Textbook on Keratoconus: New Insights Adel Barbara
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SECTION 1
2Epidemiology, Genetics and Pathology

Epidemiology of KeratoconusCHAPTER 1

Malecaze Francois,
Ancele E,
Butterworth J
 
Introduction
Keratoconus is a noninflammatory, ectatic corneal disorder that manifests later on in the disease process and involves central corneal thinning, corneal protrusion and progressive, irregular astigmatism. Classically, the disease starts in puberty and progresses throughout the third or fourth decades of life.
The pathogenesis of keratoconus is unknown. It may be due to abnormalities in the corneal epithelium, the stromal keratocytes or an extracellular matrix component.
It is probable that keratoconus is a spectrum rather than a single identifiable disease; the end result of several different pathological processes.
Although the etiology is not clearly known, several epidemiological factors such as atopy and eye rubbing have been reported to be associated with keratoconus.1
 
Incidence, Prevalence
The frequency of keratoconus in the general population is quite low: varying depending on different studies. Publications note a frequency of between 4/1000 (Applebaum 1936) and 6/1000 (Kennedy 1986),2 which has been relatively stable over the past 50 years. According to other authors, the frequency is lower, between 1 and 2.3/1000,3 or higher (2.3%), as in the population studied by Jonas in the Maharashtra region in central India.4
The incidence is approximately 1/2000 per year.1,2
The prevalence also varies according to different geographical areas. It can range from 86/1,00,000 in Denmark5 to 54.5/1,00,000 eyes in Minnesota2 to 20/1,00,000 eyes in the Asir Province in Saudi Arabia, to 1/1,00,000 eyes in England (Duke-Elder 1965) to 2.5/1,00,000 eyes in Holland.6
The figures vary greatly from one country to another according to the diagnostic criteria used by the authors. Higher incidence in certain geographic areas, such as New Zealand7 or the Asir Province in Saudi Arabia,6 could be partly explained by their population's high exposure to UV (ultraviolet) light. Kenney with publication about “the cascade hypothesis of Keratoconus” have proposed that keratoconus corneas have underlying defects in their ability to process accumulated reactive oxygen species, and that UVB is a source of reactive oxygen species.8
These differences in keratoconus frequency between the different populations studied are probably linked to the combination of several factors: genetic and environmental factors.
On the other hand, some figures are likely to be underestimated due to forme fruste keratoconus not been taken into account. These infra-clinical forms are detected more frequently among patients undergoing refractive surgery as these patients automatically benefit from a preoperative corneal topography.
Keratoconus is rarely unilateral (4% according to Lee) and clinically determined unilateral forms are in fact actually asymmetric, bilateral forms that are only detected upon performing topography examination.9,10 The number of unilateral forms has decreased as more up to date aberrometry data is able to detect early onset forme fruste keratoconus that before was not detected.
 
