procedures. Research into this promising new technique is continuing.23

The term CXL Plus pertains to treatment with CXL combined with an additional refractive treatment. Patients who are intolerant to contact lenses showing progression of the disease can be considered for Topography guided photorefractive keratectomy (T-PRK) with adjunctive CXL rather than CXL alone. T-PRK allows shaping of the irregular cornea without addressing the progressive nature of the disease in KC. Patients with early to moderate KC and a preoperative thinnest pachymetry of at least 450µm (after epithelial debridement) can be considered for T-PRK, although some investigators have included patients with a minimum pachymetry of 300µm as well. However, it is not recommended for ablations larger than 50µm.17,18 Various studies have shown improvement in visual acuity and stabilisation of keratometry with T-PRK combined with CXL.17,18 Other refractive options with CXL include Phototherapeutic Keratectomy (PTK), ICRS, Phakic IOLs and combinations of all of the above-mentioned procedures.18,19 However, long-term follow-up and additional randomized controlled studies are needed for these treatment options.

ICRS are a new modality in the treatment of mild to moderate grades of corneal ectactic disorders. ICRS consist of two tiny, clear, cresecnt shaped pieces of PMMA which can be inserted into the cornea. For myopia, ICRS work by flattening the cornea to re-focus light rays and improve vision; while in KC patients, ICRS flatten the steep part of the cone and reduce vision distortions. Based on the principle of the ‘hammock effect’, they redistribute the bio-mechanical stress and prevent further steepening of the cornea.24

CXL Plus

Intrastromal Corneal Ring Segments (ICRS)

There are 5 models available, each with variations in their curvature, radius, thickness and arc length, according to the effect to be achieved. (1) Ferrara rings (2) Keraring (3) Intrastromal rings, Intacs and Intacs-SK (Severe Keratoconus) (4) Myoring; and (5) Cornealring. The characteristics of the most popular ICRS implants have been described in (Table 1).

Keraflex

Indications: Indications for use of ICRS in KC patients are mild to moderate KC with contact lens intolerance having central clear corneas and a corneal thickness of 450 µm or greater at the proposed incision site.24,25

Keraflex (KXS) is a new procedure that aims to cause significant flattening using thermal heat below the corneal surface.20 A single low-energy microwave pulse lasting less than 1 second is applied to the cornea using a dielectrically shielded microwave emitter, which noninvasively contacts the epithelial surface. Through capacitive coupling, the single pulse raises the temperature of the selected region of corneal stroma to approximately 65°C, shrinking the collagen, and forming a toroidal lesion in the upper 150 μm of the stroma below Bowman’s membrane. The treatment is then followed by CXL to “lock in” the flattening effect.20,21 Clinical trials to study its efficacy are under way.

Technique: The devices are inserted into stromal tunnels that may be fashioned manually using a handheld diamond blade or automatically using a femtosecond laser with no difference in results.26,27 The femtosecond laser has multiple Table 1: Characteristics of ICRS Implants

Future Prospects in CXL

Rocha and colleagues introduced the concept of ‘flashlinking’, whereby a new cross linking agent (polyvinyl

Characteristics

INTACS

Ferrara Ring

Keraring

Arc Length (degrees)

150

160

90,120,160,210,240

Cross section

Hexagonal

Triangular

Triangular

Thickness (mm)

0.25-0.45 (0.05 increments)

0.20-0.35 0.15-0.30 (0.05 increments) (0.05 increments)

Inner Radius (mm)

6.77

4.40

5.0

Outer Radius (mm)

