1. Myopia Control: How Can We Stop Myopia Progression? Serdar A. Özler, MD Eye Physician and Surgeon İzmir - Turkey Hoya Faculty 2018, Budapest

2. Financial Disclosure I have neither any financial interest nor any relationship with a company, or a product that I will be mentioning in this talk Please take note that I will be talking on off-label drug use

3. Acknowledgements Sait Eğrilmez, MD Professor of Ophthalmology Department of Ophthalmology Aegean Unıversity Member of optics, refraction and LVA society Izmir, Turkey Hikmet Başmak, MD Professor of Ophthalmology Department of Ophthalmology Osmangazi Unıversity Member of optics, refraction and LVA society Eskişehir, Turkey Alp Alaluf, MD Full private ophthalmologist Member of optics, refraction and LVA society, İzmir, Turkey Emrah Hayırcı, MD Full private ophthalmologist

4. Myopia  Myopia prevalances: Asia: 80-95%, USA & Europe: 20-50%, *Turkey: 33%  Increase in myopia progression rates :  East Asia/childhood myopia: 1D/year  USA increase in myopia (12 to 54-year-old): 25% 42% in 33 years (1971-2004)  The prevalance and progression rate increases, the starting age decreases  24% of myopic children high myopic in adulthood  Severe high myopia > blindness retinal detachment, myopic maculopathy, developement of premature cataracts, and glaucoma  In Year 2050: Half of the World Population will be Myopic! *Onal S, Toker E, Akingol Z, Arslan G, Ertan S, Turan C, Kaplan O. Refractive errors of medical students in Turkey: one year follow-up of refraction and biometry. Optom Vis Sci. 2007; 84:175-180.

5. Early Diagnosis May Prevent Cancer, May Early Diagnosis Prevent Myopia? Turkish Postal Stamps 1972 1997 1947 Is it even difficult to deal with myopia progression problem compared to cancer treatment?

6. Emmetropization  An active biologic process that coordinates the development of the various components of the optical system of the eye to prevent ametropia for example axial length, refracting power of the cornea, depth of the anterior chamber, and other parameters  With the help of emmetropization, the wide range distribution of the human refractive errors in newborn has markedly reduced at the age of 6  refraction error distribution, newborn, +8,00 to -7,00 median +2,00  refraction error distribution, age 6, +3,50 to -0,50 median +0,50

7. Myopia/Spending Time Outdoors I  Retina is an unusal tissue/own dynamics. Even if the optic nerve is cut or fovea is ablated the emmetropisation continues through the peripheric retina  With light entering the eye, domapine is released from the peripheric retina and the scleral fibroblastic activity starts  The increase in the axial length of the eye then stops and the scleral thickness increases  This adjustment is not related to ultraviolet light  Even if the eye and skin are protected from the ultraviolet rays, the eye still continues to receive the necessary light

8. Myopia/Spending Time Outdoors II  The only activity that significantly prevents the developement of myopia is spending more time at the outdoors  Spending an extra hour per week outdoors decreases the risk of myopia development by 2%  2 to 3 hours of outdoors activity after school is effective in the prevention of myopia developement  -The Turkish Ministery of Education is planning to increase the breaks between classes from 10 minutes up to 20 minutes

9. DIGITAL WORLD

10. Digital World Corrects Its Own Malpractice Spending time outdoors + Looking far away  The digital world realised the epidemiology before we the ophthalmologists and produced a game called Pokemon Go

11. Invest Ophthalmol Vis Sci. 2014;55:4552–4559 Humans Became a Population With Very Low Vitamin D Levels  This is true, even in a sunny country like Turkey  80% of children and adults of the Turkish population have a vitamin D deficiency  Publications have indicated that myopic subjects had serum vitamin D concentrations 2.63 times lower than the nonmyopic subjects

12. Is Vitamin D Deficiency a Cause or an Outcome? Invest Ophthalmol Vis Sci. 2014  Since we do not get enough outside exposure we have both vitamin D deficiency and myopia  However, we do not become myopic only because we have vitamin D deficiency  Thus, like vitamin D deficiency it is another outcome

