Myopia: Cause and CureCause and Cure

Professor Chris HammondSt Thomas’ Hospital, London

Dept Twin Research & Genetic Epidemiology

www.twinsuk.ac.uk

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

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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

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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)

Click to edit Master title styleAge and Myopia Prevalence

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Williams KM et al, in review

Click to edit Master title styleCohort Effect?

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Cohort effect

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

varies between populations …

Morgan I. Prog Retin Eye Res. 2005;24:1-38

Outdoor activity

Rose KA et al, Ophthalmology 2008: 1279-85

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

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-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

GWAS: all the rage!

CREAM international meta-analysis

Verhoeven et al, Nature Genetics 2013

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

23andMe GWAS

Kiefer et al, PLoS Genetics 2013

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?

Click to edit Master title style

Who to treat?

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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

How fast do myopes progress?“control” SVL arms in RCTs

Deng L et al, ARVO 2012

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

Overall Myopia Progression:All PALs, Bifocals, Multifocals

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

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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

Overall Myopia Progression:Pharmaceutical Agents

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

Overall Myopia Progression:Contact Lenses

Click to edit Master title styleVarifocal CLs

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Sankaridurg et al, IOVS 2011;12:9362-67

Overall Myopia Progression:Novel Lenses

Overall Axial Length Progression:Non-randomized Ortho-K Studies

Click to edit Master title styleOrthokeratology

11/3/2014 50Cho P. Invest Ophthalmol Vis Sci. 2012;53:7077–7085

Click to edit Master title style

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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!

Click to edit Master title styleAcknowledgements

Guide Dogs

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Guide Dogs for the Blind Association

National Institutes of Health, USA