Emerging Diagnostics and Therapies for Keratoconus: What Ophthalmology Residents Should Know

Keratoconus is a non-inflammatory, progressive corneal ectasia, characterized by bilateral asymmetric degeneration, leading to paracentral thinning and protrusion.^1,2 Non-surgical treatment of the reduced vision often seen in keratoconus includes spectacle correction and contact lenses (rigid gas-permeable (RGP), scleral lenses). Surgical treatment modalities that do not require corneal transplantation include photorefractive keratectomy (PRK), intracorneal ring segments and intraocular lens placement.² These surgical techniques can help correct refractive error, but are not designed to halt disease progression.² Additionally, although these treatment modalities may correct vision for a period of time, at least 20% of keratoconus patients may still progress to the point of requiring corneal transplant (penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK)).²

Recently, there have been many exciting advances in technology surrounding diagnosis and treatment of keratoconus, allowing eye care providers to help preserve and enhance vision for these patients in ways we never could before. This article reviews novel corneal imaging techniques and their role in providing earlier diagnosis and detection of keratoconus. I’ll also elaborate on corneal crosslinking (CXL) as a method to halt keratoconus progression, as well as methods to enhance and improve vision for these patients, from specialty contact lenses to laser vision correction, to intraocular surgery.

Enhanced diagnostics

Prior to availability of advanced imaging modalities for keratoconus (e.g. tomography, topography), most clinicians were dependent upon exam findings such as unstable refractive changes (i.e. increasing myopia and astigmatism), and worsening symptoms (e.g. blurred vision, glare, streaking of images). Corneal pachymetry can provide information about corneal thinning over time, but may miss early cases (“forme fruste”) of keratoconus.^3-5 Similarly, slit lamp examination may not show signs of early keratoconus (e.g. Vogt Striae, Munson sign, etc). Manual keratometry can demonstrate abnormal corneal contour (blurred/distorted mires, high astigmatic values); meanwhile, automated keratometry provides information regarding astigmatic values that may be too high for measurement with manual methods.^6,7 Computerized imaging—tomography and topography—can map out abnormal corneal shape, change in anterior and posterior astigmatism, and even permit diagnosis of forme fruste keratoconus.^8-10 As such, new diagnostic scales (e.g. Belin-Ambrósio enhanced ectasia display) have been developed to help track progression, and document risk factors for visual loss.^8-13

Enhancement in imaging diagnostics has brought about research into corneal epithelial mapping of keratoconus patients. It has been shown that epithelial distribution in keratoconus eyes follows a specific pattern, and therefore screening for these patterns in keratoconus patients may help pick up early cases and serve as effective adjuncts to examination of potential refractive patients.¹⁴ Although use of epithelial mapping is not as widespread as other tomography/topography methods, as it becomes better understood, its use will likely increase amongst corneal and refractive specialists.^14,15

After diagnostics—halting progression and corneal cross-linking

Corneal collagen cross-linking (CXL) for keratoconus has been shown to improve the biomechanics of the cornea.¹ It has been demonstrated that in keratoconus, the collagen is disorganized, leading to irregular astigmatism, high myopia, and alteration of refractive function.^1-2,16-19 Wollensak et al. demonstrated that application of riboflavin eye drops to eyes with keratoconus, followed by exposure to UVA light at a specific wavelength (370nm, 3mW/cm²) resulted in the halting of keratoconus progression in all subjects studied.² In addition, 70% of patients had regression, with reduction of the maximal keratometric (K) reading by 2.01 diopters (D) and refractive error by 1.14D.² In Wollensak’s and others’ CXL studies, corneal and lens clarity, intraocular pressure, and endothelial cell counts remained unchanged after cross-linking, with visual improvement in 65% of patients.^1-3,16-19

Epithelium-off cross-linking

First described by Dresden in 1997, epithelium-off (“epi-off”) cross-linking is considered standard of care and is the only FDA-approved method of CXL in the United States.^1,2 It involves manual debridement of the corneal epithelium (usually the central 8mm zone), followed by application of 0.146% riboflavin eye drops for at least 30 minutes, and finally application of UVA light (365nm wavelength) for an additional 30 minutes.^1,2 A bandage contact lens (BCL) is usually placed at the end of the procedure and the patient is given antibiotic and anti-inflammatory eye drops for at least 1-4 weeks. The BCL is removed once the central epithelial defect has resolved. This treatment technique has demonstrated improvement in maximum corneal curvature as well as best-corrected visual acuity (BCVA).²⁰