Epidemiological Characteristics of Affected Keratoconus Patients
 
GENDER AND HORMONAL INFLUENCE
Results concerning the male and female partition among affected keratoconus patients vary also from one study to another. Certain studies found a female dominance, such as Amsler in 1961 (65%), Hammerstein in 1972 (66%),11 Laqua in 1971 (57%)12 and more recently Jonas 4in 2009 (53%).4 Contrary to this, other studies found a male predominance: this is the case for Pouliquen in1981 (57%),13 Street in 1991 (62%),14 Pobelle-Frasson in 2002 (62%), Owens in 2003 (59%)7 and Fatima (53%)15 and Ertan (62%) in 2009. Others did not find any difference between male and female partition.16 Even though the interpretation tends to be a more male predominance, it remains modest and so it is difficult to conclude if there is a keratoconus gender dominance.
Fink in his study in 2005 based on a population studied in CLEK (Collaborative Longitudinal Evaluation of Keratoconus) reported functional patient discomforts (eye dryness) were more frequent among women, but without there being a male to female difference in clinical examination. Moreover, infected females were older (40 years versus 38 years) and had a higher frequency of familial keratoconus hereditary (17% versus 11%).17
Moreover, hormonal changes have been implicated in the development of keratoconus because of the association of puberty with disease onset. Although it is recognized that gender and sex hormones influence corneal anatomy and disease, the literature is inconclusive with regards to hormonal predilection for keratoconus. Reports of patient populations with keratoconus contain limited information about how sex hormones modulate the expression of the disease.
Spoerl et al studied the effect of estrogens on the biomechanical properties of the cornea by incubating pig corneas in 10 mmol/L of b-Estradiol solution for 7 days. The laboratory concluded a 36% reduction in the hardness of the cornea when treated with Estradiol compared to corneas incubated in the same conditions but without Estradiol.18 The hormonal status of patients and the influence this has on the biomechanical properties of the cornea could therefore contribute to the development of an ectasy.
Fink tried to show evidence for a hormonal influence on the development or evolution of keratoconus.19 He compared three groups of patients: a group H of males, a group HA (hormonally-active females) of non-menopausal females, and a group HI (hormonally-inactive females) of menopausal females. He did not find significant differences between these different groups studied.
One case report on the possibility of a hormonal influence on keratoconus was described by Gatzioufas in 2008.20 Indeed, pregnancy represents a major alteration in the maternal endocrinologic status characterized by modified function of the thyroid gland. In this study, he describes a 33-year-old pregnant woman suffering from acute keratoconus, who presented simultaneously a remarkable deterioration of the disease during gestation and thyroid gland dysfunction. Acute keratoconus in this patient coincided with the lowest plasma T4 level reached during pregnancy. This report suggests that changes in maternal thyroid hormone levels during pregnancy can aggravate the progression of keratoconus.
 
AGE
Keratoconus classically has an onset at puberty and develops until the third or fourth decade of life, after which it usually arrests. It may however commence later in life and progress or arrest at any age. It is rarely congenital.
In literature, the average age for the discovery of keratoconus is approximately 25 years:
  • Pouliquen, 1981 : 20.4 years13
  • Kennedy 1986 : 29 years2
  • Tuft, 1992 : 25 years21
  • Zadnik, 1998 : 28 years22
  • Owen, 2003 : 22.9 years7
Some authors report a premature age of onset.
Li, in a study carried out on 233 keratoconus subjects found a development of myopia at the age of 14 years with a significant decrease in the best-corrected visual acuity in 85% of the patients less than six years later. Olivares Jimenez described an age of around 15 years with a more premature development among females.23
In his study concerning an Asian population, Saini reported that eyes with severe keratoconus present at a younger average age (18.8 +/− 5.35 years) than moderate keratoconus (23.69 +/− 8.07 years).24 Likewise, Ertan reports in his study an inversed correlation between age and keratoconus severity, finding in the group of over 40 years old a frequency 10 times lower than younger subjects.16 We know that corneal collagen interfibrillar spacing decreases with age, whereas the collagen bundles become thicker. These structural changes may modify the rigidity and elasticity of the cornea. An increase in corneal rigidity with age could be a hypothesis explaining the decrease of keratoconus with increasing age.
 
ETHNICITY
Literature also claims that ethnicity is a possible risk factor. In a retrospective study carried out in the United Kingdom on 176 774 patients, Georgiou et al showed 5that keratoconus incidence was significantly higher among subjects of Asian origin (principally originating from North Pakistan) compared to Caucasian subjects (25 per 1,00,000 and 3.3 per 1,00,000 respectively, p<0.001).25 Within a population of approximately 9,00,000 patients in the United Kingdom, Pearson et al evaluated the incidence of keratoconus to be 19.6 per 1,00,000 among subjects of Asian origin compared to 4.5 per 1,00,000 among Caucasian subjects.26
Similarly, Assiri found in a popualtion from the Asir Province in Saudi Arabia, severely affected keratoconus subjects with a rapid evolution among young subjects.6
Zadnik puts forward the different ethnicity percentages represented in the American CLEK population; 68.5% Caucasian, 19.9% Black and 8.2% Hispanic.22 Reeves studied keratoconus prevalence in a Minnesota population of over 65 year olds. It diminishes with age and is higher in Caucasians compared to Blacks and Hispanics.27
With regards to Owen, he did not find any ethnicity influence on keratoconus in the New Zealand population analyzed.7
 
