IXT Cotter Denmark 2018 HANDOUTChildhood Intermittent Exotropia Financial Disclosures No financial interest in materials or methods discussed herein Grant Support NIH/NEI: EY011751

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Childhood Intermittent Exotropia

Financial Disclosures

No financial interestin materials or methods discussed herein

Grant Support NIH/NEI: EY011751 & EY022595

Intermittent Exotropia (IXT)

What We Don’t Know

What We

Know

• Most common form of childhood-onset XT • Normal alignment & sensory fusion sometimes• Good stereoacuity at near (generally)• Amblyopia is rare

• Natural history• Best form of treatment

Course Objectives: PEDIG Findings• IXT treatment based on randomized clinical trials� Overminus lenses � Part-time patching� Surgery

• Natural history of IXT based on 3-year observational study• Define / describe outcome measures

What Should We Measure?

Outcome Measure for Studies of IXT?

Magnitude ?Stereoacuity ?

% Time of Alignment

Control of IXT

Outcome Measure for Studies of IXT?

% Time of Alignment or Frequency

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Ways of Assessing Control of IXT

• Patient and parental report• Cover testing–Proportion of time XT is manifest – Speed of recovery - see video

• PEDIG IXT control scale

PEDIG IXT Control Scale

Mohney BG, Holmes JM. Strabismus 2006;14(3):147–150

�

4321

5 Constant XT

XT >50% of time

XT <50% of time

> 5 seconds to recover

1-5 seconds to recover 0 < 1 second to recover

Observationfor

30 seconds

�

No XT unless dissociated 10 sec;

Worst of 3 consecutive 10-sec dissociations

Step 1: 30 sec observation before dissociation at distance

1..2..3..4..5..6..7..8..9..10..11..12..13..14..15..16..17..18..19..20..

21..22..23..24..25..26..27..28..29..30

Spontaneously XT for 10 of 30 seconds (33% of 30 seconds)

Control of XT: Start at Distance PEDIG IXT Control Scale


�4321

5 Constant XT

XT >50% of time

XT <50% of time



Tropia Observed

�No XT Unless Dissociated

Step 2: Near - 30 second observation before dissociation

1..2..3..4..5..6..7..8..9..10..11..12..13..14..15..16..17..18..19..20..21..22..23..24..25..26..27..28..29..30

No spontaneous tropia at nearControl score must be <3

(so….must dissociate at near)

Control of XT: Near

1..2..3..4..5..6..7..8..9..10

1..2..3..

4NOTE: If recovery >5 seconds for OD, control score = 2

& no further testing needed

Dissociate (occlude) for 10 sec; Uncover & observe recovery 3X: OD, OS, Worst eye

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1..2..3..4..5..6..7..8..9..10

1..2..3..4..5..6

7NOTE: If recovery >5 seconds for OD, control score = 2

& no further testing needed

Dissociate (occlude) for 10 sec; Uncover & observe recovery 3X: OD, OS, Worst eye

Near Control = 2



�

4321

5 Constant XT

XT >50% of time

XT <50% of time



Tropia Observed

�

No XT Unless Dissociated

Distance Control = 3

Near Control = 2


Outcome Measure for PEDIG IXT Studies

% Time of Alignment•At present, taking the mean of 3 measures during

exam vs. using a single measure*• Better represents overall control than single

measure*Hatt et al. Am J Ophthalmol 2011;152:872–876.

Cover Testing: Clinical TipTest distance at far can make a difference

Use remote test distance

Divergence Excess XT 3m vs. 6m

Increased angle 5-15Δ 64%

Surgery (yes/no) 32%

Surgical dose different 32%

Kushner & Morton. Ann Ophthalmol 1982;14:86-9.

Samantha: IAXT (50%) 14Δ at 3m; CAXT 25Δ at 50ft

Evidence in Relation to Treatment of Childhood IXT

PEDIG RCT’s

Part-timePatching

OverminusLenses

IXTRCT’s

RCT: Patching vs Observation• 3 to <11 years• 12 to 35 months

Surgical Procedure

RCT: Over-minus vs Observation• 3 to <7 years

RCT: Bil LR Recession vs Unilateral Recess-Resect for Basic IXT• 3 to <11 years

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Effectiveness of part-time patching in reducing risk of deterioration of

IXT over 6 months?