Epithelium-on CXL

Epithelium-on (“epi-on”) has evolved as an alternative modality (although not yet FDA approved) for CXL. This technique does not involve epithelial debridement, in an effort to reduce risk associated with creation of an epithelial defect (e.g. corneal ulceration, keratitis and pain, among others).^21-25 While this technique is favorable for the aforementioned reasons, it does have a higher failure rate and therefore higher rate of need for retreatment—possibly due to limited riboflavin penetration into the stroma due to corneal tight junctions.^21-25 To combat this, alterations in the riboflavin molecule, addition of photo-enhancers, and iontophoresis have been trialed as techniques to help improve success of epi-off CXL.^21-25 Recently, Avedro (Waltham, MA), the company that gained US FDA approval for epi-off CXL, has completed enrollment for a US-based epi-on CXL Phase 3 clinical trial. It is important to note that not every patient with keratoconus is a good candidate for CXL— for example, pachymetry less than 400µm and corneal scarring are considered contraindications.²⁰

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What to do after cross-linking?

Following the introduction of CXL internationally in 2003, and the United States FDA approval in 2016, it has gained acceptance worldwide as a method of halting the progression of ectasia in keratoconus, allowing for potential visual improvement and rehabilitation.^1-3,16-19 At this time, there are many emerging treatment algorithms for visual enhancement after CXL in keratoconus.

Contact lenses

For many years, rigid gas permeable contact lenses have been used to aid vision in keratoconus patients, as well as patients with other corneal irregularities.^26-30 Over time, advances in contact lens (CL) manufacturing has provided more comfortable contact lenses (i.e. scleral, hybrid, and PROSE (Prosthetic Replacement of Ocular Surface Ecosystem) lenses) which has enhanced wear-time as well as visual improvement options for keratoconus patients.^26-30 In addition, corneal flattening that occurs post-CXL may permit soft CL wear with excellent comfort and visual results.^26-30

Surface ablation (PRK)

Given the irregular contour of the cornea, as well as focal thinning that may persist after cross-linking, conventional excimer laser ablations are usually not indicated. However, to date, multiple studies have demonstrated the efficacy of topography-guided surface ablation/photorefractive keratectomy (PRK) in keratoconus patients who have undergone cross-linking.^31-35

Topography-guided custom PRK is a technique using an excimer laser to treat corneas with variable topographic indices (i.e. keratoconus).^34-41 Conventional and wavefront-guided laser therapies used for ‘routine’ PRK and LASIK work by reducing the corneal tissue to a lower level, thus removing a larger amount of tissue in order to create a more spherical cornea, based on the flattest part of the cornea.^34-44 This can be challenging, (or impossible) in eyes with high refractive error or significant corneal irregularity.34,40,41 Thus, in cases where it is important to correct irregularity without large tissue reserves available (i.e. keratoconus), wavefront laser treatment is not an optimal option—or not an option at all.^33-41

Topography-guided ablation offers a unique advantage by removing significantly less tissue than wavefront-guided ablation, frequently saving one-third more tissue.^34-41 Utilizing this technique broadens the spectrum of treatable patients, even those with significant surface irregularities.^31-43

There have been multiple publications on technique as well as sequence of PRK surrounding CXL for keratoconus patients. The Athens protocol, as described by Dr. Kanellopoulos, is a successful immediate-sequence treatment of CXL and nomogram-adjusted PRK.^18,19 In addition, the largest US-based study by our team has demonstrated safe and efficacious techniques of CXL followed by topography-guided PRK once keratometric and refractive stability had been achieved (at least 3 months post-CXL).³⁷ Topography-guided PRK following CXL can provide substantial visual and topographic improvement—in some studies improving vision to 20/40 or better in more than 80% of cases.³⁷

Recently, Dr. Mark Lobanoff has published on a sophisticated algorithmic software (Phorcides) for programming topography-guided laser treatments, which may be extrapolated for keratoconus eyes post-CXL in the near future.⁴⁴

