by Donald S. Fong, MD, MPH, and Reginald Ariyasu, MD, PhD, Baldwin
Park, Calif.
For centuries, our efforts to correct nearsightedness have been focused
on modifying the light that enters the eye and more recently modifying the
refractive media of the eye. But many ophthalmologists do not realize that
in the not too distant future, we may be combatting myopia in an entirely
different manner. We may be attacking this condition at its root, by modifying
the mechanism that causes myopic eyes to grow too long. In this article,
we'll provide an update on what we know and where we are headed.
How myopia develops
Genetics undoubtedly play a substantial role in the development of refractive
error. We know that the refractive error is more similar among monozygotic
than dizygotic twins1,2 and we know that children with two myopic parents
will have longer eyes and less hyperopic refractive error than those with
one or no myopic parents.3 However, clinical and laboratory evidence strongly
suggests that environment is as important as or more important than genetics.
Ample data indicate that myopia develops as a result of prolonged exposure
to near images.
From birth to adulthood, the human eye increases its diameter by 40 percent
and its volume by 300 percent on average.4 However, as we all are aware,
some eyes grow far longer (and some far shorter) than others. Our understanding
of why this happens is far from perfect. Studies to date indicate the following:
Emmetropic eyes that accommodate for prolonged periods during near work
grow in length so that the extensive accommodation is no longer necessary.
Consider first the epidemiological evidence:
An analysis of the Health Interview Survey revealed that individuals who
read for long periods of time are more likely to have myopia.5
A large-scale study of U.S. patients showed that the incidence of myopia
increases with education. When researchers isolated patients 18 to 24 with
less than five years of schooling, they found that only 3.1 percent had
myopia. In comparison, 30 percent of patients in the same age group with
more than 12 years of education had myopia.6 Of the adult population which
did not attend college or military academies, 10 percent developed myopia.
Twenty to 40 percent of those who had higher education develop nearsightedness.7
A study of Eskimo volunteers from Barrow, Alaska8 showed that the prevalence
of myopia was 8.4 percent among parents and 58 percent among children. This
study also showed that no Eskimos over the age of 51 were myopic. Researchers
observed that prior to 1947, this community only offered the first six grades
of education. After 1947, children were required to attend through eighth
and ninth grades. Myopia in the group without compulsory education was 1.5
percent. Of those with compulsory education, 40.3 percent had myopia.
Three other studies also offer interesting findings:
In an analysis of refractive error and accommodation among patients with
diabetes enrolled in the Early Treatment Diabetic Retinopathy Study (ETDRS),
we showed a negative association between myopic refractive errors and amplitudes
of accommodation. Patients without myopia had 4.33 D of accommodation, while
those with myopia had 4.03 D of accommodation (p=0.0049). This association
was statistically significant even after controlling for age, race and occupation.1
The Beaver Dam Eye Study measured refractive error in adults 43 to 84 years
old. Prevalence of myopia increased from 14 percent in those older than
75 to 43 percent in those 43 to 54 (Table 2).9
Another study showed that the prevalence of myopia was 20 percent in persons
65 and older but 60 percent in those 23 to 34.10
We do not know the reason for these findings. But they are consistent with
the hypothesis that myopia develops because of increased near work.
The next logical question might be "How does this happen?" Once
again, we do not know for sure. But the evidence from animal studies points
to an intraocular regulatory system that causes the eye to lengthen or shorten
depending on visual stimuli.
Researchers have used several methods to manipulate the visual environment
in animals and then studied the results. They have sutured the eyelids closed,
covered the eye with translucent occluders, and blurred the retinal image
with plus and minus lenses. All have proved capable of inducing refractive
errors (Figure 1).11,12,13 Researchers have shown that placing plus lenses
in front of the eye can lead to hyperopia, while both deprivation and minus
lenses lead to myopia. Remarkably, removal of the devices can result in
reversal of the induced refractive state.14
Further research has done much to explain why this happens. Once, scientists
hypothesized that myopia developed as a result of elevated intraocular pressure
and passive stretching of the sclera.15 While the process is associated
with prolonged accommodation,16 we also know that it is not the only cause
of myopia.17, 18
Accommodation and likely other as yet unknown (and possibly more important)
mechanisms involving the retina appear to set in motion intraocular and
central nervous system feedback systems that control eye growth. We don't
yet understand the chemical process involved, but animal studies strongly
suggest the involvement of retinal dopamine (which may act on D2 receptors).19-23
Vasoactive intestinal peptide (VIP)24 and nitric oxide may also play important
roles in regulating eye growth.25 We also know that all these chemicals
are found in cells of the inner retina, suggesting an important role in
the process of eye growth.
