It is generally accepted that the most pronounced growth of the cornea stops by age 6, although the exact timing of corneal growth is still debated (von Reuss 1881; Greeff 1892; Grod 1910; Asbell et al. 1990; Oyster 1999; Ehlers et al. 1968; Ko et al. 2001; Hymes 1929; Duke-Elder 1963; Ronneburger et al. 2006). During the prenatal period, the diameter of the cornea has been demonstrated to increase in a linear fashion from an average of 2.7 mm at 12 weeks to 9.7 mm at 40 weeks (Ehlers et al. 1968; Ko et al. 2001). Hymes found that the rapid phase of corneal growth after birth ended between 9 months and 1.5 years (Hymes 1929), a conclusion that was largely accepted by Duke-Elder who noted, however, that some growth might be evident up to the end of the second year (Duke-Elder 1963). Ronneburger et al. concluded that the fastest growth of the cornea after birth occurs in the early months of life and represents a rapid deceleration of the fetal growth of the cornea (Ronneburger et al. 2006).

A number of other changes take place in the eye during postnatal development, including an increase in the axial length of the eyeball and the size of the lens (Oyster 1999; Larsen 1971). Changes in curvature and thickness of the cornea also occur with age (Kotulak and Brungardt 1980; De Silva et al. 2011; Uva et al. 2011; Ehlers et al. 1976; Inagaki 1986). Studies of premature infants have demonstrated that corneal curvature and central corneal thickness change dramatically after birth, with the corneal curvature changing from 65 diopters at 28 weeks to 49 diopters at 42 weeks of post-conceptional age. The flattening of the cornea continues after birth, with average keratometry readings of 45 diopters by eight weeks of age. Change in corneal curvature slows at this point. Central corneal thickness decreases from 794 to 559 μm during the prenatal and neonatal period, with stabilization by 3 years of age (De Silva et al. 2011; Uva et al. 2011; Ehlers et al. 1976).

Müller and Doughty have included in their study of corneal growth an extensive review of the literature of corneal diameter measurements. It increases at the rate of 1.1 mm per month over the fetal period with growth in corneal diameter of 0.14 mm per month over the first year of life; after 1 year of life the growth rate abruptly slows to a mean of just 0.01 mm per month. They also have failed to detect growth of the cornea above six years of age (Müller and Doughty 2002).

The adult structure of the cornea is reached at 6 months of age. A decrease in corneal power with a corneal flattening counteracts the effects of axial elongation, crystalline lens flattening and thinning, and the decrease in lens power that are the hallmarks of normal eye growth in emmetropes from ages 6 and 15 years (Lesueur et al. 1994; Zadnik et al. 2004). In normal eyes no changes in lens thickness, corneal curvature radius, and corneal astigmatism have been detected between age 10–18 (Fledelius 1982).

Astigmatism is common in early infancy, but decreases in prevalence from 3 to 9 months subsequently remaining stable between 9 and 36 months. The reduction in astigmatism in infants appears to be caused by decreases in the with-the-rule toricity of the cornea and the against-the-rule lenticular toricity (produced by the toricity of the posterior lens surface). The cornea and anterior lens surface became more spherical with age, contributing to the shift away from with-the-rule refractive astigmatism (Mutti et al. 2004; Howland and Sayles 1985). Between 9 and 21 months of age, there is a rapid emmetropization in normal children (Ehrlich et al. 1997).

The etiology of keratoconus is not well understood. Genetic, biochemical, and physical factors have been hypothesized to play a role. A reduced number of collagen crosslinks and a higher susceptibility to pepsin digestion have been suggested as possible explanations for the overall structural weakness of the corneal in keratoconus, which results in corneal stiffness that is only 60% of the normal cornea (Rabinowitz 1998). The mechanisms that underlie this observation remain poorly understood. Defective formation of extracellular constituents of corneal tissue, fewer collagen lamellae, fewer collagen fibrils per lamella, and closer packing of collagen fibrils have all been suggested as possible factors in the decreased mechanical stability of the cornea that plays an important role in the progressive ectasia that characterizes keratoconus (Andreassen et al. 1980).

Although typically keratoconus is an isolated condition, there have been associations with multiple other eye and systemic conditions including retinitis pigmentosa, blue sclera, magnesium deficiency, Down syndrome, Turner syndrome, Marfan syndrome, Ehlers–Danlos syndrome, mental retardation, Leber congenital amaurosis, osteogenesis imperfect, and pseudoxanthoma elasticum (Rabinowitz 1998; Cullen and Butler 1963).

