Although keratoconus was described by Dr Benedict Duddell in 1736, the early literature is confusing because of the variety of names used for the disease, including, hyperkeratosis, ochlodes, sugar-loaf cornea, cornea conica, staphyloma pellucidum, keratoncus, and keratoconus, to name but a few.1 Increasingly well-described over the next 100 years, nonetheless, limitations of technology and understanding of the disease led Pickford (1844) to acerbically note, “there is probably no disease to which the eye is subject, hitherto so rebellious to medicine, so intractable in its nature, and, at the same time, so fatal to vision, as conical cornea; and not one, the pathology and treatment of which are so little understood.”1–3 Subsequently, Nottingham,2 in his 270-page magnum opus (1854), described keratoconus with clarity and great accuracy for the time, including aspects of corneal thinning and shape, progressive refractive changes, optical correction, and treatment—although corneal transplantation was still in its infancy.
From those early pioneering days, where much learned writing lay in the astute observation and clinical experience of the author, we have evolved to an age of high-technology analysis and near-instant information sharing. Indeed, the past 20 years have witnessed an explosion in our knowledge of, and ability to diagnose, keratoconus with the total peer-reviewed literature on keratoconus growing from approximately 750 articles up to and including 1994, to nearly 5000 articles by 2014 (PubMed accessed 20th December 2014; www.ncbi.nlm.nih.gov/pubmed).
TRANSFORMATION OF MANAGEMENT OPTIONS
This burgeoning clinical and scientific literature has been accompanied by radical transformation of management options for keratoconus. In the past, clinicians have generally accepted a number of key “facts” in relation to keratoconus: (1) it is a progressive corneal ectasia, (2) the etiology is noninflammatory, (3) progression is accompanied by increasing irregular astigmatism, possible scarring or hydrops corneae, (4) ultimately, it may be associated with loss of best-corrected vision and the possibility of corneal transplantation, and (5) the etiology is incompletely understood but has genetic and environmental components.3 However, more than a century after its comprehensive description by Nottingham,2 the exact cause of the disease remains to be fully elucidated, and some of these “facts,” such as the noninflammatory nature of the disease, may be challenged in the future. Certainly, the etiology is probably multifactorial or it may be that the keratoconus phenotype represents a final common pathway for a number of different disease processes in the cornea. Increasingly, a “2-hit hypothesis” of the disease is generally accepted with an underlying genetic predisposition to keratoconus influenced by external environmental factors, including eye rubbing and atopy.3–6
VARIABLE PREVALENCE OF KERATOCONUS
Any contemplation of disease management must consider etiology, prevalence, and natural history, especially in a relatively uncommon disease like keratoconus. The prevalence of keratoconus has been reported to vary from <10 to >50 cases per 100,000 and is frequently quoted as approximately 1:2000.3 Conversely, in high-prevalence areas such as the Middle East, topographic features of keratoconus have been noted in 3.3% of a young adult population.7 This wide variation in reported prevalence is in part due to different genetic predisposition, differing exposure to cofactors, and perhaps most importantly different diagnostic criteria. Certainly, diagnosis has moved from traditional techniques such as retinoscopy, refraction, slit-lamp assessment, and Placido disc to contemporary techniques including topography, tomography, higher-order aberrometry, anterior segment optical coherence tomography, and biomechanical assessment.3,6–8
APPLYING COMPUTERIZED TOPOGRAPHY AND TOMOGRAPHY IN KERATOCONUS
Computerized corneal topography has now been applied to the diagnosis and prognosis of keratoconus for a quarter of a century, and this has enabled the development of key diagnostic indices related to central corneal steepening, asymmetry of apical power, and asymmetric inferior corneal steepening.9 Early topographic studies of asymptomatic family members highlighted that topographic abnormalities and abnormal indices were present in 50% of family members.9 Subsequent studies have confirmed that abnormal topographic patterns are more common among relatives of those with keratoconus,10 and in one high-prevalence region, evaluation of relatives revealed that 21% of relatives exhibited keratoconus or subclinical keratoconus topographic patterns.11 Thus, subclinical and early keratoconus might be much more prevalent than commonly reported. Fortunately, corneal topography patterns, combined with a plethora of quantitative indices and algorithms, are now regularly used in the classification and screening of keratoconus, with tomographic approaches that include corneal thickness and posterior elevation being more sensitive.12–14