Role of Mechanical Factors
 
EYE RUBBING
Eye rubbing has been described as a possible risk factor inducing keratoconus.28–30
The association was described for the first time by Ridley in 1956. It's incidence within the disease history is close to 70% (varying from 12 to 80% depending on different studies) and it is often associated with allergies or mental retardation.
Tretter showed that keratoconus patients do rub their eyes more often than normal controls (80% versus 58%). The CLEK study reported that 48.2% of keratoconus patients rubbed both eyes vigorously, whereas 2.2% rubbed only one eye. Moreover, a recurrence of keratoconus after graft can occur because of itch-provoked rubbing of the eyes.31
Some studies have tried to reveal allergies as a risk factor for the development of keratoconus, however often the results were not significant enough for the atopic history, but more for the ocular rubbing effect frequently associated. Besides, asymmetric keratoconus cases, or unilateral cases, due to an excess of ocular rubbing in one eye compared to the other have been described.28,29,32,33 Coyle reported the case of an 11-year-old boy who, at the age of 5, discovered he could stop his paroxysmal atrial tachycardia by vigorously massaging OS (up to 20 times per day).34 At the age of 7, his ocular examination was normal. By the age of 11, the patient developed unilateral keratoconus OS (plano-refraction OD, −18 + 2 − 70°). Similarly, Gritz reported a patient with a history of vigorous daily ritual massage of OS leading to unilateral keratoconus OS.35
Different hypothesis of the role of eye rubbing on the development of keratoconus have been proposed: Cristina Kenney et al hypothesized a pathway whereby a stressor (UVB, atopy, eye rubbing, contact lens) leads initially to oxidative damage or cellular disruption.36 Irreversible damage may lead to cellular apoptosis with loss of the stroma. Reversible damage, on the other hand, may lead to repair with increased activities of degradative substances (lysosomal enzymes, gelatinase, proteinase inhibitor, IL-1 receptor, prostaglandin E2). Tissue remodeling and fibrosis are the final result of reversible damage. Theoretically, epithelial microtrauma from any mechanism including eye rubbing, contact lens wear, and atopy could release IL-1. The hypersensitive keratocytes in a susceptible individual, with increased numbers of IL-1 receptors, could undergo apoptosis and tissue remodeling, leading to the clinical findings of keratoconus.
We can believe that the microtrauma of eye rubbing by susceptible individuals injures the epithelium, leading to cytokine release, myofibroblast differentiation, a change in biomechanical forces, and thinning of corneal tissue, which produces the ectatic process recognized as keratoconus. In fact, trauma may be the common underlying factor in eye rubbing, vernal and atopic disease, contact lens wear, and Down syndrome that, via a common biochemical cascade, leads to development of keratoconus. Clinicians should question patients with keratoconus about ocular trauma and advise them to discontinue activities that may cause progression of the disease.
 
FLOPPY EYELID SYNDROME
This often unknown syndrome is a tissue hyperlaxity problem concerning the static palpebral. A possible association with keratoconus was suggested in some publications.37–39 Accordingly, among the 5 cases infected by this syndrome described by Donnenfeld, the only patient displaying a bilateral keratoconus also 6expressed floppy eyelid syndrome, whereas the other cases presented a unilateral keratoconus on the same side.38
Woo Jae Lee studied the different associated ocular defects within a population of 18 floppy eyelid syndrome patients. He found 28% suffered from a superficial punctate keratitis and 1 keratoconus patient in 3 (17% of cases). Keratoconus was bilateral in 1 case and unilateral in the 2 other cases. Others suffered from the presence of corneal astigmatism or corneal opacities.10
Sleep apnea syndrome induces intermittent hypoxia, together with local mechanical factors (sleeping face down,) that have been suggested as pathogenic mechanisms that lead to floppy eyelids, keratoconus and corneal endothelial dystrophy.
Mojon confirms his association with floppy eyelid syndrome in his study carried out on 72 patients suffering from sleep apnea syndrome. Only 1 patient expresses a bilateral keratoconus.40 Another study found a significant relationship between floppy eyelid syndrome, sleep apnea and keratoconus.41
These 2 studies raise the question of the possible influence of sleeping face down position on keratoconus development.
 
