GRABOWSKA A1, NOVAL S2, VILLAFRANCA HOLGUÍN M3, GRANADOS FERNÁNDEZ M4, PERALTA J5
Graduate in Medicine. Ophthalmology Service. La Paz University Hospital/Autonomous
University of Madrid. IdiPAZ Research Institute.
2 Ph.D. in Medicine. Pediatric Ophthalmology Service. La Paz University Hospital/Autonomous University of Madrid. IdiPAZ Research Institute.
3 Optometrician. Vissum Ophthalmological Corporation. Madrid.
4 Graduate in Medicine. Pediatric Ophthalmology Service. La Paz University Hospital/Autonomous University of Madrid. IdiPAZ Research Institute.
5 Ph.D. in Medicine. Pediatric Ophthalmology Service. La Paz University Hospital/Autonomous University of Madrid. IdiPAZ Research Institute.
Alterations in the emmetropization process can give rise to the development of refractive defects such as myopia, hypermetropia and astigmatism. Research suggests that genetic factors play a crucial role in the development of myopia and hypermetropia. However, there is evidence about the influence of environmental factors. The role of genetic factors in the development of astigmatism is controversial. This review presents the definition, prevalence and etiopathogeny of refractive errors in the pediatric population.
Emmetropization is considered to be a coordination process involving the power of the cornea, the lens and the axial length, with the input of visual stimuli, so that in the adult age the focal point will impinge on the plane of the retina. The mean refractive defect of 3 month-old infants is of +2.16 diopters (D), with a standard deviation (SD) OF 1.30 (1). The currently most accepted model considers that poor focus caused by this hypermetropic defect stimulates ocular growth in order to reduce hypermetropia (1). The mean axial length when reaching emmetropia in adult age is of 23.6 mm (SD 0.7 mm)2.
Between month 6 and 12, the increased axial length is offset with changes at the anterior pole level. The cornea diminishes its reflective power and increases its radius, while the anterior chamber goes from a depth of 2.4 mm at birth to 3.5 mm at month 12, giving rise to an increased distance between the cornea and the lens which translates in an overall refractive power reduction of 0.8. After the first year and up to the end of emmetropization, adjustments are carried out mainly in the lens, with the anterior radius going from 5 mm to 10 mm and to the posterior radius from 4 to 6 mm at the end of emmetropization. Generally, emmetropia is reached between age 9 and 14 (1,3).
Two theoretical emmetropization mechanisms have been described: one is passive, under genetic control, and the other is active under environmental control. The active emmetropization model caused by visual feedback assumes that the eye regulates its growth in response to stimuli produced by focal length errors, in an attempt to reduce said errors. At present, three active emmetropization mechanisms have been described: by deprivation (4,5), by loss of focus (6), and by drugs (7). The deprivation mechanism is observed after the occlusion of one eye, and the loss of focus mechanism by the aposition of a negative lens in the visual axis.
Both mechanisms regulate scleral growth, increasing the axial length of the ocular globe, mainly regulated by the collinergic system. The drug-induced mechanism can vary. In the case of topiramate (8), it seems related to its inhibiting effect on carbonic anhydrase and induction of cilio-choroidal effusion.
An alteration in the emmetropization process can cause the development of refractive defects such as myopia, hypermetropia and astigmatism. In children, refractive error must be measured under cycloplegia to avoid an overestimation of myopia or underestimation of hypermetropia due to its considerable accommodation capacity (9).
Simple myopia is a spherical ammetropia, i.e., that the refractive error is equal in all corneal meridians where the parallel rays coming from the infinite, instead of focalizing on the retina, focus in front of it.
The prevalence of myopia differs in published series according to its definition, the population being studied and the method utilized for refraction. The prevelance of myopia in the first year of life has been estimated between 4% and 5% (10) and increases progressively with age. The CLEERE (Collaborative Longitudinal Evaluation of Eth¬nicity and Refractive Error) (11) study on US children, which included 2523 children between 5 and 17, indicated that the prevalence of myopia was of 9.2%. Said prevalence was greater in Asian children (18.5%) followed by Latin American children (13.2%) and Africans (6.6%). The lowest prevalence was found in Caucasian children (4.4%). The results of the Pediatric Refractive Study in India (12), Chile (13), Africa (14), Malaysia (15) and China (16,17) confirmed that a low prevalence (<5%) between age 5 and 6 increases significantly up to 15 years of age. It emphasized the high prevalence (>35%) of myopia in the older and female Chinese population.
