CEGUERA
CEGUERA
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Figure 3 Histograms of the distribution of refraction in 11–13 years in Australia, Northern Ireland, and Japan.
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Table 2 Variation between refractive error and intra-pair where, R(t) is the refraction at time t; Ro is the refraction
difference in monozygotic twins from Sorsby et al48 at birth; Eg is the gain of emmetropisation controller; Rs is
Absolute refractive error (D) Absolute intra- Number of twin pairs the refractive set-point target; Et is the emmetropisation
pair differences time constant; Rc is the myopic offset; a, is the myopic
progression shape; to is the myopia onset time; Gn(t) is the
o0.5 D 40.5 D growth associated biological noise; Gb(t) is the genetic bias
o0.5 24 1 25 In essence, this model combines the four components
40.5 37 16 53 described above. First, the starting point of refraction at
birth is captured by the term Ro. Emmetropisation is
Additional breakdown of 40.5 D group captured in the simplest possible manner as an
0.75–2.0 30 9 39
2.25–4.0 6 2 8
exponential model (with parameters for the gain of
44.25 1 5 6 emmetropisation, the set-point towards which the eye
grows, and a time-constant reflecting the time-limited
There is a significant association between the refractive error and the
degree of refractive discordance with the discordance increasing with nature of the process). The modified Gompertz formula
absolute refractive error (Fisher’s exact test, two-tailed P ¼ 0.016). developed by Thorn et al33 is included to capture the
process of myopic progression as it describes this better
as much as a cause.62,63 Amblyopic eyes display different than any other model to date. The Rc and a parameters of
patterns of vitreous chamber growth to the fellow eye.64 the original model are maintained for ease of comparison
Prematurity, even in the absence of retinopathy of but the Rc parameter is omitted as the starting refraction
prematurity, has been demonstrated to impair is determined by the first two terms. The biological noise
emmetropisation in at least a subset of children.65,66 and bias terms (Gn(t) and Gb) are specified as generalised
A more dramatic failure of emmetropisation can be functions, although in general these factors only seem to
observed in Down’s syndrome despite the good visual be dominant in limited range of clinical scenarios.
acuity usually observed in this condition.67,68 It has been Equation 1 has been specified to allow calculation of
proposed that the apparent absence of emmetropisation refraction at a given age depending on the value of the
in Down’s syndrome would reveal the underlying various parameters and does not allow for interaction
pattern of genetically determined eye growth.69 The between the different components. This is clearly a
patterns of refractive development in Down’s syndrome simplification but the first three factors are largely
are instead highly variable and display the mathematical independent on the basis that the operative factors have
features of a random walk typical of a stochastic little or no temporal overlap. A more complete
process.67,68 mathematical description would specify all four
processes as part of a differential equation incorporating
stochastic components as this would provide for the
A comprehensive model of the mechanisms involved in interaction between each of the processes. Such a
refractive development treatment is beyond the scope of the current paper.
This paper has reviewed the major influences on This model allows the simulation of the distribution of
refractive development from birth to adulthood. These human refraction from birth into adulthood and each of
are the initial refraction at birth, the efficacy and duration the parameters can be estimated from existing clinical
of the emmetropisation process in the first few years of studies. To model a population, each of these parameters
life, the poorly understood mechanisms of myopia onset can be subjected to random variation using either a
and progression, stochastic influences on eye growth, Gaussian or Beta probability function, and once again
and, more rarely, sources of major genetic bias towards existing studies provide a basis for estimating such
myopia or hyperopia. This allows the creation of a model parameters. The following Monte Carlo simulations are
for the development of refractive errors from birth to based on 20 000 subjects with the parameters given in
adulthood. This model encapsulates each of these Table 3 and performed using custom Matlab (Mathworks
processes in a simple mathematical form. Equation (1) Inc., Natick, MA, USA) functions that are available from
provides a mathematical description of this model and the author on request. With the exception of the variation
Figure 7 provides an annotated explanation of each in the gain of emmetropisation (Eg), the distributions
component and parameter. chosen for the parameters listed in Table 3 were based on
published data for such parameters33 or estimated from
human distribution data from a variety of sources. As the
t
RðtÞ ¼ Ro þ Eg ðRo Rs Þ 1 e Et stochastic and bias elements are dominant only in
pathological situations, these elements have not been
t to
þ Rc 0:07295a þ Gn ðtÞ þ Gb 1 included in the following simulations.
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Emmetropisation and the aetiology of refractive errors
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Figure 7 An annotation of equation 1 describing the biological mechanisms associated with each component of the model (a) and an
annotation of equation (1) describing the biological relevance of each component parameter (b).
Table 3 Parameters and distribution models used for development in this model up to the age of 6 because of
Monte Carlo simulations of refractive developments shown in the observed age range of the to parameter (myopia onset
Figures 8 and 9
parameter), but represents a dominant shape factor at
Parameter Distribution Values Notes/modifiers older ages.
