Amblyopia as a Window to Neuroplasticity in the Visual System Leonard J. Press, O.D., FCOVD, FAAO

Observational Data Is Necessary But Insufficient

Yet Data Can Be Manipulated to Draw One’s Own Conclusions

NEI Sponsored Research: Clinical Trials

      PEDIG: Pediatric Eye Disease Investigator Group – www.nei.nih.gov/ats3 OSU, SCCO, UAB, PCO, NECO, SUNY, IU, SCO Diane Tucker OD Cleveland Clinic Foundation Melissa Rice OD Mayo Clinic Wilmer, Bascom Palmer Michael Gallaway OD  PCO & Private Practice, NJ

NEI Sponsored Research: Putting Clinical Trials into Context

 PEDIG: The Pediatric Eye Disease Investigator Group – mixed group of ODs and MDs in multicenter private and institutional practice. www.nei.nih.gov/ats3  A Randomized Trial of Patching Regimens for Treatment of Severe Amblyopia in Children.

Ophthalmology 2003;110:2075-2087.

Study Results

  Children age 3 – 7 Entering VA 20/100 – 20/400  No patching treatment prior 6 mos.

 No amblyopia treatment any type prior mo.

 Outcome: 6 hrs. daily patching produces increased VA similar to full-time patching

PEDIG Study Results on Use of Atropine in Moderate Amblyopia

 PEDIG. The course of moderate amblyopia treated with atropine in children: experience of the Amblyopia Treatment Study. Am J Ophthalmol 2003;136:639-639.

  Children Age 3 – 7 Entering VA 20/40 – 20/100   Patching group > 6 hrs/day Atropine group 1 drop daily

Outcome of ATS for Atropine in Moderate Amblyopia

 Improvement initially faster with occlusion than atropine  At 6 months both groups equal   Mean improvement was 3 lines of VA (20/60 to 20/30) But … is atropine necessary daily?

PEDIG Daily Atropine versus Weekend Atropine

 PEDIG. A Randomized Trial of Atropine Regimens for Treatment of Moderate Amblyopia in Children. Ophthalmology 2004;111:2076-2085.

 Daily atropine group vs. weekend atropine group (Sat. and Sun.)  Outcome after 17 wks. similar results

Treatment of Amblyopia in Older Children

 PEDIG. Randomized trial of treatment of amblyopia in children aged 7 to 17 years. Arch Ophthalmol 2005;123:437-447.

 NEI background: “Most eye care practitioners believe that there is an age beyond which attempting to treat amblyopia is futile. It is generally held that the response to treatment is best when it is instituted at an early age and is poor when attempted after 8 years of age.”

Editorial Accompanying 2005 PEDIG Amblyopia Study

 “As physicians we pride ourselves in our use of scientific method to give the best care to our patients. Yet many of our daily decisions reveal us more as apprentices than scientists. We choose a particular treatment not because a clinical trial determined that it worked better, but because that is the way our mentors did it.”

Outcome of Treatment for Older Children from PEDIG Study

  Age 7 – 12: 2 - 6 hrs. per day of patching with near activities and atropine can improve VA even if the amblyopia has been previously treated.

Age 13 – 17: 2 – 6 hrs. per day of patching with near activities may improve visual acuity when amblyopia has not been previously treated.

Treatment of anisometropic amblyopia in children with refractive correction

 Ophthalmology 2006;113:895-903.

  Phase one of a two-part study Children ages 3 – 7  No prior Rx or treatment of any kind  Entering VA 20/40 to 20/250  Spectacle Rx was only treatment

Study Results of Anisometropic Amblyopia

 Followed for 30 wks; VA ck every 5 wks  For 77% VA improved >/= 2 lines  For 60% VA improved >/= 3 lines  Conclusion: Rx alone is a powerful tx modality for young children with aniso, and in moderate cases may be the only treatment necessary.