Role of Atopy
The association between atopy and keratoconus was first reported at the beginning of the 20th century in a number of descriptive studies. The first reported association was described by Hilgartner et al in 1937. Since then many conflicting reports have been published. Brunsting et al in 1955, Galin and Berger in 1958,42 Spencer and Fisher in 1959,43 and Roth and Kierland in 1964,44 diagnosed keratoconus in only a small number of patients from a large series of atopic individuals. Furthermore, Lowell and Carroll in 1970 in an analytical study, found no significant difference between the incidence of atopic traits in keratoconus patients when compared with a group of controls.45 Despite the low rate of keratoconus in these published reports, Copeman in 1965 reported that 32% of patients with keratoconus had eczema compared with a 3% incidence of eczema in the general population.46 However, two thirds of these patients admitted that they rubbed their eyes excessively making it unclear whether atopy itself or the eye rubbing was the most important factor in the etiology of keratoconus. Davies et al in 1976, in a controlled study reported a history of atopy in 35% of keratoconus cases, compared with 12% in the control group.47 In a large controlled study, Rahi proved within a series of 182 keratoconus cases a higher frequency of allergic diseases (35%) compared to a control group (12%), as well as higher IgE plasma levels. Asthma, eczema and seasonal allergic rhinitis (hay fever) were the most frequent.48 Gasset et al showed in a survey of 162 keratoconus patients that the prevalence of asthma was 1% in the control group compared with 17.9% in the keratoconus group.49
A study in Dundee revealed an associated skin disorder in 34% of patients, hay fever in 36%, and asthma in 21%.50
A more recent study by the same author discovered in a population of 200 patients: 23% asthmatic cases, 14% eczematic cases and 30% allergic rhinitic cases.51
Harrison found the presence of one or several atopy histories among 56.7% of patients.52 Watchtmeister equally confirms this association.53 Moreover, in their two studies Bawazeer and McMonnies54,55 insist on the implication of ocular rubbing in the pathogenesis of the disease. Besides, the latest study mentioned indicated a significant correlation between the dominant hand and the most keratoconic evolved eye.
A publication in 1997 by Jacq revealed a significant difference concerning the positiveness of allergic tests (positive prick tests) between the keratoconus group (63.6%) and respectively the infraclinic keratoconus group (23.5%) and the control group (22.7%).56 Despite this, the videotopography study of patients carrying an ocular allergy did not give any proof of images displaying keratoconus or infraclinical keratoconus.
In conclusion, atopy exists in approximately 25% of cases associated with keratoconus but the nature of this association is uncertain as atopy is also common in the general population.
 
Association with Connective Tissue Disorders
There are several reports linking keratoconus and connective tissue disorders, such as Ehlers-Danlos syndrome, osteogenesis imperfecta and mitral valve prolapse, suggesting that keratoconus may be the result of a localized dysfunction of collagen metabolism.57
 
EHLERS-DANLOS SYNDROME
Within this group of tissue disorders, some studies make reference to Ehlers-Danlos syndrome, a rare mesodermal dysplasia affecting collagen and elastic tissue.7
Kuming in 1977 was one of the first authors to claim an association between this disorder and keratoconus. Keratoconus manifested by these patients remains rare.58 For example, McDermott found only one patient presenting a keratoconus by corneal topography among 72 patients infected with Ehlers-Danlos syndrome.59 It was Robertson in his study in 1975 that found the highest number of associated keratoconus cases: within 44 affected patients, 50% had a ligament hyperlaxity relating to the fingers associated with type II Ehlers-Danlos syndrome.60
 