13. Autoimmune Diseases Respiratory Tract Cancer Obesity Muscle Diseases Cardiovascular System Skin Diseases Infection Diseases Vitamin D is Actually Very Important in Protecting Us From Many Diseases VDR regulates at least 200 gene expressions exists more than 30 tissues  We have to encourage our children to go out not only to prevent myopia but more importantly for their whole bodily health and to live longer

14. Near Work / Myopia Development I  -Intense near vision activities performed by children have been associated with myopia development  When looking at a near object, accommodative lag occurs. This has been found to be higher in myopes than in emmetropes  The accommodative lag increases with proximity and creates a stimulus for the eye to elongate, leading to myopia progression Myopia and effective management solutions number 73 Autumn 2016

15. Near Work / Myopia Development II  -More time spent on near work activities was associated with higher odds of myopia  The odds of myopia increased by 2% for every 1 D-hr more of near work/week  The risk of developing myopia increases as the working distance is shorter than 30 cm and the amount of near work is longer  -It is recommended that children limit near tasks to a maximum of 2 hrs/day. Infants under age two should have zero screen time  All ages can benefit from the 20/20/20 rule of thumb, which refers to 20 minutes of near work followed by a minimum 20 seconds break by looking a distance of 20 feet

16. Monofocal Eyeglasses - Overcorrection  We have learned from the planned intermittant exotropia studies that OVERCORRECTION of myopia in children has a clinically insignificant risk of inducing myopia Kushner (Arch Oph, 1999) -0.54D myopic shift 5 years Rowe (Eye, 2009) -0.62D myopic shift 3 years Ekdawi (AJO, 2010) -0.26 D myopic shift/year Rutstein (Optom Vis Sci, 1989) Hyperopes -0.13 D myopic shift/year Emmetropes -0.26 D myopic shift/year Myopes -0.75 D myopic shift/year

17. Monofocal Eyeglasses - Undercorrection  Evidence based Cochrane’s database and other studies have demonstrated that undercorrection causes 0.15 D more myopia progression  Children should be fully corrected with monofocal eyeglasses  At our practice we do not want the children to be undercorrected for a significant period of time. We follow them every 6 months to check for myopia progression Cochrane Database Syst Rev. 2011 Dec 7;(12):CD004916 Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD.

18. Bifocal Eyeglasses  S ome investigators have used bifocal eyeglasses to eliminate the accommodative lag  Studies have demonstrated that in this case there is less than 0.16 D myopia progression after 3 years  There is no data with respect to the outcomes after the cessation of bifocals  We should point out that 0.16 D of gain within 2-3 years is statistically significant but is clinically insignificant!! Cochrane Database Syst Rev. 2011 Dec 7;(12):CD004916 Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD.

19. Prismatic Bifocal Eyeglasses Myopia progression : Bifocals average -0.96 D (SE, 0.09 D) Prismatic bifocals average -0.70 D (SE, 0.10 D) Essilor’s website Cheng D, Schmid KL, Woo GC, Drobe B.Arch Ophthalmol. 2010 Jan;128(1):12-9. archophthalmol.2009.332. Randomized trial of effect of bifocal and prismatic bifocal spectacles on myopic progression: two-year results.  If we use prisms on bifocals to relax convergence for near we observe 0.26 D less myopia progression  We have to consider, however, that it is very difficult to wear these kinds of eyeglasses, and very low benefits are obtained after many years of use

20. Progressive Eyeglasses Gwiazda J, Hyman L, Hussein M, Everett D, Norton TT, Kurtz D, Leske MC, Manny R, Marsh-Tootle W, Scheiman M, and the COMET Group: A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 44: 1492-1500, 2003.  There are 2 studies on the use of progressive eyeglasses to slow down myopia progression, COMET 1 and 2  These are progressive eyeglasses with +2 addition used during childhood  At the end of 2 years it was observed that children who were using progressive eyeglasses had 0.30 D less myopia progression  This, too, is a statistically significant but a clinically insignificant prevention method