A Randomized trial to evaluate 2 hours of daily patching for strabismic and anisometropic amblyopia in children

 Ophthalmology 2006;113:904-912    Second part of two phase study Children ages 3 – 7 Entering VA 20/40 – 20/400  Patients requiring Rx had to complete phase 1 (see previous study)

Mixed Study of Strab & Aniso Amblyopia

 After Rx phase completed, subgroup assigned patching/near activities  2 hrs of daily patching and >/= 1 hr of near activities while patched  Near eye/hand such as crafts; connect dots; hidden pix; video games – monitored via log  These activities resulted in additional improvement of half to one line

Personal observations

  To obtain >3 lines of VA improvement, patching/near activities were necessary (21% of this group had at least 4 lines improvement vs. 5% of control group) When VA was in range of 20/125 – 20/400, 43% of patching/near activities group improved at least 3 lines, vs. 7% of control group

Management of Patients with Amblyopia

 Appropriate Rx if any   Quality time patching if moderate “Belt and suspenders” approach to atropine and patching if moderate  Refractive amblyopes OK with primarily home-based procedures  Strabismic amblyopes require more vigilance in-office and prone to regression (need “fortified amblyopia therapy”)

Tips for Successful Management (Undoing Occlusion Confusion)

 Severe Amblyopia < 20/100   Direct maximal occlusion (factor in function) Moderate Amblyopia (20/60 – 20/100)  Minimal occlusion  Shallow Amblyopia > 20/60  No occlusion  Value of Rx and nearpoint activities

Issues in Compliance with Patching

 Young children resist patching because it doesn’t make any sense to occlude better eye  Children of all ages are concerned about their appearance  Children are adept at beating the system

Methods of Occlusion

Methods of Occlusion

Methods of Occlusion Patchees (www.bernell.com)

Patchees (works like Colorforms)

Broadening the View of Amblyopia

 Levi, Ciuffreda, Selenow – text on Amblyopia (1991)  Best visual acuity less than 20/40?

 Two line difference in best visual acuity?

 BVA < 20/20?



Amblyopia is a developmental disorder of spatial vision

Functional Abnormalities in Amblyopia Beneath the Surface of Reduced Acuity

 Contrast Sensitivity  Spatial Distortion  Spatial Interaction  Crowding  Accommodation  Eye Movements  Suppression  Interaction of spatial and temporal functions

Functional Consequences of Amblyopia Kurt Simons PhD JAAPOS 2008;12:429-30

   Amblyopic subjects’ binocular reading speed is significantly slower than that of normal subjects, despite the amblyopic subjects having the same levels of binocular visual acuity and reading acuity as the normal subjects.

It appears then that amblyopia, although it has its onset in childhood, has a major functional effect at the other end of the lifespan.

Is there additional ophthalmologic literature that acknowledges amblyopia results in functional deficits through the lifespan that should be treated?

The Effect of Amblyopia on Fine Motor Skills in Children . Webber AI, Wood JM, Gole GA, Brown B.

Invest Ophthalmol Vis Sci

2008;49:594 –603   Fine motor skills were reduced in children with amblyopia, particularly those with strabismus, compared with control subjects. The deficits in motor performance were greatest on manual dexterity tasks requiring speed and accuracy.

Clinicians may want to make parents of children with amblyopia aware of this more global impact when discussing the consequences of the condition.

 From the School of Optometry & Institute of Health & Biomedical Innovation, Queensland University of Technology; Department of Paediatrics & Child Health, University of Queensland, AU. Presented in part at ARVO 2007

Grasping Deficits and Adaptations in Adults with Stereo Vision Losses. Melmoth DR, Finlay AL, Morgan MJ, Grant S.

Invest Ophthalmol Vis Sci

2009;50

:

3711 –3720  High-grade binocular stereo vision is essential for skilled precision grasping. Reduced disparity sensitivity results in an inaccurate grasp-point selection and greater reliance on nonvisual information from object contact to control grip stability.

 Prioritizing the recovery of high-grade binocularity, rather than just vision in the affected eye, should provide generalized benefits for visuomotor control in this disorder.

 From the Department of Optometry and Visual Science, The Henry Wellcome Laboratories for Visual Sciences, City University, London, United Kingdom.

Visual Motion Processing by Neurons in Area MT of Macaque Monkeys with Experimental Amblyopia. El Shamayleh Y et al. J Neurosci 2010;20(36):12198-12209.

    Amblyopia is a developmental visual disorder that manifests as loss of acuity without obvious organic cause.

Commonly associated with deficits in spatial vision, but behavioral studies also uncover significant impairments in visual motion processing.