The end result is an active remodelling of the scleral extracellular matrix,
resulting in a lengthening of the globe.26-29
Interestingly, studies indicate that intraocular processes are especially
important in regulating eye growth. In one study using chicks, researchers
cut the optic nerve in half and then exposed the baby chicks to form deprivation.
The myopia development was not grossly affected. In another study, researchers
poisoned ganglion cells and then performed the same experiment, with similar
results.30-33
Possible remedies
As we've learned more about the process of myopia development, we've also
been investigating potential therapies to slow the progress.
Many readers may be surprised to learn that an effective medical therapy
for myopia has been reported in a well-designed clinical study. A Taiwanese
study convincingly demonstrated that atropine, the strongest cycloplegic
available, is effective in slowing the progression of myopia.34 (A couple
of other studies dealing with cycloplegia35,36 also suggest a significant
treatment effect, but the follow-up in one of the studies was short and
in the other, the subjects were not randomized.) The effect may simply be
due to the paralysis of accommodation. However, studies using different
acetylcholine analogs in chicks found muscarinic antagonists can also act
through nonaccommodative mechanisms to block induced myopia.37 Type 1 muscarinic
receptors,38 but not types 2 or 3 receptors appear to be involved.
Unfortunately, cycloplegia in its current form is a less than ideal treatment
due to the associated pupillary dilation. Children using this treatment
should not play outside without the use of dark glasses, and they would
need to wear bifocals. Such drugs are also associated with a toxic and/or
allergic response in some children. A topical cycloplegic medication that
paralyzes accommodation without affecting pupillary size might slow mypia
progression without adverse side effects.
Several clinical trials have investigated the effectiveness of bifocal glasses
on the progression of myopia. Unfortunately, no study has demonstrated that
they are an effective treatment.2,3 This may be because bifocals do not
arrest accommodation completely, or because only a subgroup of children
(with nearpoint esophoria) may be responsive to such therapy. It's also
important to note that these studies had little statistical power because
of too few subjects.
Now, researchers are examining whether there may be an opportunity to regulate
chemical messengers that mediate eye growth. We know that the growth factors
TGF-ß and basic FGF influence experimentally induced myopia in chicks.
Occlusion can reduce the amount of basic
FGF found in the eye, and administering basic FGF can reduce the amount
of myopia caused by occlusion, although we don't know why.39 We also know
that TGF-
ß1 inhibits the action of bFGF in animals. However, TGF-ß1 does
not induce myopia in unoccluded eyes, or increase myopia in occluded eyes.40
Animal studies also suggest that correction of neonatal refractive errors
may arrest or reduce emmetropization processes that normally function to
reduce such errors by childhood.41 It may be better to give infants and
very young children partial correction or full correction at intermittent
wearing schedules to help modulate the process. However, we need to be very
careful with this approach, as it may not work in patients who already have
large refractive errors, anisometropia, strabismus or amblyopia. It's also
important to note that overcorrection of refractive errors may intensify
their development (although treatment of exotropes with overly powerful
minus lenses does not support this hypothesis.42
Conclusion
In the not-too-distant future, we may know substantially more about why
myopia develops and be able to influence its development using optical devices
or medications. For now, our only recommendation to parents is to avoid
prolonged near tasks for their children. Outdoor visual stimuli have high
contrast, since the contrast between sunlight and shadows is nearly a thousandfold.
More images are positioned at optical infinity, minimizing the role of accommodation.
Although not considered a disease, myopia is probably the most common condition
treated by eyecare providers. Genetics no doubt play a part in myopia, but
what is exciting about the the research so far is that treatments for environmental
factors will most likely be available before treatments for genetic factors.
While there is no clearly proven treatment for myopia, advances have now
made it time to revisit this topic and develop an effective treatment.
Dr. Fong is a retina/vitreous specialist with the Southern California Permanente
Medical Group and Assistant Clinical Professor of Ophthalmology, UCLA School
of Medicine. His interest is in the epidemiology of myopia.
Dr. Ariyasu, a cornea specialist with the Southern California Permanente
Medical Group, is Assistant Clinical Professor of Ophthalmology, UCLA School
of Medicine. His interest is in understanding refractive error development
in chicks.
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