Although corneal tomography for keratoconus is increasingly refined and relatively widely available, its use in the screening of the general population for keratoconus is not viable because of the relatively low prevalence of the disease and high cost/low benefit for the small number of cases that would be detected. However, there may be some population exceptions in which the prevalence of keratoconus is particularly high. Indeed, a study of 1027 university students in Iran revealed a “prevalence” of 2.5% in this selective population.15
In contrast, because there is a genetic predisposition and significant evidence of ectatic disease in near relatives, there are significant benefits from clinical and tomographic screening of family members with keratoconus. This enables targeted investigation in a small population with a high prevalence of subclinical and early keratoconus and, most importantly, provides the potential to proactively treat to halt disease progression. Once more, assessment is particularly important in regions with high prevalence or tradition of consanguinity in marriage, especially because in first or second cousin marriages, there is a collective increase of almost 4-fold in the risk of keratoconus.15,16
CONSIDERING KERATOCONUS IN INHERITED AND SYSTEMIC DISEASE
A large number of inherited diseases have been associated with keratoconus including Down, Marfan, and Ehlers–Danlos syndromes, mitral valve prolapse, and Leber congenital amaurosis.17 In many cases, the systemic disease will have been diagnosed in advance of the corneal disease; however, it is incumbent upon the ophthalmologist to be aware of the systemic associations of keratoconus and be proactive in screening for corneal disease or recommending referral to appropriate clinical services for systemic workup, where necessary.
The association between keratoconus and atopic diseases is less well defined than the association with inherited syndromes, although a common pathway may include eye rubbing in atopy, Down syndrome, and Leber congenital amaurosis. A link between atopy and keratoconus had been long postulated, but Rahi et al (1977) were the first to demonstrate that atopy occurred more commonly in keratoconus—35% of those with keratoconus compared with 12% of matched controls. Serum IgE was also raised in those with keratoconus especially in cases with atopy.18 In contrast, a UK-based study revealed that, although living in a similar environment, Asians from the United Kingdom (Indian subcontinent) were almost 8 times more likely to exhibit keratoconus than whites from the United Kingdom. Paradoxically, atopy was much higher in the white group.19 The Dundee University Scottish Keratoconus Study of 200 patients with keratoconus noted high levels of asthma (23%) and hayfever (30%), but with a particularly significant difference in eye-rubbing behavior (48%, P = 0.018) compared with controls.20
ATOPY, EYE RUBBING, AND KERATOCONUS
The concept that eye rubbing is associated with atopy, rather than atopy per se, is a causal link that has gained greater currency in the past 20 years. In a keratoconus case–control study of 120 subjects, although univariate analysis identified a number of factors including family history, allergy, and atopy, multivariate analysis revealed only eye rubbing as a key association with an odds ratio of 6.31.21 McMonnies and Boneham,22 noting a bimodal distribution of allergy, itch, and rubbing, concluded that these were only relevant when the highest levels of these factors are present. A number of plausible mechanisms by which eye rubbing and associated corneal epithelial microtrauma might produce ectasia in the genetically predisposed have been postulated.23
Synthesis of the literature enables a plausible hypothesis of how epithelial microtrauma might lead to progression of keratoconus; notably, epithelial microtrauma releases interleukin 1, keratocytes in keratoconus have 4 times the number of IL-1 receptors compared with normal corneas, and interleukin 1 triggers the release of Fas-ligand by the keratocytes. Notably, epithelial microtrauma also releases Fas-ligand directly. When Fas-ligand binds to keratocytes, apoptosis is induced, thus reducing the number of keratocytes in the keratoconic cornea.3
A CONSERVATIVE AND INTERMEDIATE MANAGEMENT PARADIGM
In terms of treatment paradigms, the evidence base suggests that conservative management must include advice in relation to avoidance of eye rubbing and prescription of topical agents where required, including mast cell stabilizers, antihistamines, and combined agents.6 Topical lubricants may also be useful in atopy associated with dry eye symptoms, and preservative-free agents should always be used where frequent topical medication of any form is being contemplated.