Anterior segment surgery

Intracorneal ring segments: alone and combined with other procedures

Intracorneal ring segments are polymethyl methacrylate (PMMA) segments originally designed to be surgically inserted into the deep corneal stroma for refractive correction of mild myopia (-1.00 to -3.00D).⁴⁵ In the early 2000s, use of intracorneal ring segments were expanded to help flatten severe degrees of keratometric astigmatism. Their use has had great degrees of visual and astigmatic success, as well as demonstrated improvement in contact-lens tolerance.⁴⁵

INTACS (Addition Technology, Inc. Lombard IL) are intracorneal ring segments approved for use in the US. Most published studies suggest that the best indications for INTACS are patients with mild-moderate keratoconus with a clear optical zone and contact lens intolerance.^45,46 Guidance regarding safe use of INTACS requires the following:

upper limit of the steepest keratometry reading should not exceed 58D
no scarring in the visual axis
corneal pachymetry at least 450µm thick in the area in which the INTACS are to be placed^45,46

Most studies to date show an average of 2-3D of flattening accompanied by 2-3 lines of gain in best-corrected visual acuity.^45-48 It is felt that improvement in BCVA is due to the decrease in higher order aberrations (HOA) produced by the INTACS.47-49 Long-term studies of up to 9 years for keratoconus and 6 years for post-LASIK ectasia have demonstrated safety and stability with maintenance of the initial refractive effect, although a small percentage of patients may still progress.^47-49 Given this, and the widespread use of CXL to halt progression of keratoconus and ectasia, many surgeons are considering combined use of CXL and INTACS (whether immediate or delayed sequential approach) to help maintain and enhance their patients’ vision.^49-51

Additional surgical techniques to help enhance vision in keratoconus patients is through the use of intraocular lenses (IOLs) with INTACS.^45-51 The theory for success in this technique is that INTACS can help improve BCVA by reducing higher order aberrations, and an IOL can be used to help address uncorrected myopic refractive error.^45-51 In patients with clear crystalline lenses, phakic IOLs may be used (e.g. Visian ICL, STAAR Surgical, Monrovia CA; Verisyse Phakic IOL, Abbott Medical Optics, Santa Ana CA), whereas those patients with cataractous lenses may undergo cataract surgery with intraocular lens placement. Use of toric (astigmatism-correcting) IOLs may be successful in these circumstances.^51-55

Cataract surgery

In patients where keratoconus has stabilized (naturally or via CXL), and who have visually significant cataracts, and lack of corneal scarring, cataract surgery may be performed to help provide visual improvement. Options for IOLs used here include traditional monofocal IOLs, as well as toric IOLs to help correct astigmatism.^56,57 Multifocal or presbyopia-correcting IOLs are generally not recommended in keratoconus eyes as the irregular corneal shape and increased HOA can induce disturbing and even disabling visual aberrations. Following cataract surgery with monofocal IOL, vision can be further rehabilitated with glasses and/or contact lenses and even PRK in certain circumstances.^51-57 Use of a toric IOL can significantly improve uncorrected (UCVA) and best corrected visual acuity (BCVA) in patients with mild-moderate and stable keratoconus.^56,57

Corneal transplantation

Corneal transplantation, whether penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK) still plays a role in the treatment of advanced cases of keratoconus not amenable to crosslinking, glasses, contact lenses or other procedures.^58-62 These patients usually have severely thinned corneas and/or corneal scarring preventing significant visual improvement with other methods. Corneal transplantation is generally associated with good visual results and excellent graft outcome in these patients.^58-62 Following corneal transplantation, visual rehabilitation options include glasses, contact lenses, and even surface ablation in some cases.

Conclusions

Our diagnostic and treatment options for keratoconus have experienced a massive evolution over time—we are now able to prevent the need for corneal transplantation in some patients due to earlier detection and treatment. Combination of early diagnostics and a variety of successful management strategies allows for better and more advanced treatment of our keratoconus patients, as well as the ability to preserve and enhance their vision. As more research is done, and more patients are being treated, we are surely on our way to ‘reshaping’ keratoconus.

