Myopia: Cause and CureCause and Cure
Professor Chris HammondSt Thomas’ Hospital, London
Dept Twin Research & Genetic Epidemiology
Why study myopia?
• Common!• Cost• Complications
– Retinal detachment– Retinal detachment– Myopic maculopathy – Glaucoma– Cataract
Click to edit Master title styleMyopic Maculopathy
Vogphanit et al
>-1 D (control)-1 to -3 D-3 to -5 D
11/3/2014 4
Flitcroft DI. Prog Ret Eye Res. Nov 2012; 31: 622-660
-3 to -5 D-5 to -7 D-7 to -9 D
<= -9D
Click to edit Master title styleRetinal Detachment
Ogawa & Tanaka
>-1 D (control)-1 to -3 D-3 to -5 D-5 to -7 D-7 to -9 D
<= -9D
11/3/2014 5Flitcroft DI. Prog Ret Eye Res. Nov 2012; 31: 622-660
Eye Disease Control Study
>-1 D (control)-1 to -3 D-3 to -8 D
The epidemiology of myopia
… increasing rapidly in some areas… varies between populations… varies between populations… associated with urbanisation, education
and IQ.... outdoor activity is protective
Click to edit Master title styleTaiwan
11/3/2014 7
appears to be increasing … Lin LL. Ann Acad Med Singapore. 2004;33:27-33
Click to edit Master title styleUSA NHANES
11/3/2014 8Vitale, S. et al. Arch Ophthalmol 2009;127:1632-1639.
E3 Consortium
• 33 studies– Epidemiological cohorts
– Case-control studies
• Up to 124,000 participants
• Myopia Prevalence– 15 studies, 61,000 participants
– meta-analysis: 24.3% (95% CI 20.1-28.5)
– age-standardised European prevalence: 30.6% (30.3-30.8)
Effect of Education
• 15% higher education born pre 1940 compared to 32% born after 1940
• Does this explain increased myopia • Does this explain increased myopia prevalence?
Williams KM et al, in review
Outdoor Activity
• Chinese children age 6-7• Myopia: 3.3% Sydney, 29.7% Singapore • Similar parental myopia (70%)• Similar parental myopia (70%)• Similar reading amounts• Outdoor activity: 13.7 hrs a week cf 3.1
Rose KA et al, Arch Ophth 2008; 126: 527-530
Click to edit Master title styleThe population distribution of
refractive error: a complex trait
11/3/2014 18
-30 -20 -10 0 10Spherical Equivalent (Dioptres)
Twin studies: refractive error 80% heritable
Genome-Wide Association StudiesSingle Nucleotide Polymorphism (SNP): marker of genetic variation in DNA
Gene 19
26 loci
Neurotransmission: GRIA4, GJD2, RASGRF1Ion Transport: KCNQ5, CD55, CHNRGRetinoic acid: RDH5, RORB, CYP26A1ECM remodelling LAMA2, BMP2ECM remodelling LAMA2, BMP2Eye development: SIX4, PRSS56, CHD7
Loci explain 3 -4% of variation
23andWe myopia GWAS
• “have you been diagnosed with nearsightedness”
• “approximately what age were you diagnosed?”diagnosed?”
• 26,000 myopes, 17,000 non -myopes
Click to edit Master title styleCREAM vs 23andMe
11/3/2014 28Wojciechowski R & Hysi PG. PLoS Genet 2013
What have GWAS taught us?
• Myopia is not AMD!• Many genes of small effect• Analogous to height: 40 SNPs, 5% of
variation variation • Size is important!• Large meta-analyses finding same results• Still unexplained heritability• Is this useful for personal prediction?
Myopia Progression fastest in...
• The earlier the onset– Myopia before age 8 = -6D by adulthood
• Children with myopic parents– Most significant risk factor of all– Most significant risk factor of all
• Children who have high IQ, school achievement, read lots, less time outdoors..
• NB significant proportion of myopia is adult-onset
Principles of treatments
• Close work theory– Accommodation must be bad– Accommodation lag in myopes
• Animal models– Muscarinic antagonists (eg atropine) work in animal models– Muscarinic antagonists (eg atropine) work in animal models
• Peripheral retina– Monkey ablation experiments– Myopes prolate cf oblate eyes– “built up” environment causes hyperopic defocus
• Light
Principles of treatments
• Close work theory UNDERCORRECT/BIFOCALS/PALS– Accommodation must be bad– Accommodation lag in myopes
• Animal models– Muscarinic antagonists (eg atropine) work in animal models– Muscarinic antagonists (eg atropine) work in animal models
• Peripheral retina– Monkey ablation experiments– Myopes prolate cf oblate eyes– “built up” environment causes hyperopic defocus
• Light
Undercorrect or fully correct?