Keratoconus has a hereditary component, as there is a greater incidence of keratoconus in relatives of patients with the disorder, as compared to the general population (Carmi et al. 2006). Approximately 6–24% of cases reported in literature demonstrate clinically recognized familial aggregation (Rabinowitz 2003; Edwards et al. 2001). Both dominant and recessive models have been observed in individual keratoconus pedigrees (Wang et al. 2000; Falls and Allen 1969). In addition, segregation analyses (Wang et al. 2000), twin studies (Zadnik et al. 1984), and gene mapping studies (Tyynismaa et al. 2002; Brancati et al. 2004; Hutchings et al. 2005; Tang et al. 2005; Li et al. 2006) have also indicated the important role of genetic factors (Li et al. 2007).

In the vast majority of cases (in excess of 90%), keratoconus is bilateral; however, the severity of the disease may be asymmetric. In many cases the disorder may start in one eye, but over time the other eye becomes involved (Holland et al. 1997). Although keratoconus is most frequently diagnosed after adolescence, the corneal ectasia likely starts at a much younger age (Rabinowitz 1998).

Epigenetic and environmental factors certainly play a role in expression and progression of keratoconus. Many pediatric keratoconus patients have comorbidities including atopic dermatitis (Cullen and Butler 1963), and ocular allergic tendencies that vary in severity from mild seasonal allergic conjunctivitis to more severe diseases such as vernal keratoconjunctivitis (VKC) (Arora et al. 2012). VKC compounds the problems with keratoconus as continued surface inflammation and the tendency towards eye rubbing accelerate keratoconus progression, often leading to advanced disease at a young age (Rahman and Anwar 2006; Panahi-Bazaz et al. 2014; Ioannidis et al. 2005; Cullen and Butler 1963). Therefore, children with atopy should be referred for a comprehensive ophthalmic examination, even in the apparent absence of visual symptoms, to ensure the timely diagnosis and management of any atopy-associated ocular disease, including keratoconus. Prompt referral is particularly essential for young atopic children, since keratoconus in this setting can quickly advance to the stage beyond which corneal crosslinking can be performed safely, thus worsening the prognosis for maintenance of stable vision (Downie 2014). Patients and parents should be counseled about the importance of avoiding eye rubbing. Management of systemic allergic disease is essential to minimize ocular complications. The management of allergic eye disease in children is discussed in Chap. 4 (Cruzat and Colby).

Recent studies suggest that thyroid gland dysfunction due to inflammatory or immunological causes can be associated with keratoconus. Patients with hypothyroidism should have corneal topography to assess for early stage keratoconus. In addition, patients with keratoconus should be evaluated for thyroid dysfunction (Gatzioufas et al. 2014). Other reports suggest that hormonal changes occurring during pregnancy, including a modified function of the thyroid gland (Gatzioufas and Thanos 2008), may adversely affect corneal biomechanics and may have a severe impact on the progression of keratoconus (Soeters et al. 2012; Hoogewoud et al. 2013; Bilgihan et al. 2011).

Keratoconus caused pathologic changes in multiple layers of the cornea (Sherwin and Brookes 2004). The epithelium shows central thinning, with irregular or thickened basement membrane and defects in the Bowman layer. Stromal scarring and evidence of apoptosis have been identified in proximity to breaks in the Bowman layer (Kaldawy et al. 2002; Sykakis et al. 2012). In vivo confocal microscopy has demonstrated decreased sub-basal nerve density correlating with decreased corneal sensation, as well as reduced basal epithelial density (Patel et al. 2008). There is a loss of stromal collagen lamellae and altered collagen fibril orientation. Decreased keratocyte density, particularly in the central anterior stroma, has also been reported (Mathew et al. 2011). Descemet membrane and endothelium are generally unaffected, except in cases with corneal hydrops, although elongation of endothelial cells with pleomorphism has been reported in a small percentage of cases (Rabinowitz 1998). Changes from corneal hydrops, demonstrated on histopathology and more recently with anterior segment optical coherence tomography, include epithelial and stromal edema, intrastromal fluid clefts, and detachment of the Descemet membrane (Basu et al. 2012a, b).

The disease course of keratoconus differs from patient to patient and from eye to eye. Early in the disease there may be no symptoms, and the only sign may be an inability to refract the patient to a clear 20/20 or a refraction showing a mild astigmatism, usually at 70° in the right eye and 110° in the left eye. The problem becomes evident to the patient when the cornea begins to thin and gradually curves outwards, deforming into a cone shape. The irregular shape changes the refractive power of the cornea, producing image distortion and blurring of vision. The patient initially complains of worsening in visual quality, image distortion, and progressive blurring of vision.