As previously noted, a family history has been established for many years in keratoconus; however, the exact mechanism of inheritance is uncertain because typically 10% or fewer family members clinically exhibit the disease although topographic cases are more common.3,4,6,9–11 Many studies suggest an autosomal-dominant pattern of inheritance with variable phenotypic expression, although others have suggested a non-Mendelian mode of inheritance.4,9,17,24
In view of this variability in inheritance, routine genetic testing is not warranted in affected individuals, although in large studies, genomewide association studies are likely to provide more data in the near future. However, tomographic screening of family members may be useful in picking up early disease.
Inevitably, some subjects cannot be managed conservatively because of the natural history of the disease. Keratoconus generally commences in puberty and has a variable progression, being gradual, rapid, or intermittent from puberty to the fifth decade when progression typically slows. Nonetheless, ultimately, approximately 20% of subjects may require keratoplasty to rehabilitate vision.3 Interestingly, careful consideration of the literature confounds the widely held perception that keratoconus stabilizes in the 40s. Indeed, keratoconus may be considered a disease that “never sleeps” with the Collaborative Longitudinal Evaluation of Keratoconus study revealing a mean increase of 1.6 diopters (D) of curvature in the flat corneal meridian over 8 years, with 24% of eyes exhibiting >3.0 D progression. Importantly, this observation was in a group with a mean age of 39.3 years on entry to the study.25 In a study of subjects with keratoconus referred to a public hospital corneal service in the United Kingdom at a mean age of 23 years, 67% continued with successful contact lens wear but 31% progressed to penetrating keratoplasty (PK) at a mean of 8.5 years after diagnosis.26 Studies from New Zealand have revealed keratoconus as the most common indication for keratoplasty in 1991 to 1999 (45.6%) and 2000 to 2009 (41.1%).27,28 Because of the risk of progression to keratoplasty, key objectives in creating treatment paradigms for keratoconus must include early diagnosis, regular monitoring, and use of interventions to slow or prevent disease progression.
RAPID EVOLUTION OF CORNEAL COLLAGEN CROSSLINKING
Until the beginning of the new millennium, the treatment paradigm for keratoconus was essentially a simple 2-option process: (1) if the keratoconus was stable or exhibited minimal progression, with good best-corrected visual acuity (BCVA), the subject would be managed by spectacle or rigid gas-permeable contact lenses and any ocular atopy or eye rubbing treated with topical medication, (2) if the keratoconus was advanced or associated with scarring or reduced BCVA, the subject would be offered PK, and possible subsequent visual correction by contact lenses. However, there has been an explosion in options for treating keratoconus in the past 20 years, such that such treatment plans are now outdated. The main goals of treatment of keratoconus are now to maximize visual acuity and prevent progression of the disease.29
Conservative and surgical approaches to keratoconus management must now include a large number of options, including spectacles, contact lenses, regular tomographic review to detect progression, therapies to reduce eye rubbing, collagen crosslinking (CXL), intracorneal ring segments, surface-based keratorefractive laser procedures, phakic intraocular lenses (IOLs), cataract extraction with toric IOLs in older subjects, and PK or deep anterior lamellar keratoplasty (DALK) in advanced disease.3,6,29
Foremost among the major changes in the management of keratoconus have been the development and rapid widespread acceptance of corneal CXL using riboflavin as a photosensitizer combined with UV-A light exposure.30–33 Indeed, as early as 2006, Wollensak30 wrote that crosslinking treatment of progressive keratoconus brought “new hope” to a disease hitherto frustratingly difficult to manage without major surgical intervention in 21% of cases. The Dresden group, in a 6-year follow-up of 241 eyes, noted a mean maximum keratometry reduction of 1.9 D with some improvement in astigmatism and BCVA.31 Wittig-Silva et al in Melbourne, in one of the very few published randomized controlled