MARFAN SYNDROME
Likewise, Marfan syndrome has also been associated to keratoconus.
Marfan syndrome is the most frequent conjunctive tissue hereditary dystrophy and is usually autosomal dominant. Most associated ocular disorders are increased axial length, lens subluxation and retinal detachment. Association with keratoconus remains relatively rare.61
 
LOBSTEIN'S DISEASE
Osteogenesis imperfecta is a hereditary disease more commonly known as “Lobstein's disease”. It is related to a collagen type I anomaly and is expressed as an excessive bone fragility and repetitive fractures. The most frequent ophthalmologic manifestation is a nature of a “blue sclera”. A keratoconus (nonevolutive after puberty) was described in some Lobstein's disease families.62,63
 
MITRAL VALVE PROLAPSE
Mitral valve prolapse according to some is more frequently associated to keratoconus.64,65 For others, there is no relation between keratoconus and mitral valve prolapse.14
The prevalence in the general population is 2.4% and its diagnosis is made by echography. Lichter carried out a corneal topography of 36 mitral valve prolapse infected patients (echographically proven) and 25 control patients. A keratoconus was detected in 22% of the mitral valve prolapse infected group compared to only 4% of patients in the control group.64 Sharif studied mitral valve prolapse prevalence among 50 keratoconus patients. This (58%) was much higher than that of the control group (7%).65 These results oppose those obtained by Street in 1991.14 This study did not find any difference in the prevalence of mitral valve prolapse between the control and keratoconus group.
Frasson in 2003 published a study in which a cardiac echography of 50 keratoconus affected patients was carried out: 22% expressed a mitral valve anomaly (prolapse 4%, mitral insufficiency 10% and mitral regurgitation 8%). This prevalence is four times higher than in the general population. Within these patients, the genuine prolapses identified concerned patients with a developed phase of the disease.
A possible hypothesis that could explain an association between keratoconus and mitral valve prolapse is the presence of some common collagen types shared between these two disorders.
 
Association with Down Syndrome
Among the 143 Down syndrome infected patients studied by Cullen in 1963, 5.5% expressed a keratoconus. The other most manifested ophthalmologic defects were cataract (15%) and convergent strabismus (32%).66 Pierse, Slusher, Kenyon67–69 and many other authors have shown a higher incidence of acute keratoconus cases among patients having undergone ocular traumatisms more frequently. Overall, the rate of postoperative complications after transplant remains higher (stitch breaking, traumatism, rejection…) compared to the general population. However, Wroblewski over a period of 35 months obtained good results in terms of the transparency of the transplants, and only some cases of postoperative complications due to stitch breaking.70 Among a series of 39 transfixing transplants, Garcia Garcia sites 15 cases of rejection. In his study, the most frequent postoperative complications were vernal keratoconjunctivitis and cataract.71 He insists on the idea of using this surgery for cases with a minimum of mental retardation, with moderate compulsive behaviors concerning the eyes, in order to decrease the risk of postoperative failure. On the contrary, his study forces the preference for such patients a lamellar transplant other than a transfixing transplant.
On the other hand, it would seem that keratoconus frequency of Down syndrome patients would vary according to the ethnic group studied. Thus, a study involving 60 infected Down syndrome patients living in Malaysia discovered a higher incidence of other ocular 8defects, such as epicanthus, nystagmus or even strabismus. Nevertheless, no keratoconus cases were found.72 Conversely, Shapiro found a keratoconus frequency of 15% within a population of 53 Down syndrome patients of Caucasian origin.73
Keratoconus prevalence in Down syndrome is 10 to 300 times higher than in the general population. This fact implies the intervention of chromosome 21 in keratoconus physiopathology. Several genetic studies have been carried out but no mutation has been put forward to date. As a result, Rabinowitz studied the alpha 1 coding gene of collagen 4 as a candidate localized on chromosome 21. The implication of this locus was excluded for the disease.74
 
Other Associations
 
DIABETES
The association with diabetes has been analyzed but diabetes prevalence with keratoconus is not higher than in the general population. On the other hand, diabetic patients develop less severe forms.75 A hypothesis could be the appearance of biochemical property modifications of the cornea due to abnormal glycosylation of stromal collagen fibers in the cornea of the diabetic. The protective effect of diabetes could be explained by the induction of cross-links in the stroma, preventing biomechanical weakening of the cornea. This hypo-thesis is also explained by Seller who reports a protective effect of type 2 diabetes on the appearance of keratoconus.
 