21.  IN TURKEY:  PAL, DIGILUX JUNIOR, available, Akay Company  Bifocals, MYOPILUX, available, Essilor Company  Single vision lenses, MYOVISION, unavailable, Carl Zeiss Company Carl Zeiss Vision, MyoVision™ Peripheral Vision Management Technology  A 12-month wearer efficacy trial amongst 210 Chinese school children resulted in reducing progression of myopia by an average of 30% in a subgroup of 19 younger children (6 to 12 years old) with at least one myopic parent.* This is statistically significant Zeiss’s website  In a 2-year study amongst 87 children aged 7 and 13, it was found that Myopilux® spectacle lenses slowed down myopia progression by up to 62% Essilor’s website

22. Contact Lenses  To slow down myopia progression neither Soft Contact Lenses (SCL) nor Rigid Gas Permeable (RGP) lenses are effective  CLAMP study demonstrated  A significant difference between SCL and RGP lenses after one year, RGP lenses caused less steepness of the cornea  However, at the end of 3 years there was not a significant difference in axial length  Slowing down of myopia was not achieved with RPG lenses, the effect was reversible

23. Orthokeratology I  Orthokeratology is actually the most effective method among the eyeglasses and contact lenses  This is because contact lens touches the central cornea and steepens the periphery  We actually become myopic because of peripheral retinal hypermetropy  If the peripheral retinal hypermetropy is corrected and becomes more myopic, indeed the signals from peripheral retina but not the foveal signals would adjust axial length correctly

24. Orthokeratology II  Orthokeratology can correct myopia up to -6.00 D during daytime  Orthokeratology also slows down myopia progression by approximately 40%  We are talking about a contact lens which stays overnight on the cornea and pushes it back and then it is removed from the eye in the morning  This is most contrary to normal physiology  The long-term efficacy as well as side effects like infections have not been assessed yet, however a recent *study demonstrated the rebound effects of orthokeratology *Cho P, Cheung SW. Contact lens and anterior eye. 40 (2017) 82-87

25. Multifocal Contact Lenses  Recently, two one-year studies on children have shown a reduction of approximately 35% in myopia progression with multifocal soft contact lenses  Although these studies provided promising results for the first year, there were no data beyond that. Thus evaluation of rebound risks upon the cessation of wearing multifocal soft contact lenses was not available  Using MiSight new technology multifocal dual focus 1 day soft contact lenses 59% reduction of myopia progression was shown after three years  For peripheral retinal defocus, contrary to hard lenses, it seems soft contact lenses will be very valuable in the future Nicola S Anstice, John R Phillips. Effect of dual-focus soft contact lens wear on axial myopia progression in children. Ophthalmology 2011; 118: 1152-1161 Chamberlain P Et al. Clinical evaluation of a dual focus myopia control 1 day soft contact lens – 3 year results BCLA June 2017

26. Cholinergic Receptor Types M1 CNS, nerves M2 Heart, smooth muscle, ciliary muscle M3 Smooth muscle, exocrin glands, ciliary muscle M4 CNS, nerves M5 CNS, ciliary muscle Atropine blocks all muscarinic receptors, however, blocking M1 and M4 does not have any effect on ciliary muscles  Atropin. Accomodation is not the responsible factor in myopia progression. We can not solve the myopia progression problems by totally eliminating accomodation.  Atropine actually is an anticholinergic drug, and blocks all muscarinic receptors from M1 to M5.  Since ciliary muscle does not contain M1 and M4 muscarinic reseptors the mechanism is not related with accomodation.  Mechanism could be really related to not spending time outdoors.