IXT: Part-time Patching Background• Reported benefits� Eliminates suppression � Reduces magnitude +/or frequency� Changes character of deviation

• Commonly prescribed by peds ophthalmology� Varying dosages, duration, outcomes� Retrospective, small samples, no comparison group

Intermittent Exotropia-2 (IXT-2)

RCT’s Comparing Part-time Patching with Observation for

Children with IXT

Cotter S. et al. PEDIG. Ophthalmology 2014;121(12):2299-310 & Mohney B. et al. PEDIG Ophthalmology 2015;122:1718-25.

Study Objective• Determine effectiveness of prescribed part-time patching for

reducing risk of deterioration of IXT over 6 months among children:� 3 to <11 years old� 12 to 35 months old

Major Eligibility Criteria• Age: 3 to < 11 years; 12 months to 35 months• Previously untreated IXT (any type)

� IXT or CXT at distance; & IXT or XP at near

� ≥ 10∆ at distance � ≥ 15∆ at distance +/or near

• Near stereoacuity of 400” (only older cohort)• No amblyopia or amblyopia treatment in last year

• Investigator / child / parent willing forgo all other IXT treatment until deterioration criteria met

Observation(SRx if needed)

Patching3 hours / day

Previously Untreated Children with IXTYounger: 12 to 35 months

Older: 3 to <11 years

6-month Primary Outcome

3-months 3-months

6-month Primary Outcome

IXT-2 Study Overview

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* Masked assessment (Retest ≥10 min IF deterioration) of: - Stereoacuity- XT control (PEDIG office control score)- Ocular alignment

* *1-month wash out; stop patching at 5 months

ObservationRefractive correction if needed

Patching3 hrs/day

RandomizedPreviously Untreated IXT

3-months*

6-month Primary Outcome* *

3-months*

6-month Primary Outcome**

IXT-2 Study OverviewPrimary Outcome: Deterioration by 6 Months

Formal Deterioration Criteria:

• Constant XT ≥10∆ at Dist & Near*

or

• Near stereopsis: drop ≥ 2 octaves from baseline*

*Masked examiner with retest

Preschool Randot Stereoacuity

Baseline Stereoarc sec

Stereo at FU visit to meet

deterioration*

40 200 or worse

60 400 or worse

100 400 or worse

200 800 or worse

400 Nil

Also Considered DeteriorationIf non-protocol treatment started without meeting formal deterioration criteria:

1. And no allowed exceptions2. Even if allowed exceptions of”−Debilitating diplopia −Overwhelming social concern (parent/child)−Failure to keep up with stereo age-norms

Part-Time Patching Results?

3 to <10 year olds

• Difference in proportions = 5.4% • Lower limit of 1-sided exact 95% CI = 2.0%; P = 0.003

Deterioration by 6 Months Was Uncommon

6.0%

Deteriorated

Not Deteriorated

0.6%Observation Patching

6% 0.6%

94% 99.4%

Cotter S. et al. PEDIG. Ophthalmology 2014;121(12):2299-310.

Deterioration by 6 MonthsObservation

(N=165)Patching(N=159)

Number (%) Deteriorated 10 (6.0%) 1 (0.6%)

• Formal deterioration criteria met 7 (4.2%) 1 (0.6%)

Constant XT ≥10∆ D&N 1 (0.6%) ** 0

Stereo worsened ≥ 2 octaves 6 (3.6%) 1 (0.6%)

Both criteria 0 0

• Started treatment against protocol 3 (1.8%) 0

**Had 40 sec RDS on Randot Preschool; protocol-required UCT not performed

3 to <10 Years Small Difference in Deterioration By 6 Months

• Difference in proportions = 5.4% ; Lower limit of 1-sided exact 95% CI = 2.0%; P = 0.003