OTHER OPHTHALMOLOGICAL GENETIC DISEASES
 
Leber's Congenital Amaurosis
Leber's congenital amaurosis is a hereditary disease causing bad eye sight from birth. This disease seems to be more frequently associated to keratoconus compared to other blinding diseases.76 Repeated ocular rubbing (“oculo-digital” signs) is definitely a favorising factor, although a genetic factor could also be the cause. The hypothesis of a genetic link between these two diseases is discussed by Stoiber in the observation of a recurrent very premature and bilateral keratoconus after transplantation of a young infected Leber's congenital amaurosis patient.77
 
Corneal Dystrophies
Keratoconus can very rarely be associated with corneal dystrophies.
 
Endothelial dystrophies
Darlington reported a case in which documented bilateral, but asymmetric keratoconus, was associated with unilateral corneal guttata in the more involved eye.78
 
Macular dystrophy
Association with macular dystrophy has been described by several authors. Javadi describes two cases of macular dystrophy associated to keratoconus with histopathological evidence.79
Biochemical similarities have been seen in the two entities: both keratoconus corneas and those with macular dystrophy show decreased levels of keratan sulfate and an increased ratio of dermatan to keratan sulfate. Regarding these findings, one can hypothesize a biochemical alteration in collagen fibril size or packing induced by the abnormal deposits in macular dystrophy, which may predispose to thinning and ectasia. On the other hand, this association might be caused by a single genetic alteration.
 
Granular dystrophy
Granular dystrophy can also be associated to keratoconus.80,81 In this case, carrying out a lamellar transplant is preferential for a keratoconus in case of dystrophy deterioration. Mitsui described a keratoconus infected familial case also associated with granular dystrophy.82
 
Posterior polymorphous corneal dystrophy
Posterior polymorphous corneal dystrophy (PPCD) is a rare, usually autosomal dominant, bilateral dystrophy of the Descemet membrane. Cases of keratoconus associated with posterior polymorphous corneal dystrophy have also been reported in literature. Gasset and Zimmerman were the first to describe the association in 1974.83 After, other studies were published on the subject,84 similarly with descriptions of familial cases.85
 
Conclusion
The mutations responsible for these diseases have not been encountered in nonsyndromic keratoconus, by far the most frequent form.
 
TOBACCO
Spoerl published a study in 2008 on 180 infected keratoconus patients treated with crosslinking. He found 9a negative correlation between nonsmokers and keratoconus. He suggests that the products in cigarettes enhance collagen fiber crosslinking in the cornea and therefore lead to the prevention of keratoconus.86 The study by Hafezi et al is in favor of this hypothesis as they find an increase in CH and CRF in corneas of patients that smoke compared to nonsmokers.87
These results suggest that chronic smoking has a beneficial effect on corneal biomechanics. Obviously, we do not recommend tobacco smoking in patients suffering from keratoconus due to the associated health risks.
 
Conclusion
Keratoconus is probably one of the most frequent “rare disease”. The prevalence is still certainly underestimated as suggested by recent publications using modern topographic devices (with a high capacity of detection of forme fruste keratoconus).
Epidemiological studies on keratoconus have shown that, as many other diseases, is a multifactorial disease with a genetic and environmental influence. The epidemiological studies outlined the contribution of environmental factors but didn't make it easier to discover the mechanism responsible for keratoconus.
In 2010, keratoconus remains a mysterious disease. A lot of effort is being made to try to understand keratoconus. New techniques are getting us closer.
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