trials (RCT), also noted a reduction in maximum keratometry and a tendency to improved corrected visual acuity.32 In an RCT by the author and coworkers in New Zealand, “at 24 months a mean difference of 2.2 D was detected in maximum keratometry in treated versus the contralateral untreated, control eyes” (unpublished data). This RCT included in vivo confocal microscopy, which highlighted complete loss of the subbasal nerve plexus and anterior stromal keratocytes after treatment; however, by 12-month after CXL, there was complete regeneration of the corneal nerve plexus and repopulation of the anterior stroma by keratocytes. Hyperreflective bands were noted in the region demarcating the boundary between treated and untreated stroma.34 Notably, CXL has been well established and available within the private sector since 2007, including recognition by health insurers, and also became available in the New Zealand public health sector in 2014.
Interestingly, the published evidence base that supports the use of CXL in keratoconus, although extensive, is not of as high quality as one might expect.33 Although approximately 500 references are identified by electronic searches, a recent Cochrane review (2015) of CXL notes, “Despite the numerous prospective and retrospective studies available in the literature and the fact that CXL seems to be accepted world-wide as a breakthrough treatment in the management of keratoconus, evidence is limited due to the lack of properly conducted RCTs.” Indeed, the authors of this Cochrane review note that of 51 full-text reports obtained to consider for inclusion in the review, only 8 reports were suitable, including 3 RCTs that enrolled a total of only 225 eyes. Conclusions of this Cochrane review included the following: treated eyes had a less steep cornea—approximately 2.0 D, uncorrected visual acuity improved by approximately 2 lines or 10 letters, and no studies reported loss of 0.2 logarithm of the minimum angle of resolution visual acuity. However, data on corneal thickness were inconsistent, and adverse effects of CXL treatment were not uncommon but mostly of low clinical significance.33
INTRASTROMAL CORNEAL RING SEGMENTS FOR KERATOCONUS
Intrastromal corneal rings and segments were originally developed for the treatment of low myopia. Colin et al (2007) reported a prospective evaluation of this technology in the treatment of keratoconus, highlighting that contact lens tolerance was restored in 80% of treated eyes. Eyes with a BCVA of ≥20/40 increased from 22% at baseline to 54% at 24 months. The spherical equivalent reduced by a mean of −3.1 D with a similar dioptric reduction in mean keratometry.35
It is now generally accepted that intrastromal corneal ring segments (ICRS) have a key role in treating keratoconus, and their application has become safer and more precise with the use of femtosecond lasers with consequent improvement in visual, refractive, and keratometry values.6 Visual acuity typically improves more in eyes with poorer preoperative BCVA, although there is no improvement in eyes with advanced keratoconus. Contemporary ICRS techniques can also be successfully combined with CXL and photorefractive keratectomy (PRK). ICRS in isolation has no effect on the disease process, and the duration of the effect, corneal changes at a biomechanical level, and an optimal method for combining ICRS and CXL have yet to be determined.36,37
CONSERVATIVE, INTERMEDIATE, AND ADVANCED MANAGEMENT OPTIONS
On the basis of these advances in the management of keratoconus, a management paradigm can be developed that divides management options into 3 broad categories—conservative, intermediate, and advanced pathways (Fig. 1). In eyes with stable or minimally progressive keratoconus and good BCVA, conservative option 1 would use spectacles, contact lenses, and treatment for atopy and eye rubbing. However, in addition, conservative option 2 would also include the possibility of CXL, especially in younger subjects where progression is still possible or where confirmed progression is identified. Where definite progression is confirmed in early reviews, the subject would be better suited to an intermediate pathway that includes all options in the conservative pathway but might be staged: intermediate 1, progress to CXL; intermediate 2, CXL plus ICRS; intermediate 3, CXL ± ICRS ± laser keratorefractive surgery (PRK).