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Deterioration by 6 MonthsObservation

(N=165)

Patching

(N=159)

Number (%) Deteriorated 10 (6.0%) 1 (0.6%)

• Formal deterioration criteria met 7 (4.2%) 1 (0.6%)

Constant XT ≥10∆ D&N 1 (0.6%) * 0

Stereo worsened ≥ 2 octaves 6 (3.6%) 1 (0.6%)

Both criteria 0 0

• Started treatment against protocol 3 (1.8%) 0

*Had 40 sec RDS on Randot Preschool; protocol-required UCT not performed

• Difference in proportions = 5.4% ; Lower limit of 1-sided exact 95% CI = 2.0%; P = 0.003

3 to <10 Years Only 1 Subject Developed Constant XT

Part-Time Patching 12 to 35 month olds

Results?

Deterioration by 6 Months Observation(N=87)

Patching(N=90)

TOTAL Number (%) Deteriorated 4 (4.6%) 2 (2.2%)• Formal deterioration criteria met 2 (2.3%) 2 (2.2%)

Constant XT ≥10∆ D&N• Started treatment against protocol 2 (2.3%) 0

Difference in proportions = 2.4%1-sided exact 95% CI = -3.8% to +9.4%; P = 0.27

No Difference in Deterioration By 6 Monthsin 12 to 35-Month-Old Children

Mohney B et al. PEDIG. Ophthalmology 2015;122(8):1718-1725 Mohney B et al. PEDIG. Ophthalmology 2015 Aug;122(8):1718-1725

Deterioration by 6 Months Observation(N=87)

Patching(N=90)

TOTAL Number (%) Deteriorated 4 (4.6%) 2 (2.2%)• Formal deterioration criteria met 2 (2.3%) 2 (2.2%)

Constant XT ≥10∆ D&N• Started treatment against protocol 2 (2.3%) 0

Difference in proportions = 2.4%1-sided exact 95% CI = -3.8% to +9.4%; P = 0.27

No Difference in Deterioration By 6 Monthsin 12 to 35-Month-Old Children

Part-time Patching for the Treatment of Childhood IXT

Take Home Message

•Deterioration of IXT over 6 months was uncommon

•3 to <11 yrs: Observation or PT-patching both reasonable management approaches

•12 to 35 mo: Insufficient evidence to recommend PT patching

Cotter S. et al. PEDIG. Ophthalmology 2014;121(12):2299-310 & Mohney B. et al. PEDIG Ophthalmology 2015;122:1718-25.

Overminus Lens Therapy for IXT

What We Don’t Know

What We

Know

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Overminus Lens Therapy for IXT

• Rx more minus (or less plus) than distance refraction•Mechanism?�Magnitude reduced by stimulating A/C�A/C triggers reflex fusional vergence�May allow clear distance vision, facilitating fusion• Stimulation of accommodation by:• Excessive convergence required for fusion (convergence

accommodation)?• Reliance on excessive AC to overcome XT?

Intermittent Exotropia Study 3 (IXT3)

A Pilot Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia

Chen A & PEDIG. Ophthalmology. 2016;123(10):2127-36 .

Assess initial short-term response of IXT to overminus lenses

Intermittent Exotropia Study-3: Study Objective Major Eligibility Criteria

• Age: 3 to <7 years

• IXT

�Distance control score ≥ 2 (mean of 3)

�Near control score ≠ 5 (mean of 3)

�≥ 15∆ exo at distance by PACT

�Near not exceed distance by >10 ∆ (PACT)

• SE between +1.00 D and -6.00 D OD & OS

IXT-3 Study: 3 to < 7 Years

Randomization

Overminus GroupSpectacles with full CR plus 2.50D overminus

Enrollment

Observation GroupNon-overminus spectacles

or no spectacles

2-week Phone Call from Site

8-Week Primary Outcome Exam (Masked Exam)