Ro Gaussian m ¼ 2.5 D s ¼ 2.2 D
Figure 8 shows the results of Monte Carlo simulations
Eg Bimodal beta a¼8 b ¼ 0.5 High-gain population from 3 months of age up to 6 years. The evolution of the
a¼3 b¼6 Low-gain population refractive distribution from a normally distributed
Rs Gaussian m ¼ 0.5 s ¼ 0.5
Et Beta a¼5 b¼2 2.0 Beta
population with wide variation to a positively skewed
Rc Beta a¼1 b¼4 10 Beta leptokurtotic population closely mirrors that seen in
a Beta a¼7 b¼6 population studies. Figure 9 extends these models from
to Beta a ¼ 1.75 b¼6 5 þ 20 Beta
age 6 years up to age 24 years. The left-hand graphs on
this figure have set 15% of the population to be
susceptible to myopic progression and the right hand
To create the behaviour observed in human popula-
graphs 55%. Both in terms of increasing myopia
tions it proved necessary to divide the population
prevalence (o 0.5 D) and the shape of the distribution
into a proportion with a high gain of emmetropisation
these graphs also mirror the statistics of refractive
(90–95% of the population) and a corresponding
distributions in low and high myopia prevalence
proportion with low gain. The variation between modern
populations.
day Australian distributions (eg Figure 3), historic UK
distributions (eg Figure 1), young Asian and older Asian
distributions (eg Figures 3 and 6) could be created by
Discussion
varying the proportion of those who undergo later
myopic progression (ie those who are both genetically This analysis of emmetropisation and the development
sensitive and exposed to myopic environmental triggers). of refractive errors are intended to provide a
This proportion has minimal impact on refractive framework for a more rational discussion and
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Figure 8 Results of Monte Carlo simulations of human refractive development from 3 months of age to 6 years.
Figure 9 Results of Monte Carlo simulations of human refractive development from 8 years of age to 24 years. The left-hand panels
model a population with a low tendency to develop myopia and the right-hand panels a population with a high tendency to develop
myopia.
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Emmetropisation and the aetiology of refractive errors
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177
approach to refractive errors. Since refractive error is the eye growth lead to refractive errors, in particular
end result of a long, complex growth process over several myopia? An intriguing suggestion is that, as shown in
decades, it is no longer valid to consider refraction in the tree shrews, the older eye loses the ability to respond to
same manner as a simple trait. Adult hyperopes and myopic defocus that might slow or halt eye growth but
myopes errors have quite different life courses in terms continues to be sensitive to hyperopic defocus that
of ocular development and would appear to be the result promotes axial elongation.69
of fundamentally different processes. Furthermore, any It seems reasonable to assume that human infant
given refractive error can be the result of a wide variety emmetropisation reflects the optically guided growth
of influences. These influences include the following: mechanisms that have been identified in lens-rearing
where in the refractive distribution range of an eye starts studies in animals. Both are most active early in life74 and
at birth; the effectiveness (ie gain) and set-point of human infants display other features that are predicted
emmetropisation; the impact of stochastic factors when by an optically guided process.75,76 Partial hyperopic
emmetropisation is deficient; the susceptibility to later correction in infants does not seem to impair the end
myopiogenic factors; the exposure to such factors; and result of emmetropisation though it does appear to slow
the regulation of the adolescent phase of ocular growth in the process.77 In keeping with the predictions of an
axial length and lens power. Therefore, rather than optically guided control model, the rate of
accepting a single figure for the heritability of refraction emmetropisation has been reported to be correlated with
we should be asking what aspects of this process are the magnitude of the initial refractive error.78 We
genetically determined, what aspects are essentially therefore have a good animal model for emmetropisation
random (stochastic) and what aspects are influenced by but we do not have an animal that helps us understand
visual experience or other environmental factors. how, in later childhood, eyes undergo a rapid refractive
The model presented in this paper is based on well- acceleration in the direction of myopia. Until we can
defined, if not fully understood, phenomena within define and understand the triggers and growth
refractive development. That a single model can provide mechanisms mediating this initial acceleration and
a mechanistic explanation of both the evolution of subsequent stabilisation, we cannot claim to explain the
refractive distributions since birth through childhood aetiology of the vast majority of myopia.
into adulthood and the variations in refractive
distribution shape seen in different adult populations is a
Conclusion
testament to validity of the underlying concepts. The
parameters also have clinical relevance and are, in the The bulk of emmetropisation occurs in early childhood
most part, measurable. The question of examining and is largely complete by age 6. Therefore, refractive
genetic and environmental contributions to refractive errors that exist at this age can be considered failures of
error may become more tangible if the different aspects emmetropisation. The commonest refractive error at age
of the refractive life-course encapsulated within this 6 is hyperopia with both anisometropia and myopia
model and its parameters are considered in isolation. being far less common at this age. Since the prevalence of
Although the term emmetropisation is often used to myopia shows a marked increase in later years, only a
describe the process where older hyperopes ‘grow out of very small proportion of myopic refractive errors can be
their glasses’,70 it is clear from this review that true attributed to a primary failure of emmetropisation.
emmetropisation occurs early in life. The process of Therefore, an understanding of how and why
growing out of their glasses, that is observed in some but emmetropisation fails will be of particular importance in
by no means all childhood hyperopes, occurs at the same understanding hyperopia rather than myopia.
age that myopia is starting to emerge. Is this late Anisometropia remains the least understood refractive
hyperopic ‘emmetropisation’ merely another abnormality and a fuller understanding may require
manifestation of the processes driving myopia onset/ the addition of chance (ie stochastic factors) to the
progression or is it an entirely different process. This is traditional pair of nature and nurture. When considering
an interesting and unanswered question. If it were true the aetiology of refractive errors it is no longer tenable to
and the factors driving myopia onset and progression consider refraction as a trait without considering the
could be determined, then such factors could be used to developmental processes involved. It is hoped that the
develop novel management strategies for the hyperopia model presented in this paper may be of assistance in
and accommodative esotropia. bringing together different aspects of eye growth.
There is clear evidence from myopia intervention While myopia has public health implications in the
studies that the growth of the older human eye is adult population,79 within paediatric ophthalmology
sensitive to optical defocus.71–73 If the human eye it is hyperopia and anisometropia that create the
remains sensitive to defocus why does the later phase of greatest morbidity. Far less attention has been devoted
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The author declares no conflict of interest.
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