8.10

5.60

6.0

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advantages over conventional tunnel creation including lesser discomfort, faster creation with very little tissue disturbance, faster postoperative recovery, precise control of tunnel depth, width and centration with lesser risk and better customization of the tunnel.26,27 For greater effect, two hemi-spherical segments may be placed instead of one. These segments may be implanted symmetrically if the keratoconic cone is located centrally, or asymmetrically if the cone is decentred. With asymmetrical placement, a thicker segment is implanted in the axis of greatest steepening. To a large extent, the depth at which the segments lie determines their effect. Maximal flattening occurs with segments at 60-79% corneal thickness. Shallower than 60%, the effect may be lessened and the likelihood of a variety of ocular surface complications increased. Deeper than 80%, there may be no topographic effect at all.28 Outcomes: ICRS confer a modest visual benefit with a gain in 1-2 lines of BSCVA.24-28 The newer segment designs INTACS SK and Kerarings, although intended for severe ectasia, rarely result in visual gain of more than 2 lines. Instead, being smaller in diameter and hence closer to visual axis, may often result in more visual aberrations.29 A sizeable reduction in corneal astigmatism ranging from 1-3D and in mean Ks by 3-5D regardless of the type of segment employed or the stage of disease occurs with ICRS.25-29 Increasingly, there are reports of combining ICRS with UVCXL. While cross linking stops the progression of the ectasia, ICRS flatten or normalize the corneal shape. Combining both the modalities together has a synergistic action and can be performed simultaneously or sequentially. The sequencing is critical: to achieve maximal flattening, ICRS should be implanted before or simultaneously with UV-CXL. To do the opposite (UV-CXL, then later ICRS) limits the flattening effect of the segments since the cornea has been already fixed into a sub-optimal configuration.30,31

Refractive Surgeries In Keratoconus

Excimer Laser: Traditionally, KC or its fruste form was considered a contraindication to keratorefractive surgery with excimer laser. Recently, these techniques have been utilized in the treatment of patients with fruste KC or its mild forms with satisfactory visual results. PRK has the benefit of leaving a thicker residual stromal bed after surgery than laser in-situ keratomileusis (LASIK) and is a safer option in suspect or thin corneas.32 This technique is ideal for the treatment of small ametropias, such that it is not recommended for large ablations (ideally, less than 50 microns) given the possibility of postoperative haze. With the associated high amounts of aberrations, topographyguided systems are perhaps an even better option in KC, potentially allowing correction of optical zone decentration and better irregular or asymmetric astigmatic correction. Studies have reported an improvement in Uncorrected Distance Visual Acuity (UDVA) in fruste KC patients treated with PRK.33,34 No KC progression was seen during followup period.33,34 Based on these results, PRK seems to be a safe strategy on eyes suspected of having frank KC.

The combination of PRK with crosslinking has been a widely utilized strategy and, in these cases, the criteria for its application has to do with the residual stromal bed posterior to ablation, which ideally should be greater than 400-450µm. The techniques that combine these procedures can be sequential or applied in the same sitting. In majority of the reports, the combination of these techniques are associated with a significant improvement in respect to UDVA, improvement in keratometries and halting of KC progression.35,36 However, laser treatment experiences in KC must be taken with caution because of the few reports and short term follow-ups reported until now in the literature. Phakic IOLs: Alternatives to intra-corneal implants and excimer laser are IOLs. They offer correction of higher spherical and astigmatic errors than ICRS and have a much faster rehabilitation than corneal transplantation. Contact lens intolerant patients with a clear cornea and stable refraction along with deep anterior chambers(AC) are good candidates for phakic IOLs. They are less suitable for eyes with advanced KC or in presence of high irregular astigmatism. Anterior chamber and posterior chamber phakic IOLs are available. Posterior chamber phakic IOLs are placed between the iris and crystalline lens. Options include the Visian Implantable Collamer Lens (ICL) and the Visian Toric ICL. The latest available model of Visian ICL comes with centraFLOW technology that comprises a central KSAquaport (a central hole of size 0.36 mm) eliminating the need for peripheral iridectomy that was necessary before. They are made from hydrophilic porcine scleral tissue, a collagen-based biocompatible material. Studies have shown excellent visual outcomes with 96 to 100% of eyes achieving +1.00 D of intended spherical target, post-operative residual cylinder less than 1.00 D in 87% and significant improvements in uncorrected visual acuity.37 Disadvantages: Unlike corneal-based treatments that aim to normalise the shape of the keratoconic cornea, IOLs can correct only spherical and cylindrical error. It is known that eyes with KC have significant aberrations that affect visual quality, with higher levels of vertical coma, primary coma and coma-like aberrations as compared to normal eyes. Complications include significant pigment dispersion and risk of endothelial cell loss with anterior chamber IOLs and development of anterior subcapsular cataract, glaucoma and rotation of toric ICL in cases of posterior chamber IOLs.