Control assessed 3 times

throughout a single exam

Baseline XT Control at Distance

42%

23%

35%

44%

22%

33%

0%

10%

20%

30%

40%

50%

60%

0 to <1 1 to <2 2 to <3 3 to <4 4 to 5

Observation (N=31) Mean = 3.2Overminus (N=27) Mean = 3.2

N/A N/APerc

enta

ge o

f Pa

tient

s

Control Score

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35%

29%

19%

10%6%

26%

44%

19%

7%4%

0%

10 %

20 %

30 %

40 %

50 %

0 to <1 1 to <2 2 to <3 3 to <4 4 to 5

Perc

enta

ge o

f Pat

ient

s

Observation (N=31) Mean = 1.5Overminus (N=27) Mean = 1.3

Baseline XT Control at Near

43

Over-Minus LensesResults?

Overminus Group Had Better Mean Distance Control at 8 Weeks

45

0

1

2

3

4

5

2.8 points

2.0 points

Mea

n 8-

wee

k Dist

ance

Con

trol

Difference = -0.80 (-1.49 to -0.11)P = 0.01 for one-sided test

Observation Over-minus Chen A & PEDIG. Ophthalmology. 2016;123(10):2127-36. 3.2

Overminus Lenses for 3 to <7 Year Old Children With IXT

Take Home Message

Chen A & PEDIG. Ophthalmology. 2016;123(10):2127-36 .

Improved distance control at 8 weeks

Larger & longer RCT needed to assess effectiveness of overminus lenses

on and off treatment

Currently Recruiting

Intermittent Exotropia Study 5 (IXT-5)

RCT of Overminus Spectacle Therapy for IXT

Currently Recruiting:12 months on treatment, then wean off treatment

Overminus Lens Tx: Cotter Clinical Impressions• Patient profile�Age?�Accommodative function?�AC/A ratio? (Basic or DE; not CI)

• Determination of overminus power?�Decrease in IXT magnitude?�Decrease in IXT frequency? Look for improvement in this--

-�What if results in eso at near? Rx a bifocal

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Overminus Lens Therapy• Length of treatment? • Parental education – very important• Myopia progression: no evidence of this yet� Retrospective chart reviews

*Group Initial RE Change After 5 Y Change After 10 YControl (62) 0.00 ± 1.40 -1.40 ± 2.00 -2.41 ± 2.20

6-mo Tx (74) 0.00 ± 1.50 -1.52 ± 1.80 -2.34 ± 2.405-yr Tx (34) -0.10 ± 1.50 -1.54 ± 1.90 -2.36 ± 2.10

*Kushner BJ. Arch Ophthalmol 1999. 117:638-642; Rutstein RP et al. OVS 1989; 66:487-491

Natural History of IXT in Children?

For Example: Surgery - Balance of Possibilities

ü Improvement of social concerns

ü Possibility of improving distance &

retaining near stereoacuity

Pros Cons

ü Possibility of spontaneous improvement

ü Surgical complications & high rate of

reoperations

ü Possibility of loss of stereoacuity through surgical overcorrection*

*21% overcorrection 6-mo post-surgery;

Buck et al. BMC Ophthalmology 2012

IXT-2 Study OverviewRandomized

3-Months

12, 18, 24, 30 month FU Visits 36 months: Natural History Outcome

Observation: No Treatment

6-Month Outcome for RCT

Patching

3-Months

12, 18, 24, 30 month FU Visits36 months - Study Completed

6-Month Primary Outcome -RCT

Masked Examinations•Ocular alignment• Stereoacuity•XT control

Natural History of IXT in Young Children

Objective

PEDIG. Unpublished data

Deterioration of IXT Over 3-Year Period in Children with Untreated IXT Ages

3 to 10 Years Old

Baseline IXT Characteristics

§ 183 children randomized to observation

§ 83% completed the study

§ Mean age = 6.1 years

§ 63% female; 61% white

§ 40-60 arc sec stereo at near: 62%

§ Type of IXT: 69% basic exo; 21% pseudo-DE

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Baseline: Character of the Exodeviation