Multiple studies have demonstrated that myopization has a genetic base. Studies on twins have observed a high rate of inheritance of refractive defects and all involved components (axial length, corneal curvature and lens power). Nine loci related to myopia have been detected, including seven with dominant ausotomic inheritance pattern (21q22.3, 18p11.31, 12q21-q23, 7q36, 17q21-q22, 4q22-q27, 2q37.1), one autosomic recessive (14q22.1- q24.2) and one recessive linked to chromosome X (Xq28, Xq23-q25) (18,19). Experimental studies indicate that these genes expressed cytokines, neurotransmitters, scleral matrix proteins, and vitreous and eye growth regulators (20-22). Although the actual parallelism between myopia induced in animals with human physiological myopia, animal studies lead to a fundamental conclusion: that emmetropization is a genetically controlled process even though it depends on the visual environment.
In one third of cases there is evidence about the role of the environment in the development of myopia (23). In the past it was suggested that exposure to artificial light during the first 2 years of life constituted an important pathogenic factor. The study by Quinn et al (24) revealed that 10% of children who slept without artificial lighting, 34% who slept with a night lamp and 55% of children who slept with artificial light developed myopia. The research by Gwiazda et al (25) and Zadnick et al (26) did not confirm these results, which could suggest that nocturnal artificial lighting could have some protective effect. The differences between studies, such as the mean age of children, could influence results. Additional research is required to clarify this.
Reading habits and other near sight activities seem unrelated to the risk of developing myopia in children under 6 (27). However, these habits do seem to have an influence in children above that age. The SCORM study (Singapore Cohort Study of the Risk Factors for Myopia) (28), which assessed children between 7 and 9, concluded that the children who read more than 2 books a week had a higher probability of developing myopia above 3.0 D. An additional study carried out in the Chinese children population of Singapore and Sydney demonstrated a correlation between diminished outdoor activities and the risk of developing myopia (29). The differences between the rural environment and urban areas confirmed that the appearance of myopia is influenced by environmental factors (30).
Lower weight at birth and the severity of premature retinopathy has been associated with higher risk of myopia. Twenty percent of lactating babies with very low weight at birth (under 1,251 g) exhibit myopia in the first 2 years of life and 4.6% exhibit a severe type of myopia (>5.0 D) (31). The ETROP study (Early Treatment for Retinopathy of Prematurity) (32) observed how a 48.4% risk of developing myopia in premature retinopathy cases that resolved without treatment increased to 60.6% of cases treated at the pre-threshold high risk stage and to 80.9% in eyes treated at the threshold stage.
Finally, myopia has been associated to some ocular anomalies and systemic diseases (table 1) due to changes in the corneal curvature, in the lens refraction index or in the ocular axial length. For example, in the Marfan syndrome two possible responsible mechanisms have been described: anterior migration of the irido-lens diaphragm that anteriorly displaces the focal point of the eye and the lens thickening that increases its refractive power (33). Alterations of the elastic component of the sclera and the cornea could also cause an increase of the axial length and therefore myopia (34). A similar mechanism would account for the development of myopia in other connective tissue diseases.
This is a spherical ametropia where theoretically parallel light rays coming from a far object are refracted in such a way that they converge at a point behind the plane of the retina. The most frequent cause is a reduction of the anterior-posterior axis of the eye (axial hypermetropia) of genetic origin. However, there are other types of hypermetropias (due to curvature, index and alteration of the lens position) (table 1).
Slight hypermetropia is a physiological condition in the pediatric population. In contrast with myopia, hypermetropia usually diminishes with age. Mutti et al (1) observed in a group of 221 3-month old babies that 24.8% exhibited a cycloplegic refraction of at least 3.0 D of hypermetropia. When they were 9 months old, the prevalence has diminished to 5.4% (35). In the CLEERE study (11), the prevalence of hypermetropia also diminished with age. However, other studies indicate an increase of hypermetropia, up to age 7 (36,37). As for the prevalence of hypermetropia (at least +1.0 D) in different ethnic groups, by order of frequency it is greater in Caucasian children (32.4%) than in Latin American children (20.7%), Afro-American children (12.2%) and Asian children (12.0%) (11).
