Are there drugs against myopia and where can I get them?
(a)
Atropine, a relatively unspecific muscarinic antagonist, has been
found effective against myopia development in children (literature
for example: Shih et al, 2001; see
medline, look for "shih" and "atropine").
However, it paralyzes accommodation (no focus for close objects,
reading glasses necessary) and its mode of action is complex (at
least 5 targets of action). Used in the far East, rarely in Europe
or USA.
The effect of atropine on
myopia has recently been more extensively examined in the "Atropine
in the Treatment of Myopia" ("ATOM") study (Singapore)
in which initially 400 myopic children (refractions -1 to -6D) were
randomly assigned to either 1% atropine eye drops, given unilaterally
every evening, or to placebo treatment.
After one year, the myopia progression in the placebo-treated eyes
was -0.76 D ± 0.44 D but in the atropine-treated eyes there
was a regression of myopia by +0.3 D ± 0.50 D (difference
p < 0.0001). Axial length increased by +0.20 mm ± 0.30
mm and even regressed by -0.14 mm ± 0.28 mm (p < 0.0001),
respectively.
After 2 years, the increase in myopia was -1.20 D ± 0.69
D, versus -0.25D ± 0.92 D in the atropine treated eyes.
At a special interest group meeting at ARVO 2004, it was shown that,
after 24 months, myopia started to progress also in the atropine
treated eyes, so that the largest difference between atropine and
vehicle treatment occurred probably at 1.5 -2 years.
This study also showed that younger kids are more sensitive to atropine
treatment, and that slowly progressing myopes showed better effects.
Generally, it looks as if
the eyes adapt to atropine treatment so that the effects on myopia
wear out. The assumption receives support from the observation that
the pupils appear no longer fully dilated after 2 years of continuous
atropine treatment.
(b)
Pirenzepine has been claimed to reduce myopia progression in children
by about 50% (= 0.26D less myopia progression in 12 months, 117
children with Pirenzepine 2%, 57 with placebo, ages 8-12 years;
Siatkowski et al, ARVO 2003, Poster #4778).
However, similar to atropine,
the effects of pirenzepine on myopia progression occur mostly in
the first year of treatment. In addition, pirenzepine is generally
less potent and, to achieve a significant effect, a 6mm strip of
pirenzepine gel (2%) had to be placed in the cul de sac every evening.
Subconjunctival injections of Pirenzepine in rhesus monkeys have
shown (ARVO 2004, #1745, see
"abstractsonline.com", search for "Glasser")
that significant reductions of accommodation amplitudes and pupil
responses occur already with a 0.02% concentration of the injected
solution, suggesting that pirenzepine is no longer M1 receptor-specific
even at this low dose. At a concentration of 2%, as used in myopia
treatment, it is likely that Pirenzepine binds to all muscarinic
and probably also to other receptors.
The patent for Pirenzepine treatment of myopia was licensed by Novartis
at the begin of 2003.
However, it was returned
to ValleyForge at the end of the year, perhaps because the data
from the second year of the trial were less convincing than expected.
Currently, it is no longer
so clear whether Pirenzepine will become commercially available
in the near future as an accompanying therapy for myopia in children.
Also, the mechanisms by which Pirenzepine exerts its effects on
myopia are still poorly understood, and there are almost no data
on its effects on retinal function.
Since Pirenzepine did not show reliable effects on myopia progression after extended application, the phase III clinical study was not undertaken and it will not be marketed.
Fig. 1: After some time with Merck, the patent
was returned to the University of Pennsilvania but then taken over
by Valley Forge
Fig. 2
Fig. 3: January 2003
Pirenzepine has been licensed by Novartis from Valley Forge
(c)
Glucagon: selective agent against deprivation and lens induced myopia
in chickens.
Even more powerful than glucagon itself was Oxyntomodulin, also
a glucagon-related peptide (Vessey, Rushford and Stell, ARVO 2004,
#1231; see
"abstractsonline.com", search for "Stell").
The retinal glucagon pathway seems to be a promising target for
pharmacological intervention. However, glucagon could not be detected
in the retina of mammals. It is necessary to uncover the peptides
that have taken over its function in emmetropization.
No data yet from other vertebrates.
(d)
Dopamine agonists have regained some interest recently. However,
they require extensive studies on possible changes in visual function.