5%

95%

Distance Deviation Type Near Deviation Type1%

70%

27%

2%

Constantexotrop iaIntermittentexotrop iaExophoria

Noexodeviation

Calculates cumulative probability of motor deterioration by 3 yrs

Primary Analysis: Kaplan-Meier Survival Analysis

• Dichotomous outcome: deteriorated or not deteriorated� Once deteriorated, always deteriorated

• Subjects lost to follow up: contribute to analysis for time in study� If deteriorated before lost, counted when deterioration occurred

� If not deteriorated before lost, “censored” at last study visit; credit for time

not deteriorated• Subjects who started treatment w/o meeting motor deterioration:

“censored” at that visit

Primary Outcome - Deterioration by 3 Years

§ Unpublished data presented§ Abstract available

§ Cotter SA, Mohney BG, Chandler DL, Holmes JM, Petersen DB, Kraker RT, Wallace DK, for the Pediatric Eye Disease Investigator Group. Natural history of childhood intermittent exotropia over a 3-year period. Investigative Ophthalmology and Visual Science 2016 57: E-abstract 984.


Objective



12 to 35-Month Old Childrern




12 to 35-Month Old Children

Unpublished dataAbstract found at: Cotter SA, Mohney B, Chandler D, Holmes J, Wallace D, Crouch E, Kraker R, SupersteinR, Paysse E for the Pediatric Eye Disease Investigator Group. Development of Constant Exotropia Over 3 Years in Children 12 to 35-Month-Old with Untreated IXT. Optometry and Vision Science 2016; 93: E-abstract 160026.

A Randomized Trial Comparing Bilateral Lateral Rectus Recession

versus Unilateral Recession-Resection for Basic Type IXT


Intermittent Exotropia Study 1 (IXT-1)

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Study Objective•Determine long term effectiveness of BLRc (bilateral lateral rectus recession) vs. R/R (unilateral lateral rectus recession with medial rectus resection) for treatment of basictype and pseudo-DE type IXT

Table 2: Surgical Dose* Bilateral Lateral Rectus Recession (BLRc) Angle of Largest Deviation

by PACT Amount to Recess Each Lateral Rectus (LR)*

16 PD 4.0 mm 18 PD 5.0 mm 20 PD 5.0 mm 25 PD 6.0 mm 30 PD 7.0 mm 35 PD 7.5 mm 40 PD 8.0 mm 45 PD 8.5 mm 50 PD 9.0 mm

Unilateral Lateral Rectus Recession with Medial Rectus Resection (R&R):

Angle of Largest Deviation

by PACT Amount to Recess

Lateral Rectus (LR)* Amount to Resect

Medial Rectus (MR)** 16 PD 4.0 mm 3.0 mm 18 PD 5.0 mm 4.0 mm 20 PD 5.0 mm 4.0 mm 25 PD 6.0 mm 5.0 mm 30 PD 7.0 mm 5.5 mm 35 PD 7.5 mm 6.0 mm 40 PD 8.0 mm 6.5 mm 45 PD 8.5 mm 6.5 mm 50 PD 9.0 mm 7.0 mm

•Suboptimal surgical outcome criteria (exotropia, constant ET or stereo loss) met at ANY visit

OR

•Reoperation without meeting suboptimal surgical outcome criteria

Primary Outcome Suboptimal Surgical Outcome BY 3 Years

Suboptimal Surgical Outcome

BY 3 Years (Primary Outcome)


To be published soon

Abstract found at:

Chen AM, Cotter SA, Chandler DL, Holmes JM, Donahue SP, on behalf of PEDIG.

“A Randomized Trial Comparing Bilateral Lateral Rectus Recession versus

Unilateral Recess-Resect for Basic Type Intermittent Exotropia.”

Optometry and Vision Science 2017; 93: E-abstract 175227

Treatments for IXT•Monitor; watchful waitingü Part-time patchingü Over-minus lenses• BI Prism• Vision therapyü Surgery

Non-surgical

Thank You

Susan [email protected]

Documents

IXT Cotter Denmark 2018 HANDOUTChildhood Intermittent Exotropia Financial Disclosures No financial interest in materials or methods discussed herein Grant Support NIH/NEI: EY011751