Amblyopia affects extrastriate processing in area MT by influencing integration time of motion perception and effects further downstream on coherence sensitivity.

The development of visual neuronal response properties in extrastriate cortex, like that of striate cortex, is modified by visual experience.

Reading Strategies in Mild to Moderate Strabismic Amblyopia: An Eye Movement Investigation. Kanonidou E, Proudlock FA, Gottlob I.

Invest Ophthalmol Vis Sci

2010;51:3502 –3508.

 In strabismic amblyopia, reading is impaired, not only during monocular viewing with the amblyopic eye, but also with the non amblyopic eye and binocularly, even though normal visual acuity pertains to the latter two conditions.

 The impaired reading performance is associated with differences in both the saccadic and fixational patterns, most likely as adaptation strategies to abnormal sensory experiences such as crowding and suppression.

 From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, UK.

Here’s the conclusion of the IOVS article. Good points, but what’s missing?  In clinical practice, the visual impairments and improvements in visual function in amblyopes are usually tracked with high-contrast visual acuity charts.  Amblyopes may exhibit significant deficits in visual function after treatment, in parameters such as contour integration, stability of fixation, low contrast perception, and motion detection - despite minor or absent deficits in high-contrast visual acuity.

 Our findings support previous suggestions that there may be some benefit in including standardized reading charts in the assessment of visual function in patients with strabismic amblyopia.

Amblyopia As A Developmental Disorder

 Relative to the “normal” eye, the eye with Amblyopia is developmentally disabled (DD)  Any approach that aids visual processing in DD aids visual processing in amblyopia  The mainstay of optometric therapy for DD is what vision scientists now refer to as

perceptual learning

VT As Supervised Perceptual Learning

 Haidinger Brush/MIT     Accommodative stimulation Ocular motor precision with small detail Reduce crowding    Hart Chart Saccadics Vary viewing distance Modify the chart Spatial localization  pointer in straw x – y – z dimensions  effects of lenses/prism: SILO and JNDs

Monocular Fixation in a Binocular Field (MFBF)

 Amblyopic eye functions centrally while the normally preferred eye functions peripherally  Analogy to picture-in picture TV screen

Unsupervised/Passive Learning Under MFBF Conditions

 Occlusion foils to fog non-amblyopic eye to a level of function below the amblyopic eye  Atropine penalization   Cholinergic antagonist to paralyze accommodation Dilation of pupil reduces depth of focus at all distances and induces aberrations

The Elegance of Atropine Penalization

 Titrated amblyopia therapy   Cycloplegically induced blur is maximal after 1-3 hours and begins to wane after 42 hours. Blur increases with near fixation distance  Supervised perceptual learning during active VT procedures potentiates the MFBF properties of atropine

Superivsed Perceptual Learning under MFBF Conditions

 Anaglyphic (red/green) or polarized filters to control which part of the stimulus is seen exclusively by the amblyopic eye  Feedback when amblyopic eye is suppressed or de-tuned is immediately apparent

MFBF Procedure - Letter Tracking: Letters printed in red ink seen by amblyopic eye through green filter.

Non-amblyopic eye sees only where guided by amblyopic eye

MFBF Vectogram

Applying Computerized Therapy to Amblyopia

Amblyopia iNet

 VT program based on NIH studies  Hand-eye coordination program using principles of operant conditioning and behavior modification from HTS & PTS  Encourages compliance  www.visiontherapysolutions.net

Find The Target (“Crowding”)

Find The Target (reduced size)

Windows of Opportunity in Treating Amblyopia

 Is it ever too late to treat a lazy eye?

  Optometry has maintained that age alone should not be used as a limiting factor for amblyopia therapy.

1977 article in American Academy of Optometry journal by Birnbaum et al established this in a review of the literature

Cortical Plasticity and Adult Amblyopia

 The Jane Fonda influence  Forget age limitations  The Christopher Reeve influence   Forget poor prognosis for rehab Implications from Alzheimer’s research  Accept cognitive challenges at older ages (old dogs/new tricks)

http://www.revophth.com/index.asp?page=1_14594.htm

Ophthalmology “Discovers” Neuroplasticity and Neuroadaptation

Concepts of Plasticity as Related to Amblyopia: Periods of Visual Development

 Critical period  Birth to 6 months  Sensitive period  6 months to 8 years   Susceptible period  8 – 18 years  Residual plasticity period 18 years through adulthood

“Stereo Sue”

 Sue Barry, Ph.D.