KERATOPLASTY IN KERATOCONUS: A DECADE OF DALK VERSUS PK
Increasingly, when considering keratoplasty for advanced keratoconus, ophthalmologists opt for DALK rather than PK because of the perceived advantages of the former procedure. The main advantages of DALK over PK include that it is primarily an extraocular procedure, topical corticosteroids can be used for a shorter period reducing the risk of cataract and elevated intraocular pressure, there is no risk of endothelial rejection and therefore overall follow-up and management should be simpler than PK, and in principle, there should be a greater chance of long-term allograft survival. However, some of these perceived advantages are not as well supported by the literature as much as the surgeon's enthusiasm for the technique. Limitations include a technically demanding and continually evolving DALK technique; limitations in corneas with scar, neovascularization, or previous acute hydrops; and time–cost and fiscal viability of DALK compared with PK in some regions.
Although the authors' preferred first-line approach to transplantation in keratoconus is to consider DALK, it must still be remembered that PK is a very well-established technique, and success in keratoconus is particularly high. The Australian Corneal Graft Registry notes that PK graft survival for keratoconus cases is 89% at 10 years with a mean survival of 18.2 years.38 In a longitudinal study of 125 patients in Japan, with a mean age of 25 years at the time of PK, Fukuoka et al39 reported a 10-year and 20-year graft survival of 99% and 97%, respectively.
Notably, DALK is associated with a significant surgical learning curve, and a report of 2372 keratoplasties (approximately 20% DALK) for keratoconus, performed by a variety of surgeons in the United Kingdom, identified that DALK had twice the risk of failure compared with PK and that 19% failed in the first 30 days (compared with 2% PK). However, at 3-year postsurgery, survival rates were similar (DALK 92% vs. PK 94%). Although there was no difference in astigmatism, PK eyes were more likely to obtain 20/20 (22% DALK vs. 33% PK) and DALK was associated with a greater prospect of >3.0 D of myopia.40
Nonetheless, the benefits in terms of avoiding the risk of endothelial rejection are substantial: comparing 142 DALK and 142 PK procedures revealed that although the DALK cases developed low-level stromal (11%) and epithelial rejection (1%), the PK cases exhibited stromal/epithelial rejection in 2% but potentially sight-threatening endothelial rejection in 15% of eyes. Ocular hypertension was also much more common in PK (26%) compared with DALK (6%).41 Notably, presumed corticosteroid-related elevation of intraocular pressure has been reported in up to 35% of keratoconus eyes after keratoplasty; so, the benefit of short-term steroid coverage may be significant.42
In Auckland, New Zealand, “DALK increased from less than 5% of keratoplasty procedures in 2000 to 16% by 2009—with 60.3% of these DALKs for keratoconus” (unpublished data). In a similar period (1999–2009), indications for corneal graft surgery in the United Kingdom also changed significantly with the number of PK procedures for keratoconus dropping from 453 to 322, whereas the number of DALK procedures increased >5-fold from 45 in 1999–2000 to 226 in 2008–2009, that is, 40% of all keratoplasty procedures for keratoconus.43 In contrast, the Eye Bank Association of America report for the period 2011 to 2013 highlighted that PK numbers were stable but of almost 7000 keratoplasties for keratoconus in 2013, only 9.8% were DALK procedures suggesting relatively slow uptake of DALK in the United States. Fortunately, as highlighted in the foregoing sections, PK remains a good long-term option for keratoconus.44
INTEGRATING A CONTEMPORARY MANAGEMENT PARADIGM FOR KERATOCONUS
A comprehensive management paradigm that includes the conservative and intermediate options previously highlighted (“Keratoplasty in keratoconus: a decade of DALK vs. PK” and Fig. 1) is completed by advanced options for moderate to severe keratoconus with poor BCVA (Fig. 2). On the basis of published literature and reported experience, the first keratoplasty option to be considered should be DALK; however, if there is significant scarring or previous corneal hydrops, or the clinician has limited experience with DALK, a PK approach is entirely reasonable.