In the early stages of the disease, the visual symptoms can usually be corrected with glasses. One sign of disease progression is the need for frequent changes in glass prescription to compensate for the rapid change in corneal shape. Eventually spectacles will no longer be able to correct for the corneal ectasia and hard contact lenses are needed. However, in the later stages of the disease even contact lenses are poorly tolerated because the cornea becomes more irregular in shape, thus compromising contact lens fit and comfort.

In moderate to advanced cases, conical protrusion of the cornea with stromal thinning, an iron line partially or completely surrounding the cone (Fleischer ring) and fine vertical lines in the posterior stroma (Vogt striae) can be detected during slit lamp examination. Anterior stromal scars may be seen at the apex of the cone in contact lens wearers with severe stage keratoconus, the result of chronic bearing of the contact lens on the protruding cornea. Other clinical signs include Munson’s sign, a V-shaped conformation of the lower lid produced by the ectatic cornea in downgaze, and Rizzuti’s sign, a sharply focused beam of light near the nasal limbus, produced by lateral illumination of the cornea in patients with advanced keratoconus. These diagnostic clinical signs have been largely supplanted by corneal topography, which can diagnose even early ectasia.

Several devices can help the clinicians in the early detection of the disease before signs are visible on exam. Computer-assisted videophotokeratoscopy (VK) is a sensitive means for detecting subtle changes in the topography of the corneal surface and allows for a detailed qualitative and quantitative analysis of corneal shape (Klyce 1984; Rabinowitz and Rasheed 1999). Placido disk-based computer videokeratoscopes have the combined features of both a keratometer and photokeratoscope, and can record curvature changes in both the central and paracentral cornea, and are thus well suited for detecting subtle topographic changes present in ‘early’ keratoconus and for documenting serial changes in corneal curvature over time (Wilson and Klyce 1991; Maguire and Bourne 1989; Maguire and Lowry 1991). In recent years, several quantitative indices that assign numeric values to certain topographic patterns have been developed to reduce interpretation of complicated videokeratographs into more manageable, easily interpretable quantitative indices (Rabinowitz and Rasheed 1999; Wilson and Klyce 1991; Maguire and Lowry 1991). Certain VK indices (Central K, I-S and KISA) are significantly increased in keratoconus patients and unaffected relatives of keratoconus patients as compared with normal controls (Wang et al. 2000). Thus, the progression of these indices may be an early sign of the development of keratoconus.

The advent of refractive surgery in the 1990s and the coincident risk of iatrogenic ectasia or unmasking of keratoconus spurred the development of newer diagnostic devices aimed at early detection of subclinical keratoconus. The Orbscan (Bausch and Lomb, Rochester, NY, USA) utilized slit scanning technology to provide wide-field pachymetry, anterior and posterior elevation, and keratometry maps. A later iteration, the Orbscan II, combined slit scanning with Placido-based topography analysis, and was shown to be more sensitive for detection of early keratoconus. Maximum posterior elevation compared with the best fit sphere (BFS), irregularity in the central 3 mm and 5 mm zones, as well as pachymetry have been found to be useful in discriminating keratoconus suspects from normal subjects (Lim et al. 2007). Increase in apex elevation, displacement of the corneal apex, decrease in thinnest-point pachymetry, and an increase in the mean simulated keratometry minimum value have been documented on serial analysis of progressive keratoconus (Sahin et al. 2008).

The Scheimpflug principle has been exploited in corneal tomographers such as the Pentacam (Oculus, Wetzlar, Germany) to provide three-dimensional mapping of the cornea, including direct measurement of anterior and posterior corneal surfaces, pachymetry, as well as anterior chamber angle characterization. A much touted feature of the Pentacam is the Belin/Ambrosio-enhanced ectasia display, which excludes a 4 mm zone centered on the thinnest portion of the cornea from the reference shape calculation. The resulting “enhanced BFS” is supposed to approximate a normal cornea closely, making subtle elevations more pronounced and possibly aiding in detection of early or subclinical keratoconus. Various indices in normal eyes, keratoconus suspects, as well as established keratoconus patients have been measured, although definite superiority over earlier devices is yet to be proven (Quisling et al. 2006; Ambrósio et al. 2006; Piñero et al. 2010; Uçakhan et al. 2011; Piñero et al. 2012; Muftuoglu et al. 2013). Recent interest has focused on characterization of aberrometry profiles as well as understanding of corneal biomechanics in keratoconus using instruments such as the Ocular Response Analyzer (Reichert Inc, Depew, NY, USA). Compared with controls, keratoconic eyes have been found to have excessive higher order aberrations and lower values of corneal hysteresis and corneal resistance factor (Maeda et al. 2002; Schweitzer et al. 2010; Johnson et al. 2011; Fontes et al. 2011; Alio et al. 2011).