 Steven Markow, O.D.

 Theresa Ruggiero, O.D.

 Oliver Sacks, M.D.

Stereoscopic photograph taken by Oliver Sacks, aged 12, from his bedroom window in London

Fixing My Gaze Susan R. Barry, Ph.D. 2009/2010 www.fixingmygaze.com

The Mind’s Eye Oliver Sacks, M.D., 2010 www.oliversacks.com/books/the-minds-eye

Patient Case

 MDS, female age 6  Had been examined by O.D. 12/04 and detected to have amblyopia OS of 20/400  Referred to Ped O-M.D. who Rxed   OD +1.00 sph OS +5.00 – 0.50 cx 180 • Uncooperative with patching

Initial Findings 3/2/05

 VA cc: OD 20/20 OS 20/70  CT (cc): Orthophoria D & N  Ret: OD +1.25

OS +5.25 – 1.50 cx 15  Subj: OD +1.00, 20/20 OS +5.00 -1.25 cx 15, 20/60  Stereo (cc): Randot 100 seconds of arc

Findings Continued

 Worth 4-dot (cc): Normal Fusion  Cycloplegia: OD +2.00

OS +6.00 – 1.50x15

 DFE: all structures normal  Fixation: OS central, steady

Diagnosis?

 Refractive amblyopia OS  Rx: OD +1.00

OS +5.25 – 1.25 cx 15 - Continue with full-time wear  Discussed CLs, but child averse, and mother declines

Implement Atropine Therapy

 Plan: parent to instill i gt 1% atropine OD on Friday night.

 Check on Saturday AM to see if pupil OD dilated. If not, instill one more drop.

 Come to office Monday to for instruction on home VT activities: dot-to-dot; mazes.

Progress Evaluation #1

 4 wk F/U  VAcc OS D: 20/40 -3  Plan: continue home therapy and weekend atropine instillation OD.

Progress Evaluation #2

 8 wk F/U, good compliance with atropine  VA: OS = 20/40 +1WL 20/30 L  Stereo: Randot 80 seconds of arc  Plan: Continue atropine therapy, adding “Jump Start” computer learning activities

Progress Evaluation #3

 12 wk F/U  VA: OS 20/30 -2 WL 20/30 L  Stereo: Randot 60 seconds of arc  School performance starting to decrease (reading difficulties)  Plan: discontinue atropinization in favor of 2 hrs “quality time patching” daily after school (e.g. Michigan Letter Tracking)

Progress Evaluation #4

 16 wk F/U  VA: OS 20/30 -2 WL 20/25 L   Stereo: Randot 60 seconds of arc Plan: continue “quality time patching” after school and on weekends

Progress Evaluation #5

 20 wk F/U  VA: OS 20/25 WL 20/20 L   Stereo: Randot 40 seconds of arc Plan: taper “quality time patching” after school and on weekends

Final Progress Evaluation

 24 wk F/U  VA: OS 20/25 WL 20/20 L  Stereo: Randot 40 seconds of arc  Assessment: stable acuity OS  Plan: continue full-time wear of Rx  Monitor at 6 mo intervals   Not concerned about recidivism if Rx used f/t Continue to recommend CLs

VEP (Visual Evoked Potential) www.diopsys.com

VEP (Visual Evoked Potential) www.diopsys.com

http://www.diopsys.com/opt-prac-study.php

 4 ½ yo – Rx: OD +2.00 OS +5.25

 Aided VA OS 20/40-2; unaided VA 20/200  Office based VT able to reduce aniso Rx  BVA ultimately equal OD and OS  BVA OS ultimately same cc or sc  VEP used to help objectively determine if Rx still advisable

RESOURCES

• • www.nei.nih.gov/ats3 www.aoa.org

: Clinical Practice Guidelines on Treatment of Amblyopia  www.covd.org

: Applied Concepts Course on Amblyopia and Annual Meeting  www.oepf.org

: Regional Clinical Seminars and Therapist materials  Press LJ. Applied Concepts in Vision Therapy 2008 (http://oep.excerpo.com/)

Thank You