A special circumstance in keratoconus management is the treatment of acute corneal hydrops, which typically results in significant scarring and reduced BCVA, usually leading to PK to rehabilitate vision.45 There is significant evidence that intracameral air or more commonly gas (eg, SF6) can produce a useful tamponade to shorten the duration of the hydrops.46,47
If there are other causes for poor vision in older subjects with keratoconus, for example, cataract, then phacoemulsification with a toric IOL is an option, but toric IOLs should be considered only when there is minimal irregular astigmatism, that is, a contact lens is not required to achieve acceptable BCVA. For completeness, other options that might be considered in special circumstances include phakic IOLs, clear lens extraction with IOL, epikeratoplasty, and Descemet level wedge excision (in the pellucid marginal corneal degeneration spectrum of keratoconus).
FUTURE OPTIONS IN KERATOCONUS—ADDRESSING THE UNDERLYING PATHOLOGY
The underlying disease process in keratoconus is far from fully established. As already outlined, there is a clear genetic predisposition associated with changes that include corneal thinning and protrusion.3,5,6 A 2-hit hypothesis that includes genetic predisposition and environmental factors such as eye rubbing is increasingly accepted.3,4,23 Although generally thought to be noninflammatory, recent evidence suggests that a low-level inflammatory component may be present, and this long-held presumption may need to be reevaluated.48,49 Therefore, topical agents in addition to mast cell stabilizers, antihistamines, and lubricants may in the future also include agents such as topical cyclosporine.50
In terms of surgical approach, CXL may prevent progression of the disease, and keratoplasty may replace the severely diseased central cornea in advanced keratoconus, but because the underlying processes remain enigmatic, no approaches currently reverse or cure the disease. Indeed, despite extensive investigation of the biomechanical properties of the cornea in keratoconus, the cut off between normal and early disease is yet to be well established.51 The fundamental building blocks of the cornea rely on normal keratocyte function, and it has been postulated that apoptosis is a mode of cell death in keratoconus that may lead to loss of keratocytes and ergo compromise of the corneal structure.3,23,52 In keratoconic eyes, without previous contact lens wear, in vivo confocal microscopy has confirmed statistically significant reduction in both anterior and posterior keratocyte density.53 Hypothetically, in early disease, the insertion of progenitor keratocytes grown from donor corneas, by injection or through femtosecond laser–generated channels into keratoconic corneas could allow repopulation of the cornea with healthy cells—yet avoiding corneal transplantation.54,55 Early work on this concept has already been completed, and researchers within the New Zealand National Eye Centre have demonstrated proof of concept with the repopulation of decellularized keratoconus corneas with keratocyte progenitor cells [T. Sherwin (PhD, personal communication, December 2014)] (Fig. 3).
Although many questions still remain about the etiology and best management of keratoconus, the new millennium has ushered in perhaps the most exciting period in our almost 3 centuries' knowledge of the disease. New treatment paradigms in addition to spectacles and contact lenses now include technology that enables earlier diagnosis and better monitoring of keratoconus; a treatment that halts or slows progression (CXL); a modification of keratoplasty that preserves host endothelium and avoids allograft rejection (DALK); a maturation of techniques, for example, ICRS, ICL, PRK that can maximize visual acuity; and potential future strategies that may actually “cure” the disease. Indeed, from the dim, distant beginnings of our first comprehension of keratoconus in 1736, the future of ectatic disease management has never looked brighter.
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