What other possibilities are there to reduce myopia progression?
(a)
There are human data suggesting that a "good" reading
distance (30 cm or more) is important; (see
medline, look for "Parssinen" and "Lyyra",
1993).
(b)
In chickens, there is some evidence that poor illumination can increase
myopia development; (see
medline, look for "Feldkaemper M.", 1999).
(c)
There are a number of studies suggesting that reading glasses (plus
lenses) may be beneficial.
However, the biggest effects were found in the far East; (see
medline, look for "Leung J.T." and "Brown
B.").
Less was found in the US; (see
medline, look for "Fulk G.", 2000). It is not
clear at present whether reading glasses should be prescribed to
children with progressing myopia (see also the COMET
study).
The results of the COMET
study were disclosed in the April issue of Investigative Ophthalmology
and Visual Science, the highest impact journal in Ophthalmology
The results are: similar
to previous studies, progressive addition lense reduced the myopia
progression a little bit (although this was statistically highly
significant). (fig.4)
However, the authors consider
the effect as "clinically not significant". This means,
there is no justification to prescribe reading glasses to children
with progressing myopia because the effect is only 14% reduction.
Even after 3 years with reading glasses, the difference between
the children with normal spectacles and with reading glasses was
only about 0.2D.
Nevertheless, the COMET study
shows convincingly that the spectacles have a significant effect
on refractive development also in humans. This was proposed based
on results form animal models already in 1988.
At ARVO 2004, it was shown
which subset of children in the COMET study responded best to the
treatment with progressive addition lenses (PAL). In children with
(1) near esophoria (eyes more crossed during reading), (2) lag of
accommodation more than 0.43 D (=more than the total group average),
(3) less myopia than -2.25 (which were also the slower progressors),
the PALs were actually quite effective, with an average reduction
in myopia progression by about 50% (Jane Gwiazda, Boston). The best
age for starting the treatment is 8 to 9 years (Leslie Hyman, Director,
COMET coordination center). This indicates that a kid should be
selected for treatment based on the criteria listed above.
Fig. 4: Largest study with progressive addition lenses
Fig 5: Results of the COMET study
(d)
There is also some evidence that hard contact lenses may reduce
myopia progression in children (see
medline; enter "RGP lenses myopia"), although
not in all cases.
Currently, the "Contact lens and myopia progression" study
(CLAMP study) is underway in the USA to finally clarify this question
(Jeff Walline, Columbus, Ohio).
The outcome of a major study on the effect of hard contact lenses on myopia progression was not very convinving, which made the authors conclude that "RGPs (rigid gas permeable contact lenses) should not be prescribed primarily for myopia control":
Walline JJ, Jones LA, Mutti DO, Zadnik K. A randomized trial of the effects of rigid contact lenses on myopia progression. Arch Ophthalmol. 2004 Dec;122(12):1760-6
(e)
Results from animal models show that much less myopia is induced
if the treatment with negative lenses or frosted occluders is interrupted
for only a few minutes; (see
medline, look for "Smith E., myopia", and "Wallman
J., myopia").
It is possible that also short periods of interruption of reading
and looking at a distance may be an effective way to reduce myopia
progression.
It is also interesting that defocus imposed by positive lenses (focussed
image in front of the retina) is extremely powerful to inhibit axail
eye growth in animal models. Four times of positive lenses wear
for only 2 minutes per day can completely suppress myopia development
that woould otherwise be induced by negative lenses, worn for the
remaining part of the day.
At ARVO 2004, the laboratory of Josh Wallman, New York, presented
data showing that the signal for inhibition of axial eye growth
is generated by positive lenses in only 2 minutes (Zhu, Liu, Ganiez
and Wallman, ARVO 2004, # 4285) ... does this mean that 2 minutes
of interruption of reading would be sufficient to inhibit reading-induced
myopia also in humans? (see abstractsonline.com,
search for "Wallman")
(f)
The results of the animal experiments suggest that myopia correction
by spectacles should be done hesitating (although it is clear the
good correction is necessary for driving and in lectures or school).
Low myopes could read without glasses and higher myopes with their
previous spectacle corrections, to reduce the lag of accommodation
(see Anne
Seidemann).
Since full correction at all viewing distances is
assumed to promote the progression of myopia in children, it has
been common to correct myopia not fully but perhaps a quarter of
a diopter below perfect distance correction.
