Emmetropization
Refractive errors exist when the length of the eye and its optical power
mismatch. There are two broad classes of refractive errors, myopia,
where the eye is too long for its optical (refracting) power, and hyperopia,
where the eye is relatively too short for its optical power. Most of us
are born with significant refractive errors, as are most young animals,
but these refractive errors generally disappear with development. This
process is termed emmetropization, and while at least
part of the refractive changes can be explained as an optical consequence
of normal developmental eye enlargement, there is now convincing evidence
from animal studies that eye growth is actively regulated and vision-dependent.
Specifically, emmetropization is dependent on normal visual experience,
and when this is lacking, refractive errors are the end result.
Animal models
for myopia & emmetropization
What do we know about emmetropization and the processes leading to the
development of myopia? Early animal studies made use of a form
deprivation paradigm. In most young animals, form deprivation,
either using diffusers to cover the eyes or lid suture, leads to excessive
eye growth and axial myopia. In human infants, cataracts and ptosis impose
equivalent conditions and have also been linked to excessive eye growth.
These studies imply that normal visual experience is required for normal
refractive development.
In normal development, emmetropization eliminates pre-existing refractive
errors. However, experimentally imposed focusing errors
(refractive errors) also trigger emmetropization: for example, with hyperopia
imposed with negative defocusing lenses, the eye elongates and with imposed
myopia (with positive defocusing lenses), eye growth is inhibited. In
both cases, the end result in young animals is emmetropia with the lenses
in place. Without the lenses, these eyes are myopic in the former case
(lens-induced myopia), and hyperopic in the latter case
(lens-induced hyperopia). Young chicks are able to compensate
for a wide range of imposed focusing errors in this way, but this capacity
is not unique to chicks; other animals, including tree shrews and monkeys
show active emmetropization although their response ranges
are more limited and the timing of such treatment seems to be more critical
to effective compensation.
What are the
cues to defocus for emmetropization?
The bidirectionality of the compensatory responses in the chick suggests
that the eye can distinguish between myopic and hyperopic defocus. However,
attempts to track down the cues that might be used have so far not been
successful. We, among others, have shown that neither chromatic
aberration alone or combined with accommodation
is essential to this response. Monochromatic aberrations
have become a more recent focus of research, partly driven by reports
that human myopes are more aberrated than normal.
There
also is on-going debate as to whether compensation is truly bi-directional;
an alternative uni-directional model has been proposed based on the assumption
that blur alone is sufficient to drive these response
patterns, specifically, that ocular growth directly reflects the amount
of blur experienced. This is a hot area in this field of research. Rhythmic
changes have been observed in ocular dimensions that follow a diurnal
pattern; as these changes inevitably affect ocular focus, it is possible
but yet to be established that they may play at least an indirect role
in determining ocular focus.
What
is the signal pathway for eye growth regulation?
Studies
in chick provide convincing evidence that the eye is not dependent on
the brain for growth regulation; we have shown that eyes can emmetropize,
even when the link with the brain via the optic nerve is severed although
there is some indication that the brain is required for fine tuning. The
hot news is that the expression of ZENK, an immediately
early gene and a common marker for rapid cellular responses to external
stimuli, increases and decreases with myopic and hyperopic defocus respectively
in a subclass of retinal amacrine cells, the glucagonergic amacrine
cells. The implication of this result is there are defocus selective
pathways within the retina. How this selectivity property is conferred
glucagonergic amacrine cells and how their signal is transferred to the
two main effector tissues, the choroid and sclera, is yet another hot
topic. The application of neurotoxins to selectively inactive subpopulations
of retinal cells is one of the approaches being used to tease out the
retinal circuitry involved.
Emmetropization
- What are the contributions of the choroid & sclera?
A novel finding in the chick that has since been corroborated in other
animals is that the choroid can rapidly modulate its thickness, in so
doing, varying the position of the retina and thus the state of focus
of the eye. Traditionally, the vascular choroid has assigned the far similar
role of supplying surrounding tissues with nutrients. "Choroidal
accommodation" can lead to increases in thickness of over
100 m? in a day in the chick. We understand relatively little about the
mechanisms underlying these thickness changes and their regulation. Choroidal
blood flow changes occur in the same direction as the thickness changes,
yet precede them, raising the possibility that they trigger the latter.
The thickened choroids have increased protein and water content, with
the main expansion taking place mainly in the outer layers where lacunae,
lymphatic-like vessels, reside.
The sclera constitutes
the outer support structure of the eye, and also contributes to defocus
compensation although it responds more slowly than the choroid. Choroidal
thinning is coupled to increased scleral growth and vice versa, choroidal
thickening with decreased scleral growth. Thus, at an optical level, their
responses are complementary. Whether they represent two independent mechanisms
that are independently regulated is yet to be resolved. Another piece
of hot news is that retinoic acid (RA) may play a critical
regulatory role; impose focusing errors produce opposite effects on the
levels of RA in the retina and choroid (thick choroids have increased
RA), and RA also inhibits scleral proteoglycan synthesis. There is interest
in the sclera as a target for pharmacological intervention in myopia.