REFERENCES

Padmanabhan P, Radhakrishnan A, Venkataraman A, Gupta N, Srinivasan B. Corneal changes following collagen cross linking and simultaneous topography guided photoablation with collagen cross linking for keratoconus. Indian J Ophthalmol. 2014 Feb; 62(2): 229-235
Lin DT, Holland S, Tan JC, Moloney G. Clinical results of topography-based customized ablations in highly aberrated eyes and keratoconus/ectasia with cross-linking. J Refract Surg. 2012 Nov; 28:S841-8
Kumar M, Shetty R, Jayadev C, Dutta D. Comparability and repeatability of pachymetry in keratoconus using four noncontact techniques. Indian J Ophthalmol. 2015; 63(9):722-727
Gromacki S, Barr J. Central and peripheral corneal thickness in keratoconus and normal patient groups. Optom Vis Sci. 1994; 71: 437-41
Pflugfelder S, Liu Z, Feuer W, Verm A. Corneal thickness indices discriminate between keratoconus and contact lens-induced corneal thinning. Ophthalmology. 2002; 109: 2336-41
Norden L. Keratoconus: diagnosis and treatment. Int Ophthalmol Clin. 1997; 37(1): 51-6
Luz A, Lopes B, Hallahan K, Valbon B, Ramos I, Faria-Correia F, Schor P, Dupps W, Ambrosio R. Enhanced Combined Tomography and Biomechanics Data for Distinguishing Forme Fruste Keratoconus. J Refract Surg. 2016; 32(1):479-494
Hashemi H, Beiranvand A, Yekta A, Maleki A, Yazdani N, Khabazkhoob M. Pentacam top indices for diagnosing subclinical and definite keratoconus. J Curr Ophthalmol. 2016; 28(1): 21-26
Randleman J, Trattler W, Stulting R. Validation of the ectasia risk score system for preoperative laser in situ keratomileusis screening. Am J Ophthalmol. 2008; 145: 813-818
Belin M, Khachikian S. An introduction to understanding elevation-based topography: how elevation data are displayed—a review. Clin Exp Ophthalmol. 2009; 37: 14-29
Chen D, Lam A, Reliability and repeatability of the Pentacam on corneal curvatures. Clin Exp Optom. 2009;92:110-118
Ambrosio R, Faria-Correia F, Ramos I. Enhanced screening for ectasia susceptibility among refractive candidates: the role of corneal tomography and biomechanics. Curr Ophthalmol Rep. 2013;1: 28-38
Ucakhan O, Cetinkor V, Ozakn M. Evaluation of Scheimpflug imaging parameters in subclinical keratoconus detection by topographic and tomorgraphic data. Ophthalmology. 2012; 119: 2231-2238
Li Y, Chamberlain W, Tan O, Brass R, Weiss J, Huang D. Subclinical keratoconus detection by pattern analysis of corneal and epithelial thickness maps with optical coherence tomography. J Cataract Refract Surg. 2016;42(2): 284-295
Carins G, McGhee C. Orbscan computerized topography: attributes, applications, and limitations. J Cataract Refract Surg. 2005; 31(1):205-20
Greenstein S, Fry K, Hersh P. In vivo biomechanical changes after corneal collagen cross-linking for keratoconus and corneal ectasia: 1 year analysis of a randomized, controlled, clinical trial. Cornea. 2012 Jan;31(1):21-25
Wollensak G, Spoerl E, Seiler T. Riboflavin/Ultraviolet-A-induced Collagen Crosslinking for the Treatment of Keratoconus. American Journal of Ophthalmology. 2003 May; 135(5):620-627
Krueger R, Kanellopoulos J. Stability of Simultaneous Topography Guided Photorefractive Keratectomy and Riboflavin/UVA Cross-linking for Progressive Keratoconus: Case Reports. Journal of Refractive Surgery; 2010 October; 26(10):S827-832
Kanellopoulos AJ, Binder P. Collagen Cross-Linking (CCL) with Sequential Topography-Guided PRK: A Temporizing Alternative for Keratoconus to Penetrating Keratoplasty. Cornea. 2007 August; 26(7): 891-895
NDA203324, PHOTREXA VISCOUS and PHOTREXA, and KXL SYSTEM. FDA NDA Photrexa/Photrexa Viscous, KXL System Web. Accessed 20 Mar 2020