Bowman Layer (BL) Transplantation

The most sensitive and specific indicator of KC is the fragmentation of Bowman layer – an insult that critically destabilizes the surrounding cornea, predisposing it to ongoing ectasia. In 2014, van Dijk et al introduced the idea of an isolated Bowman layer inlay for eyes with advanced KC. Delivered into a manually dissected mid-stromal pocket, the graft was intended to (partially) restore the corneal anatomy, stabilize the corneal structure, flatten the surface, and arrest progression.38 Outcomes: Following BL transplantation, BSCVA typically

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improves by 1-2 lines, although BCVA usually remains unchanged. The primary visual benefits, then, of BL transplantation may be: 1) to enable more comfortable CL wear by flattening the cornea into a more tolerable configuration; and 2) to permit continued CL wear into the future, by halting disease progression.38,39 The primary effect of BL transplantation is to flatten the operated cornea by natural healing response of the eye that generates a tractional force that “pulls” the ectatic cornea into a more normal configuration. Reports suggest a 5D reduction in mean anterior simulated Ks, 5-7D reduction in max corneal power and a 8-9D reduction in max K. These topographic changes occur within the first postoperative month and appear stable through at least two years of follow-up.38,39 Early results of BL transplantation show that at two years postoperatively, 90% of eyes with previously documented progression had stabilized, despite all eyes having preoperative Kmax’s >70D.39

Cite This Article as: Veerwal V, Jain P, Goyal JL, Arora R, Malhotra A. Management of Keratoconus: Recent Trends . Delhi J Ophthalmol. 2015;26:405. Acknowledgements: None Date of Submission: 20.05.2015

Date of Acceptance: 12.06.15

Conflict of interest: None declared

References 1. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984; 28:293-322. 2. Alió JL, Shabayek MH. Corneal higher order aberrations: a method to grade keratoconus. J Refract Surg. 2006; 22:539-45. 3. Piñero DP, Nieto JC, Lopez-Miguel A. Characterization of corneal structure in keratoconus. J Cataract Refract Surg 2012; 38:2167-83. 4. Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol 2011; 95:1044-50. 5. Raiskup F, Spoerl E. Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. Am J Ophthalmol 2011; 152:28-32. 6. Jaimes M, Ramirez-Miranda A, Graue-Hernández E, Navas A. Keratoconus therapeutics advances. World J Ophthalmol 2013; 3:20-31. 7. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-ainduced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620-7. 8. McCall AS, Kraft S, Edelhauser HF, Kidder GW, Lundquist RR, Bradshaw HE, et al. Mechanisms of corneal tissue crosslinking in response to treatment with topical riboflavin and long-wavelength ultraviolet radiation (UVA). Invest Ophthalmol Vis Sci 2010; 51:129-38. 9. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26:385-9. 10. Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 2009; 35:621-4. 11. Hashemian H, Jabbarvand M, Khodaparast M, Ameli K. Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: a randomized controlled trial. J Refract Surg 2014; 30:837-42. 12. Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg 2014; 40:1013-20. 13. Filippello M, Stagni E, O’Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012; 38:283-91. 14. Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ. Refractive and topographic results of benzalkonium chlorideassisted transepithelial crosslinking. J Cataract Refract Surg 2012; 38:1000-5. 15. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Paradiso AL. Transepithelial corneal collagen crosslinking for keratoconus: qualitative investigation by in vivo HRT II confocal analysis. Eur J Ophthalmol 2012; 22 Suppl 7:S81-8. 16. Sorkin N, Varssano D. Corneal collagen crosslinking: a systematic review. Ophthalmologica 2014; 232:10-27. 17. Kymionis GD, Grentzelos MA, Kankariya VP, Liakopoulos DA, Karavitaki AE, Portaliou DM, et al. Long-term results of combined transepithelial phototherapeutic keratectomy and corneal collagen crosslinking for keratoconus: Cretan protocol. J Cataract Refract Surg 2014; 40:1439-45. 18. Kymionis GD, Kontadakis GA, Kounis GA, Portaliou DM,