This practice was challenged
by a recent study by Chung et al (Vision Research 2002) which attracted
considerable attention in the public media. It was claimed that
the "wrong" (under) correction would result in faster,
rather than slower, myopia progression and that the correction scheme
should be revised. (fig. 6)
However, one should not ignore the magnitude of the effect. Given
that the undercorrection was quite severe (0.75D), the difference
in refraction in both groups was only 0.23D in two years (which
was statistically surprisingly significant, given that the relatively
small group sizes of about 45). It may be necessary to wait for
the results of more studies from Europe or the US before the current
correction strategy is changed.
A summary of the different
attempts to inhibit myopia progression is shown in the picture below
(re-plotted after Dr. Wei-Han Chua, presented at ARVO 2004).
A summary of the different
attempts to inhibit myopia progression is shown in the two pictures
fig. 7, fig. 8, (re-plotted after Dr. Wei-Han Chua, presented at
ARVO 2004).
The first shows the effects on myopia development after 1 year of
treatment, the second after two years of treatment. Note that atropine
in the first year is by far the most powerful intervention. Note
also that the effect of undercorrection is small despite its surprising
significance, given the relatively low number of subjects.
It may be quite important, perhaps more than the animal experiments
suggest. It is disturbing that none of the animals would have become
myopic without lens or occluder treatment. Yet, a number of kids
become myopic even though their visual experience is not very different
from other kids who remain emmetropic. As long as we don't know
how important the visual input is in myopia in humans, it can also
not be determined, how effective suggestions a - f in (2) are. If
the genetic background is the major factor, treatment with drugs
may be the major way to go. Unfortunately, reading and near work
cannot be reduced much.
At ARVO 2004, a number of attempts were presented
to identify genes that may be responsible for myopia development
(see abstractsonline.com,
search for "myopia").
Does reading at low light increase the risk of myopia in children?
Although there are no studies available from monkeys or humans, showing that reading at low light can promote myopia development, there are some hints from experiments with chickens (fig. 9).
Based on these data, it could be concluded that there may be some risk that low light can cause more myopia, although it is not as efficient as poor image contrast and low pass filtering - see myopia with the diffusers in Figure 9.
- published in Experimental Eye Research 1999:
Feldkaemper M., Diether S., Kleine G., Schaeffel F. Interactions of spatial and luminance information in the retina of chickens during myopia development Exp Eye Res. 1999 Jan;68(1):105-15)
Fig. 9: Chicks wearing "sun glasses" (ND filters) develop some myopia even though their spatial vision was not affected. At the same time, retinal dopamine release dropped, similar to condition when myopia developed with diffusers.
What is the influence of the environment on myopia development?
There are many data suggesting that myopia has a major genetic component. This can be seen, for instance, in the high correlations of the refraction in twins (about 90 percent), but also in the fact that myopic parents often have myopic children (roughly 10 percent chance of myopia with no myopia in the parents, 30 with one myopic parent and 60 with both parents myopic). In populations where everybody has similar visual experience or a similar environment, genetics determines refractive development to a large extend.
However, if individuals originating from one population have diverse visual or environmental exposure, the effects of environment show up very clearly.
This fact have all nicely been described in a review by Ian Morgan and Kathy Rose in 2005, which was, among others, discussed in the New Scientist (Fig. 10).
Fig. 10: Internet page reviewing some of the descriptions by Morgan and Rose in 2005
(original reference: Morgan I, Rose K. How genetic is school myopia? Prog Retin Eye Res. 2005 Jan;24(1):1-38. Review).
Are there new optical techniques to interfere with myopia development?
Since it has been shown by the laboratory of Earl Smith in Houston that refractive errors can be induced in monkey just by changing the focus in the periphery of the retina, people realized that the peripheral refractive error with spectacle lenses may be important also in humans. Several attempts are currently made to generate spectacle lenses that impose some myopic refractive error in the periphery while keeping the fovea in focus. In the frame of our RTN "MyEuropia", we are testing the effects of such new lenses on visual performance and peripheral refractive errors. In the future, we will test extensively how the natural refractive errors are in the periphery of the visual field in children. Finally, studies are planned in which the effects of the traditional spectacles on myopia progression are compared to the effects of newly designed ones.