Various studies have analyzed the prevalence of high hypermetropia and its importance in the development of abnormal visual function (38,39). The data of the Mutti et al study (1) suggest that children with high hypermetropia (>5.0 D) do not achieve emmetropization, against those with low hypermetropia who usually become emmetropic.
At present it is considered that genetic factors play a crucial role in the development of hypermetropia. Studies demonstrate a higher inheritance index of hypermetropia (1-7 D) in monozygotic than in dizygotic twins (40). Population studies also exhibit familial aggregation (41). In a population of 34 newborn babies having a parent or a brother with endotropia, when they reached 6 months of age 38% exhibited at least 4 D of hypermetropia, which exceeds the prevalence for the general population at the same age (42). Inheritance is different according to the type of hypermetropia. In weak hypermetropiae up to 6 D, the inheritance pattern is autosomic dominant. In high hypermetropia, inheritance is autosomic recessive and sometimes is related with ocular and general malformations.
It has recently been suggested that the risk of developing hypermetropia is associated to childhood growth. Accordingly, any delay in general growth would interrupt the emmetropization process, giving rise to short axial length (43). This could explain the high prevalence of hypermetropia in children with growth hormone deficiency (44).
In astigmatism, light rays paralell to the eye do not meet at the same image point but on two focal lines perpendicular to each other (regular astigmatism) or without defined focus points (irregular astigmatism). This is due to the irregular or thoric surface of the cornea and lens. In childhood, astigmatism is predominantly corneal. Newborns have pointed and astigmatic corneae (generally against the rule) (fig. 1). Lens ectopia in Marfan syndrome is an example of non-corneal astigmatism. The greater prevalence of astigmatism has been observed in the first year of life (45), particularly in newborns with lower weight at birth and lower gestational age (46,47). The development of the ocular globe tends to correct astigmatism in the first years of life. The CLEERE study (11) indicated that the prevalence of astigmatism (a difference between the two corneal meridians of at least 1.0 D) also differed according to the ethnic type, being of 20% in Afro-Americans, 33.6% in Asians, 36.9% in Latin Americans and of 26.4% in Caucasian children.
Fig. 1: A: Reverse or against the rule astigmatism: the maximum power Meridian is the horizontal one (between 30º and 150º), B: Direct or as per the rule astigmatism: the maximum power Meridian is the vertical one (between 60º and 120º), C: Oblique astigmatism: when one of the main meridians is at 45º (±15º) and the other at 135º (±15º).
The influence of genetic factors is controversial. Teikari et al. (48) did not find differences between monozygotic and dizygotic twins, which would reduce the influence of genetic factors vis-à-vis environmental factors in the development of astigmatism. However, the results on the research on twins carried out by Hammond et al (49) demonstrated the opposite. Clement et al (50) analyzed data of 125 families affected by astigmatism and described a dominant autosomic inheritance pattern.
Any pathology which can produce malformations in the cornea, such as chalazion or pterygion, can induce astigmatism by altering the relationship between corneal meridians. Robb et al (51) described increases in astigmatism time in 16 of the 37 children with palpebral and orbitary hemangiomas.
Ptosis and ptosis surgery have also been described as predisposing factors for astigmatism. Patients with congenital ptosis have a higher degree of corneal topographic asymmetry as well as a higher degree of astigmatism (52). Howland et al (53) suggested that corneal astigmatism could be the result of unequal forces exerted by extraocular muscles on the cornea. In addition, the stress induced by the eyelids has been proposed as a possible factor in the development of corneal astigmatism. This would explain the high prevalence of astigmatism in Down syndrome and the increase of its power over time (54). The greater prevalence of oblique astigmatism supports this theory as the correlation between the astigmatism axis and the superior inclination of the temporal edge has been observed (55).
The exact cause of refractive defects is not yet known. Research carried out to date, mainly in twins, suggests that genetic factors play a crucial role in the development of myopia and hypermetropia. However, there is also evidence of the influence of environmental factors. The role of astigmatism is controversial. The interaction between eyelids and the tension of the extra-ocular muscles seems to explain the development of astigmatism in various ethnic groups and diseases.
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