Caruso C, Ostacolo C, Epstein R, et al. Transepithelial corneal cross-linking with vitamin E-enhanced riboflavin solution and abbreviated low-dosae UVA-A: 24-month clinical outcomes. Cornea. 2016; 35(2):145-150
Wollensak G, Aurich H, Wirbelauer C, et al. Significance of the riboflavin film in corneal collagen crosslinking. Journal of Cataract and Refractive Surgery. 2010; 36(1): 114-120
Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. Journal of Refractive Surgery. 2010;26(12): 942-948
Baiocchi S, Mazzotta C, Cerretani D, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. Journal of Cataract and Refractive Surgery. 2009;35(5):893-899
Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. Journal of Cataract and Refractive Surgery. 2009; 35(5): 540-546
Rathi V, Mandathara P, Taneja M, Dumpati S, Sangwan V. Scleral lens for keratoconus: technology update. Clin Ophthalmol. 2015;9:2013-2018
Schornack M. Scleral lenses: a literal review. Eye Contact Lens. 2015; 41(1): 3-11
Jacobs D. Update on scleral lenses. Curr Opin Ophthalmol. 2008; 19(4):298-301
Barnett M, Mannis MJ. Contact lenses in the management of keratoconus. Cornea. 2011; 30(12): 1510-1516
Visser E, Visser R, Van Lier H. Advantages of toric scleral lenses. Optom Vis Sci. 2006; 83(4): 233-236
Chen X, Stojanovic A, Wang X, Liang J, Hu D, Utheim TP. Epithelial Thickness Profile Change After Combined Topography-Guided Transepithelial Photorefractive Keratectomy and Corneal Cross-linking in Treatment of Keratoconus. Journal of Refractive Surgery. 2016 Sept; 32(9): 626-634
Jeng B, Farid M, Patel S, Schwab I. Corneal Cross-Linking for Keratoconus: A Look at the Data, the Food and Drug Administration, and the Future. Ophthalmology. 2016 November;123(11): 2270-2272
Sakla H, Altroudi W, Munoz G, Albarran-Diego C. Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus. Journal of Cataract and Refractive Surgery. 2014; 40(9):1430-1438
Knezovic I, Visnjic MB, Raguz H. Partial Topography Guided PRK followed by Corneal Cross Linking in the Management of Progressive Keratoconus: Our Initial Ten-Month Results. Acta Clin Croat. 2015; 54(2): 193-200
Sakla H, Altroudi W, Munoz G, Sakla Y. Simultaneous Topography-Guided Photorefractive Keratectomy and Accelerated Corneal Cross-Linking for Keratoconus. Cornea. 2016;35(7):941-935.
Santhiago M, Giacomin N, Medeiros C, Smadja D, Bechara S. Intense Early Flattening After Corneal Collagen Cross-linking. Journal of Refractive Surgery. 2015; 31(6): 419-422.
Nattis A, Donnenfeld ED, Rosenberg E, Perry HD. Visual and Keratometric outcomes of keratoconus patients after sequential corneal crosslinking and topography-guided surface ablation: Early United States experience. J Cataract Refract Surg. 2018; 44(8): 1003-1011
Haberman ID, Lang PZ, Broncano AF, Kim SW, Hafezi F, Randleman JB. Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. J Cataract Refract Surg. 2018; 44(3): 306-312
Rocha K, Perez-Straziota C, Stulting RD, Randleman JB. Epithelial and Stromal Remodeling After Corneal Collagen Cross-linking Evaluated by Spectral-Domain OCT. Journal of Refractive Surgery. 2014; 30(2): 122-127
Reinstein DZ, Gobbe M, Archer TJ, Couch D. Epithelial thickness profile as a method to evaluate the effectiveness of collagen cross-linking treatment after corneal ectasia. J Refract Surg. 2011; 27:356-363
Moraes R, Ghanem R, Ghanem V, Santhiago M. Haze and Visual Acuity Loss After Sequential Photorefractive Keratectomy and Corneal Cross-linking for Keratoconus. Journal of Refractive Surgery. 2019; 35(2):109-114.