Keratoplasty

PK and DALK remain as the last resort for management of advanced KC especially cases with scarring of descemet’s membrane post hydrops.41-43 Risk of allograft rejection, suture and wound healing problems, progression of the disease in the recipient rim, and persistent irregular astigmatism are common complications with these procedures.42,43 Currently there are techniques based on manual and automated dissection of the donor and receptor graft (microkeratome, femtosecond laser and excimer laser) to obtain lamellar transplants at different depths.44-46 One of the new trends is to use the femtosecond laser to perform a precise tissue disruption at predetermined depths with the aim of achieving uniform dissection and better visual results.47 The newer technique of deep anterior lamellar transplant assisted by pachymetry (PALK) involves performing a photoablation with an excimer laser guided by topography and pachymetry of 95% of the stromal surface in a way that more regular cuts can be made at specific diameters.48

Conclusion

The development and addition of newer imaging techniques in the early diagnosis and management of KC has certainly resulted in an impetus to tackle this serious corneal pathology before it becomes advanced enough to require PK. The historic evolution of various techniques used to treat KC has shown tremendous advancement in the past decade. With the potential to alter the natural history of KC and possibly even halt disease progression using methods like CXL and BL Transplantation and with the newly developed procedures to provide best possible optical outcomes to these patients, need for corneal transplant in KC may become a thing of the past. Use of combined procedures and promising ongoing research in management of KC has acted as a catalyst for ophthalmologists all over the world to provide best possible visual outcomes to these patients. In the future, surely new treatment techniques will have scientific foundations in molecular mechanisms which can halt the initial onset of ectasia.

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Karavitaki AE, et al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg 2009; 25:S807–11. 19. Iovieno A, Légaré ME, Rootman DB, Yeung SN, Kim P, Rootman DS. Intracorneal ring segments implantation followed by same-day photorefractive keratectomy and corneal collagen cross-linking in keratoconus. J Refract Surg 2011; 27:915–8. 20. Vega-Estrada A, Alió JL, Plaza Puche AB, Marshall J. Outcomes of a new microwave procedure followed by accelerated crosslinking for the treatment of keratoconus: a pilot study. J Refract Surg 2012; 28:787-93. 21. Cummings AB, McQuaid R, Mrochen M. Newer protocols and future in collagen cross-linking. Indian J Ophthalmol 2013; 61:425-7. 22. Rocha KM, Ramos-Esteban JC, Qian Y, Herekar S, Krueger RR. Comparative study of riboflavin-UVA cross-linking and “flash-linking” using surface wave elastometry. J Refract Surg 2008; 24:S748-51. 23. Waring GO IV. Iontophoretic delivery of riboflavin and future applications with corneal CXL with UV-A for keratoconus treatment. Paper presented at The American Society of Refractive Surgery Symposium And Congress, 24th April, 2012, Chicago. 24. Alió JL, Artola A, Ruiz-Moreno JM, Hassanein A, Galal A, Awadalla MA. Changes in keratoconic corneas after intracorneal ring segment explantation and reimplantation. Ophthalmology 2004; 111:747–51. 25. Colin J, Cochener B, Savary G, Malet F, Holmes-Higgin D. INTACS inserts for treating keratoconus: one-year results. Ophthalmology 2001; 108: 1409–14 26. Carrasquillo KG, Rand J, Talamo JH. Intacs for keratoconus and post-LASIK ectasia: mechanical versus femtosecond laserassisted channel creation. Cornea 2007; 26:956–62. 27. Ertan A, Kamburoğlu G. Analysis of centration of Intacs segments implanted with a femtosecond laser. J Cataract Refract Surg 2007; 33:484–7. 28. Kymionis GD, Grentzelos MA, Diakonis VF Pallikaris AI, Pallikaris IG. Nine-year follow-up of intacs implantation for keratoconus. Open Ophthalmol J 2009; 3: 77–81. 29. Torquetti L, Ferrara G, Almeida F, Cunha L, Araujo LP, Machado A, et al. Intrastromal corneal ring segments implantation in patients with keratoconus: 10-year follow-up. J Refract Surg 2014; 30: 22–6. 30. Yeung SN, Ku JY, Lichtinger A, Low SA, Kim P, Rootman DS. Efficacy of single or paired intrastromal corneal ring segment implantation combined with collagen crosslinking in keratoconus. J Cataract Refract Surg 2013; 39:1146–51. 31. Legare ME, Iovieno A., Yeung SN, Lichtinger A, Kim P, Hollands S, et al. Intacs with or without same-day corneal collagen cross-linking to treat corneal ectasia. Can J Ophthalmol 2013; 48: 173–8. 32. Leccisotti A. Corneal ectasia after photorefractive keratectomy. Graefes Arch Clin Exp Ophthalmol 2007; 245:869-75. 33. Bilgihan K, Ozdek SC, Konuk O, Akata F, Hasanreisoglu B. Results of photorefractive keratectomy in keratoconus suspects at 4 years. J Refract Surg 2000; 16:438-43. 34. Bahar I, Levinger S, Kremer I. Wavefront-supported photorefractive keratectomy with the Bausch & amp; Lomb Zyoptix in patients with myopic astigmatism and suspected keratoconus. J Refract Surg 2006; 22:533-8. 35. Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg 2009; 25:S8128. 36. Tuwairqi WS, Sinjab MM. Safety and efficacy of simultaneous corneal collagen cross-linking with topography-guided PRK in managing low-grade keratoconus: 1-year follow-up. J Refract Surg 2012; 28:341-5.