27. Pirenzepine Eye Drops Cochrane Database Syst Rev. 2011 Dec 7;(12):CD004916 Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD.  The proof of that is the action of the drug named Pirenzepine.  It only bloks M1 receptors. There are no M1 receptors in ciliary muscle  Pirenzepine, which is available as a gel, does not cause accomodation paralysis but is effective in central nervous system  Studies have demonstrated 0.31 D less myopia progression with Pirenzepine  It is not available in Turkey

28. Atropine Eye Drops  Anti-myopic activity of atropine is entirely related to nonaccomodative mechanisms. There are three possible mechanisms in action:  Binding of atropine to the muscarinic receptors of amacrine cells in retina increases the release of dopamine, which is an inhibitory chemical mediator for eye growth  Reduction of γ-aminobutyric acid levels was shown to be downregulated following the atropine treatment in myopia-induced mice  Scleral fibroblast cells carry all five muscarinic receptors on their cell membrane and binding to atropine may interfere with scleral remodeling

29. Most Important Study on Atropine – ATOM - 5 Years  Atropine concentrations from 1% to 0.01% for 24 months  At the end of 24 months  the most succesful was the 1% atropine concentration group with the least myopia progression  the worst group was the one for which 0.01% concentration was used  After 12 months of cessation of the treatment  1% concentration group went downhill and almost came to the level of placebo group  Then, the study continued the treatment of children with more than 0.50 D myopia progression with 0.5%, 0.1%, and 0.01% concentrations of atropine  At the end of 60 months  the 0.01% concentration group performed the best and had 50% less myopia progression

30.  If the starting age of myopia was lower a longer atropine treatment was needed  Myopia progression was faster for patients who had initially low myopia  Recently, an eyedrop with 0.01% atropine concentration has been produced and is now available in Singapure. It is called Myopine  This eyedrop does not affect on ciliary muscle and accomodation. It works as a mediator!

31. ATOM Study 5 Year Results Mesopic Photopic 4.7 mm5.5 mm 6.9 mm 7.8 mm 3.9 mm 5.1 mm 6.7 mm 7.5 mm % 0.01% 0.1% 0.5 Atropine Concentrations w/o Eyedrop 0.8 mm 1.2 mm Near Vision 20/20 20/2520/40 16.2 11.8 6.8 3.8 Accomodation (D)  0.01% atropine compared to no medication group increases the pupil diameter 0.8 mm under mesopic conditions and 1.2 mm under photopic conditions  This is a very insignificant pupil size increase. Only 7% of people may need photocromic eyeglasses in outdoors because of photophobia  Also near vision and accomodation were not adversely affected

32. What Did We Learn From ATOM Study? Atropin slows down myopia progression, however, as the dose was increased rebound increased Side effects also increased with the increase of dose. No significant side effects were observed in low doses Best therapeutic index with atropine was 0.01% 0.01% atropine slowed down myopia progression by 50% 0.01 % atropine treatment proved to be as effective even after the cessation and restart of the therapy

33. Preparation of % 0.01 Atropine Eyedrops  We do not have 0.01% atropine eyedrops in Turkey  We have atropine ampuls at 1mg/1ml  If we remove 6 ml off from any 15 ml artificial eye-drop without BAC and add 1 ml of a 1mg/1ml atropine sulphate we can easily prepare a 0.01% atropine eyedrop  This is an off-label eye drop, and should be used with an informed consent 15 ml w/o BAC Artificial eyedrops OR +

34. 7 Methylxanthine  Trier and coworkes published a study on an oral tablet methylxanthine  The dose is 2*400 mg for children  Its active ingredient is a caffein and teobromin metabolyte and it is an adenosin receptor blocker  It thickens the scleral collagen  If methylxantine is taken orally until the age of 18 there will be less myopia progression. It seems it works  Early cessation may cause rebound phenomenon

35. Conclusion We have to change the lifestyle of our patients We have to indicate that they should see the sun at least 2 to 3 hours a day Undercorrection makes the situation worse 0.01% atropine is 50% effective with completely non-accomodative mechanisms Orthokeratology is effective by 40% but is against normal physiology In the future, eyedrops and peripheral defocused multifocal soft contact lenses could be more effective

36. Thank you very much We'll see beautiful days children We’ll drive boats toward blue seas Children believe, believe children We'll see beautiful days, sunny day Nâzım Hikmet Ran (15 January 1902 – 3 June 1963), great Turkish poet, playwright, novelist, screenwriter, director and memoirist