Pentacam Scheimpflug tomography can detect most subclinical keratoconus cases with unremarkable topography, but performance is not as good as reported and varies considerably for each index. The overall deviation, average and maximum pachymetric progression, and maximum relational thickness indices offer the highest sensitivity, which can be improved by using optimized cutoff values. Specificity constitutes an issue for some indices and up to 10% of subclinical keratoconus cases may go undetected by this technology.

Numerous clinical studies have been carried out to recognize and measure the progressive mechanical strength reduction of the keratoconic cornea over time (Maumenee 1974; Jafri et al. 2004; Gasset et al. 1978). Measurement of corneal biomechanical behavior after crosslinking (Wittig-Silva et al. 2008; Raiskup-Wolf et al. 2008) has demonstrated that this procedure increases corneal biomechanical rigidity by approximately 300% (Wollensak et al. 2003b), increases the collagen fiber diameter by 12.2% (Wollensak et al. 2004), and promotes formation of high molecular weight collagen polymers, with a remarkable chemical stability (Wollensak and Iomdina 2009).

The Reichert Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, New York) and the Corvis (Oculus, Inc), the first simple devices able to provide an in vivo dynamic measurement of corneal viscoelastic behavior (Luce 2005; Shah et al. 2007; Ortiz et al. 2007), show a significant reduction in two parameters called corneal hysteresis (CH) and corneal resistance factor (CRF), in keratoconic eyes compared with normal eyes and can be used with topography and tomography for the early detection of the disease.

Corneal collagen crosslinking (CXL), was introduced by Wollensak et al. as a treatment to stabilize progressive keratoconus, preserve existing levels of vision and reduce the need for corneal transplantation (Wollensak et al. 2003a, b; Kohlhaas et al. 2006; Spoerl et al. 1998; Spoerl and Seiler 1999; Spoerl et al. 2004; Schilde et al. 2008). Corneal crosslinking occurs with age via intrinsic enzymatic pathways utilizing transglutaminase and lysyl oxidase (Wollensak et al. 2003a). The procedure itself, which uses ultraviolet A (UVA) light and riboflavin (photosensitizer, vitamin B2), is believed to induce physical crosslinking of collagen fibrils. Topically applied riboflavin absorbs UVA and acts as a photosensitizer to produce free radicals (oxygen singlets) that subsequently activate the native lysyl oxidase pathway (Wollensak et al. 2003a). By absorbing UVA, the riboflavin also prevents damage to deeper ocular structures, including the endothelium, lens, and retina (Wollensak et al. 2003a; Romano et al. 2012). Although there is no definite evidence that CXL produces corneal collagen and proteoglycan crosslinks, since these molecular bonds cannot be seen microscopically, ex vivo laboratory studies have demonstrated an increase in collagen fiber diameter, in stress–strain measurements of stromal tissue, and in resistance to enzymatic digestion and matrix metalloproteinase cleavage, and are believed to play a role in stabilizing the keratoconic cornea and preventing disease progression (Wollensak et al. 2003b).

Since the first report of human studies of CXL by Wollensak et al. in 2003, there have numerous publications in the peer-reviewed literature with a variety of methodologies (retrospective, prospective uncontrolled and randomized controlled trials), addressing the safety and efficacy of CXL in treating adult eyes with keratoconus as well as other corneal ectatic conditions (Wittig-Silva et al. 2008; Raiskup-Wolf et al. 2008; Wollensak et al. 2003a). These studies have provided sufficient evidence that CXL is successful in slowing or halting keratoconus progression and may even demonstrate visual, topographic and aberrometric improvement by induced corneal flattening and reduction in irregular astigmatism. Importantly, medium and long-term studies have validated an excellent safety profile for standard CXL (epithelium-off Dresden protocol), with respect to the health of corneal endothelium, lens and retina despite the potential cytotoxic effect of the UVA light. Since no permanent side effects and an acceptable complication rate were observed in adults with keratoconus (Spoerl et al. 2007; Vinciguerra et al. 2009a, b; Vinciguerra et al. 2010) when strict inclusion criteria were followed, the introduction of corneal collagen crosslinking in routine clinical practice has changed the management of keratoconus in the both the adult and the pediatric population outside the US. General practice requires documented evidence of keratoconus progression before performing CXL, although some experts argue that this is not necessary. To reduce risk of endothelial damage, a minimum corneal thickness of greater than 400 microns is recommended, although strategies such as hypotonic riboflavin may allow safe treatment of thinner corneas.