• 94 Malaysian myopes 9-14 years
• randomised to full or undercorrection undercorrection (+0.75D, to 6/12)
• Stopped 2 years cf 3: faster progression in undercorrected
Chung K et al. Vision Res 2002;42:2555-9
Progressive add lenses
• Hong Kong Progressive Lens Myopia Control Study– 138 PAL, 160 SVL for 2 years
(ages 7-10)– Progression -1.26 SVL, -1.12 – Progression -1.26 SVL, -1.12
PALEdwards MH et al. IOVS 2002; 43:2852-8
• Correction of Myopia Evaluation Trial (COMET)– 469 USA myopes (ages 6-11)– Progression –1.48 SVL, -1.28
PALGwiazda J et al. IOVS 2003;44:1492-500
Principles of treatments
• Close work theory BIFOCALS/PALS– Accommodation must be bad– Accommodation lag in myopes
• Animal models ATROPINE/PIRENZEPINE– Muscarinic antagonists (eg atropine) work in animal models– Muscarinic antagonists (eg atropine) work in animal models
• Peripheral retina– Monkey ablation experiments– Myopes prolate cf oblate eyes– “built up” environment causes hyperopic defocus
• Light
Click to edit Master title styleAtropine
• ATOM Study• 200 children
randomized to atropine one eye or placebo
11/3/2014 40
placebo• 2 yr study• <0.5D progression: 66%
atropine, 16% placebo• Myopia progression
difference –0.92D (76%)• No side effects reported
Chua WH et al, Ophthalmology 2006; 113: 2285-91
Atropine ctd...
BUT one year post-cessation• Progression -1.1D atropine eyes, -0.39D
placebo• ?related to cycloplegia• Overall progression -0.95D versus -1.58D
Dilute Atropine• Atropine 0.5% -0.30±0.60 • Atropine 0.1% -0.38±0.60• Atropine 0.01% -0.49±0.63
Tong L et al, Ophthalmology 2009; 116: 572-79Chia A et al, Ophthalmology 2012; 119: 347-52
Pirenzepine
• Relatively selective M1-muscarinic antagonist
• Asia trial: 353 children 6-12 years– Baseline mean –2.3D– Progression –0.47D PIR b.d., -0.70 PIR od, -0.84 – Progression –0.47D PIR b.d., -0.70 PIR od, -0.84
placeboTan DT et al Ophthalmology 2005; 112: 84-91
• USA trial: 174 children 8-12 years– Baseline mean –2.10D– Progression –0.26D PIR bd, -0.53D placebo
Siatkowski et al Arch Ophth 2004; 122: 1667-74
Principles of treatments
• Close work theory BIFOCALS/PALS/DENMARK(!)– Accommodation must be bad– Accommodation lag in myopes
• Animal models ATROPINE/PIRENZEPINE– Muscarinic antagonists (eg atropine) work in animal models– Muscarinic antagonists (eg atropine) work in animal models
• Peripheral retina CL/VFCL/ORTHO-K– Monkey ablation experiments– Myopes prolate cf oblate eyes– “built up” environment causes hyperopic defocus
• Light
Rigid Contact Lens
• CLAMP study• 116 children randomized to RGP vs
SCLSCL• 3-year follow -up• Progression -1.56D RGP, -2.19D SCL
Zadnik et al. Arch Ophth 2004; 122: 1760-6
Click to edit Master title styleOrthokeratology
11/3/2014 50Cho P. Invest Ophthalmol Vis Sci. 2012;53:7077–7085
Principles of treatments
• Close work theory BIFOCALS/PALS/DENMARK(!)– Accommodation must be bad– Accommodation lag in myopes
• Animal models ATROPINE/PIRENZEPINE– Muscarinic antagonists (eg atropine) work in animal models– Muscarinic antagonists (eg atropine) work in animal models
• Peripheral retina VFCL/ORTHO-K– Monkey ablation experiments– Myopes prolate cf oblate eyes– “built up” environment causes hyperopic defocus
• Light GOAL STUDY/CLASSROOM
GOAL Study
• 1 hour/day extra outdoors after school• Some reduction in myopia incidence• Awaiting final results
Conclusions
• Myopia is becoming more common– Probably multifactorial: earlier education, lack of
outdoor activity, urbanisation
• Genetics identifying new pathways– Hopefully new treatments in future– Hopefully new treatments in future
• No proven highly effective treatments– Atropine (but side-effects) “best”– Ortho-K interesting…– Combination? (eg dilute atropine and VFCL)
• Send the children out to play!