Alessio D, L’abbate M, Furino C, et al. Confocal microscopy analysis of corneal changes after photorefractive keratectomy plus cross-linking for keratoconus: 4-year follow-up. Am J Ophthalmol. 2014; 158: 476-484
Jinabhai A, Radhakrishnan H, O’Donnell C. Higher-Order Aberrations in Keratoconus: A Review. Optometry in Practice. 2009; 10: 141-160
Phorcides Analytic Engine. http://phorcides.com/ Web. Accessed March 21 2020
Colin J, Cochener B, Savary G, Malet F, Holmes-Higgin D. INTACS inserts for treating keratoconus: one-year results. Ophthalmology. 2001; 108(8): 1409-1414
Rabinowitz Y, Li X, Ignacio T, Maguen E. INTACS inserts using the femtosecond laser compared to the mechanical spreader in the treatment of keratoconus. J Refract Surg. 2006; 22(8): 764-771
Siganos C, Kymionis G, Kartakis N, Theodorakis M, Astyrakakis N, Pallikaris I. Management of keratoconus with Intacs. Am J Ophthalmol. 2003; 135(1): 64-70
Rabinowitz Y. INTACS for Keratoconus and Ectasia after LASIK. Int Ophthalmol Clin. 2013; 53(1): 27-39
Bedi R, Touboul D, Pinsard L, Colin J. Refractive and topographic stability of Intacs in eyes with progressive keratoconus: five- year follow up. J Refract Surg. 2012; 28(6): 392-396
Pinero D, Alio J, El Kady B, Pascual I. Intracorneal ring segment implantation in corneas with post-laser in situ keratomileusis keratectasia. J Cataract Refract Surg. 2010; 36(1): 102-109
Kymionis G, Siganos C, Tsiklis N, Anastasakis A, Yoo S, Pallikaris A, Astyrakakis N, Pallikaris I. Long-term follow-up of Intacs in keratoconus. Am J Ophthalmol. 2007; 143(2): 236-244
El-Raggal T, Abdel F. Sequential Intacs and Verisyse phakic intraocular lens for refractive improvement in keratoconic eyes. J Cataract Refract Surg. 2007; 33(6):966-970
Kamburoglu G, Ertan A, Bahadir M. Implantation of Artisan toric phakic intraocular lens following Intacs in a patient with keratoconus. J Cataract Refract Surg. 2007; 33(3): 528-530
Coskunseven E, Onder M, Kymionis G, Diakonis V, Arslan E, Tsiklis N, Bouzoukis D, Pallikaris I. Combined Intacs and posterior chamber toric implantable Collamer lens implantation for keratoconic patients with extreme myopia. Am J Ophthalmol. 2007; 144(3):387-389
Moshirfar M, Fenzl C, Meyer J, Neuffer M, Espandar L, Mifflin M. Simultaneous and sequential implantation of intacs and verisyse phakic intraocular lens for refractive improvement in keractectasia. Cornea. 2011; 30(2):158-163
Hashemi H, Heidarian S, Seyedian M, Yekta A, Khabazkhood M. Evaluation of the Results of Using Toric IOL in the Cataract Surgery of Keratoconus Patients. Eye Contact Lens. 2015; 41(6): 354-358
Nanavaty M, Lake D, Daya S. Outcomes of pseudophakic toric intraocular lens implantation in Keratoconic eyes with cataract. J refractive surg (Thorofare NJ: 1995) 2012; 28(12): 884-889
Al-Mohaimeed M. Penetrating Keratoplasty for Keratoconus: Visual and Graft Survival Outcomes. Int J Health Sci. 2013-7(1): 67-74
Kelly T, Williams K, Coster D. the Australian Corneal Graft Registry. Corneal transplantation for keratoconus: a registry study. Arch Ophthalmol. 2011; 129 (6): 691-97
Doyle S, Harper C, Marcyniuk B, Ridgway A. Prediction of refractive outcome in penetrating keratoplasty for keratoconus. Cornea. 1996; 15:441-45
Siganos C, Tsiklis N, Miltsakakis D. Changing indications for penetrating keratoplasty in Greece, 1982-2006: a multicenter study. Cornea. 2010; 29(4): 372-74
Pramanik S, Musch D, Sutphin J, Farjo A. Extended long-term outcomes of penetrating keratoplasty for keratoconus. Ophthalmology. 2006;113: 1633-3