Pediatric keratoconus, occurring in patients under the age of 18, exhibits several unique characteristics. Studies have shown that pediatric keratoconus is often more advanced at diagnosis than in keratoconus in adults, with 27.8% of children beings stage 4 at diagnosis versus 7.8% of adults being stage at diagnosis (Léoni-Mesplié et al. 2012). In addition, keratoconus in children demonstrates a higher rate and rapidity of progression as compared to adult keratoconus (Li et al. 2007; Chatzis and Hafezi 2012; Al Suhaibani et al. 2007; Ertan and Muftuoglu 2008). The biomechanical rigidity of the cornea is inversely related to age (Kamiya et al. 2009) and children with keratoconus are frequent eye rubbers, especially children with coexisting VKC or other allergic eye diseases.

The impact of keratoconus in children is great. Reduced vision negatively affects the quality of life and social and educational development in children. Use of rigid contact lenses, the mainstay of vision correction in keratoconus, is more challenging in children. Corneal transplantation, the only option for visual restoration in advanced keratoconus, has a much worse prognosis in children (Lowe et al. 2011; Vanathi et al. 2009). Thus, a treatment that can prevent progression of keratoconus and reduce the need for corneal transplantation has obvious advantages in the pediatric population.

Personal experience teaches that according to the mental state and co-operation of an individual child, either general or topical anesthesia can be used for CXL. Some patients as young as 7 years can tolerate CXL under local anesthesia, especially with the support of a parent in the operating room. Other patients, even teenagers, may require general anesthesia. The duration of the procedure at present is a challenge for treatment of pediatric patients. Rapid riboflavin delivery by iontophoresis and accelerated UVA exposure (ACC CXL) may be utilized in pediatric keratoconus in the future to reduce treatment time for CXL, if these advances are validated in the adult population.

Thirty minutes before the procedure, systemic pain medication is administered and pilocarpine 2% drops are instilled in the eye to be treated. CXL is typically performed under sterile conditions in the surgical suite; some surgeons perform CXL in a laser suite or minor operating room. After topical anesthesia is applied, the patient is draped, the ocular surface is rinsed with balanced salt solution, and a lid speculum is applied. The central 9 mm of the corneal epithelium is removed with the aid of a mechanized (Amoils) brush. Before beginning UVA irradiation a photosensitizing riboflavin 0.1% solution (10 mg riboflavin-5-phosphate in 20% dextran-T-500) is applied onto the cornea every minute for 30 min to achieve adequate penetration of the solution. Using a slit lamp with the blue filter, the surgeon confirms the presence of riboflavin in the anterior chamber before ultraviolet irradiation is started. The cornea then is exposed to an ultraviolet source emanating from a solid-state device emitting light at a wavelength of 370 nm and an irradiance of 3 mW/cm² or 5.4 J/cm². Exposure lasts for 30 min, during which time the riboflavin solution is re-applied every 5 min. The cropped light beam has a 7.5-mm diameter. A calibrated ultraviolet A meter is used before treatment to check the irradiance at a 1.0-cm distance. Intraoperative pachymetry is usually performed throughout the procedure to assure that the corneal thickness remains at least 400 microns. The patient should be coached to maintain fixation on the target during irradiation; the surgeon monitors the centering of treatment. Topical anesthetics are re-applied as needed during irradiation. After surgery is complete, the patient receives cyclopentolate and levofloxacin drops. A soft bandage contact lens is applied and remains until the corneal epithelium regrows (typically 3–4 days). Topical antibiotic is given until re-epithelialization has occurred. Topical steroids are given (our regimen calls for 0.15% dexamethasone drops 3 times daily for 20 days). We also prescribe sodium hyaluronate 0.15% drops 6 times daily for 45 days to lubricate the ocular surface. In addition, patients receive oral amino acid supplements for 7 days. Patients are followed daily until re-epithelialization is complete. Proper hygiene and compliance with the medication regimen is essential to minimize the risk of any corneal infection. The use of amino acid supplements and antioxidants in the immediate preoperative and postoperative period is recommended to promote corneal re-epithelialization. For the first month after treatment the patient should avoid saunas, swimming pools and baths and direct sunlight exposure. Sunglasses are encouraged to reduce additional UV exposure.