New preventive medical treatment for childhood myopia
Klaus Trier, MD, ophthalmologist
The length of the human eye increases from 17 mm at birth to normally 24 mm at the age of 14 years. Among myopic children, however, the rate of growth is too high, and the growth continues until 18-20 years of age, at which time the length of the myopic eye may exceed 30 mm. At 18-20 years of age general maturation of the connective tissue of the body (cross-linking of collagen) normally prevents further elongation of the eye, and the myopia becomes stable.
Beside being a troublesome handicap demanding optical correction, myopia causes an increased risk of complications later in life. Because of these complications (retinal detachment, macular degeneration, glaucoma) myopia is one of the leading causes of blindness. Out of the 600 cases of retinal detachment ocurring in Danmark every year (population 5,5 mio.), it is estimated that 300 would be eliminated if myopia of more than 3 diopters could be prevented. In addition, a great number of cases of macular degeneration and glaucoma would be avoided. Correction of myopia with eyeglasses, contact lenses, laser treatment or implantation of intraocular lenses does not prevent these complications. Earlier belief in the efficacy of atropine eye drops 0.01 % to prevent myopia progression has given way to scepticism after several large trials have shown no effect on the rate of eye growth.
In later years, experimental results have shed light on the mechanism by which the growth of the eye is controlled. In order to obtain a focused image on the retina, the length of the eye has to correspond with the refraction of light by the cornea and the lens within a tolerance of 0.1 mm. Because this degree of precision cannot be obtained by genetic programming, a feed-back mechanism is operating to ensure continued optimal function of the eye. Thus, the rate of growth of the eye is regulated in response to the amount of defocusing registred by the retina. If the eye is hypermetropic, the collagen in the sclera will be degraded, thereby softening the wall of the eye. Because the softened sclera will yield to the intraocular pressure, the eye becomes longer. When the appropriate length of the eye has been reached, collagen production in the sclera is stimulated, and eye growth stops.
In myopic children, this mechanism is out of balance, and the content of collagen in the sclera is therefore permanently reduced. Because of this, the length of the eye will increase by up to 1 mm per year compared with the normal growth rate of 0.1 mm per year. The average growth rate of the eye among Danish myopic children in the age 8-14 years is around 0.3 mm per year, and the corresponding progression of myopia around 0.5 diopters per year.
A treatment that increases the content of collagen in the sclera will therefore work against the progression of myopia. A metabolite of caffeine, 7-methylxanthine, which is naturally present in the cocoa fruit, not only increases the content of collagen in the sclera of rabbits, but also prevents the development of myopia in rhesus monkeys. In contrast to caffeine, 7-methylxanthine does not reach the brain, and therefore has no stimulatory effect on the behavior.
Based on positive results from animal experiments, the Danish Medicines Agency in 2003 approved a trial of 7-methylxanthine for prevention of myopia progression. The results, which were published in 2008, showed that a dose of 400 mg once per day significantly reduce eye elongation over two years in myopic children aged 8-13 years.
Data collected since 2009 indicate that with a dose one tablet of 400 mg twice per day, the myopia progression is reduced by 1.1 diopter and the elongation of the eye by 0.4 mm over five years among children who are 7-9 years old at start, and by 1 diopter and 0.3 mm among children who are 10-12 years old at start. This corresponds to a reduction of around 50 %. From 14 years of age, a dose of 400 mg twice per day on average seems to prevent any myopia progression. As a result, almost none of the children had reached a myopia of 6 diopters or more after five years, provided that the myopia at start was less than 4 diopters.
With a dosing of three times per day the treatment appears to work significantly better, and preliminary results indicate that it is possible to achieve full stabilisation of the myopia already from the age of 10 years. There is therefore a realistic chance that the final myopia can be limited to less than 3 diopters.
No side-effects of the treatment were found.
The treatment is available in Denmark as a prescription drug. In order to evaluate the effect of the treatment, it is useful to measure the eye growth and the myopia progression before treatment is started and then once per year. The treatment should be continued until around 18 years of age. In case of pregnancy, however, the treatment should be discontinued. In case of severe chronic conditions, like diabetes or epilepsy, the treatment should also be discontinued.
It is important to start the treatment as early as possible, since the myopia that has already developed cannot be reduced. Unfortunately, the myopia is often not found before it has reached a level of around -1 diopter. Normally, a child at 7 years of age will have a slight degree of hypermetropia, around +1 diopter. If, however, there is no hypermetropia at this age, it is almost certain that the child will eventually develop myopia. Children should therefore, especially if one or both of the parents are myopic, be examined at the age of 7 years, and if no hypermetropia is found they should be closely followed.
Links to scientific literature:
Trier K, Olsen EB, Kobayashi T, Ribel-Madsen SM. Biochemical and ultrastructural changes in rabbit sclera after treatment with 7-methylxanthine, theobromine, acetazolamide, or l-ornithine. Br J Ophthalmol 1999;83:1370-1375
Trier K, Ribel-Madsen SM, Cui D, Christensen SB. Systemic 7-methylxanthine in retarding axial eye growth and myopia progression: a 36-months pilot study. J Ocul Biol Dis Inform 2008;1:85-93
Cui D, Trier K, Zeng J, Wu K, Yu M, Hu J, Chen X, Ge J. Effects of 7-methylxanthine on the sclera in form deprivation myopia in guinea pigs. Acta Ophthalmol 2011;89:328-34
Nie H, Huo L, Yang X, Zeng J, Trier K, Cui D. Effects of 7-methylxanthine on form-deprivation myopia in pigmented rabbits. Int J Ophthalmol 2012;5:133-37
Cui D, Trier K, Ribel-Madsen SM. Effect of day length on eye growth, myopia progression, and change of corneal power in myopic children. Ophthalmology 2013;120:1074-9
WHO Technical report 2016
Hung L-F, Arumugam B, Ostrin L, Patel N, Trier K, Jong M, Smith EL III. The adenosine receptor antagonist, 7-methylxanthine, alters emmetropizing responses in infant macaques. Invest Ophthalmol Vis Sci. 2018;59:472-486
Wildsoet CF, Chia A, Cho P, Guggenheim JA, Polling JR, Read S, Sankaridurg P, Saw SM, Trier K, Walline JJ, Wu PC, Wolffsohn JS. IMI - Interventions for controlling myopia onset and progression report. Invest Ophthalmol Vis Sci 2019;60:M132-M160