37. Kamiya K, Shimizu K, Kobashi H, Komatsu M, Nakamura A, Nakamura T, et al. Clinical outcomes of posterior chamber toric phakic intraocular lens implantation for the correction of high myopic astigmatism in eyes with keratoconus: 6-month follow-up. Graefes Arch Clin Exp Ophthalmol 2011; 249:1073-80. 38. van Dijk K, Parker J, Tong CM, Ham L, Lie JT, Groeneveld-van Beek EA, et al. Midstromal isolated Bowman layer graft for reduction of advanced keratoconus: a technique to postpone penetrating or deep anterior lamellar keratoplasty. JAMA Ophthalmol 2014; 132:495–501. 39. van Dijk K, Liarakos VS, Parker J, Ham L, Lie JT, Groeneveldvan Beek EA, et al. Bowman layer transplantationto reduce and stabilize progressive, end stage, keratoconus. Ophthalmology 2015; 122:909-17. 40. Reddy JC, Hammersmith KM, Nagra PK, Rapuano CJ. The role of penetrating keratoplasty in the era of selective lamellar keratoplasty. Int Ophthalmol Clin 2013;53:91-101. 42. Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty a report by the american academy of ophthalmology. Ophthalmology 2011; 118:209-18. 43. Han DC, Mehta JS, Por YM, Htoon HM, Tan DT. Comparison of outcomes of lamellar keratoplasty and penetrating keratoplasty in keratoconus. Am J Ophthalmol 2009; 148:744751.e1. 44 Buzzonetti L, Laborante A, Petrocelli G. Refractive outcome of keratoconus treated by combined femtosecond laser and bigbubble deep anterior lamellar keratoplasty. J Refract Surg 2011; 27:189-94. 45. Busin M, Scorcia V, Zambianchi L, Ponzin D. Outcomes from a modified microkeratome-assisted lamellar keratoplasty for keratoconus. Arch Ophthalmol 2012 ;130:776-82. 46. Tan DT, Ang LP. Modified automated lamellar therapeutic keratoplasty for keratoconus: a new technique. Cornea 2006; 25:1217-9. 47. Almousa R, Samaras KE, Khan S, Lake DB, Daya SM. Femtosecond laser-assisted lamellar keratoplasty (FSLK) for anterior corneal stromal diseases. Int Ophthalmol 2014; 34:4958. 48. Spadea L, Gizzi R, Evangelista Conocchia N, Urbano S. Optical pachymetry-guided custom excimer laser-assisted lamellar keratoplasty for the surgical treatment of keratoconus. J Cataract Refract Surg 2012; 38:1559-67.

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Corresponding author: Vikas Veerwal MS

A-109, Sector 61, Noida, Uttar Pradesh, India- 201301 India Email: [email protected]