The interrelationship between biochemical and biomechanical changes in
the sclera, and intraocular pressure, and their significance for eye size
changes is another area of on-going research.
Can eye growth
be manipulated pharmocologically?
There is significant incentive to come up with a drug that could be used
to either prevent the development or slow the progression of human myopia.
Attention to date has been mostly directed at two drug groups, dopamine
analogs, and antimuscarinic drugs. That dopamine analogs influence
eye growth is perhaps not surprising as in the retina, DA modulates contrast
sensitivity and image contrast is altered by defocus. However, the data
are not overly promising. There is also the added problem with this drug
group in terms of efficacy for treating human myopia, in that any drug
mediating its effects through changes in retinal function is likely to
be problematic in terms of side-effects. Antimuscarinic drugs
hold more promise as they appear to directly inhibit scleral growth. The
selective drug, pirenzepine, is now in clinical trial.
However, there are many other possible candidates including retinoic
acid analogs.
Human myopia
The concept that the more common form of human myopia might be visually-driven
is not new. At the turn of the century, special management strategies
to include hygiene desk and sea voyages were being used to counter the
presumed harmful effects of near work. There also is much anecdotal evidence
linking near work and myopia and recent studies provide more direct evidence
of links between visual activities and myopia.
Does near
work cause myopia and why?
Of the many theories that abound, two fit well with evidence from animal
studies. One theory argues that printed text, as most commonly encountered
in near work activities, acts as a form deprivation stimulus for all but
the central retina. On the other hand that human myopia could be a response
to hyperopic defocus is consistent with observations of increased lags
of accommodation in developing and progressing myopes. However,
the picture is by no means clear-cut in terms of causality. Also, that
eyes may progress at different rates leading to significant anisometropia
is not easily covered by this hypothesis. Currently in this area, there
are more questions than answers.
What do we
know about human myopia?
Although biometric studies are available to provide good evidence that
myopia is mainly axial in origin, there are many missing links in our
knowledge. Although myopes are over-represented in glaucoma statistics,
data are equivocal in terms of whether myopia is causally linked to increased
IOP, and much is left to be learnt about the scleral changes underlying
ocular enlargement in human myopia. More recently, attention has been
focused on ocular optical aberrations as a possible cause
of retinal image degradation leading to myopia. However, while increased
aberrations have been linked to myopia, here also the data are equivocal
and causality not established. Nonetheless, this is another hot topic.
That bifocal corrections trialed as a treatment for myopia, appear to
be somewhat successful in those exhibiting esophoria
(overconvergence) at close distances, supports the notion that defocus
may underlie myopia progression for this subgroup of myopes. Finally,
the possibility that there are diurnal rhythms in humans,
like those identified in the chick and marmoset for growth and intraocular
pressure, and the further possibility that they might be altered in myopic
eyes is only now being explored.
Myopia control
treatments
The most promising results to-date have come from pharmacological treatments.
Atropine is one of two drugs that appear to slow myopia progression. Atropine
is better known as one of the drug used to dilate the pupil of the eye
and/or prevent accommodation in the diagnostic and treatment of ocular
diseases. It is a very potent drug and is not without side-effects as
a myopia treatment; bifocal corrections and sun glasses are also generally
necessary adjuncts to this therapy. A related, more selective drug, pirenzepine,
is currently in clinical trial. As alluded to already above, bifocal
corrections have also been trialed as myopia treatments, with
“esophoric myopes” being the most likely to benefit. Finally,
the possibility that rigid contact lenses may slow the progression of
myopia is attracting renewed interest; existing evidence in support of
their use is mostly anecdotal. Note that rigid contact lenses may also
be used to mold the front corneal surface of the eye and so reduce its
refracting (focusing) power. In some patients the reduction in myopia
achieved by sleeping in such lenses is sufficient to allow them to go
without optical correction during the day. The modern version of this
technique is known as corneal refractive therapy (CRT).
This technique is more closely related to the refractive surgery
procedures (PRK, Lasik), that also modify the optical power of the cornea.
Neither qualify as treatments as neither are known to slow ocular growth.
Abnormal vision
and refractive development.
Experimental paradigms for studying myopia make use optical and/or neurotoxic
manipulations to alter eye growth and thus refractive development. Ocular
pathologies that preclude normal vision in early life are likely to and,
in most cases, do interfere with emmetropization. As already indicated,
form deprivation in animal studies has analogies in conditions that affect
the ocular media such as cataracts and ptosis that have been linked to
increased ocular growth. In addition, conditions that affect the retina,
for example, albinism, also perturb emmetropization.
Potentially of interest here is that specific conditions appear to have
characteristic refractive patterns. Understanding these conditions better
through more thorough documentation of their developmental profiles has
the potential to provide new insights into the emmetropization process.
