1. Grand Rounds 29 Feb 2016 Overminus spectacles as a treatment for IXT
Jonathan M. Holmes

2. CME Record of Attendance
Ophthalmology Grand Conference– February 29
Text JAHJUC to (507) to record your attendance today.
48 Hours to Text Attendance
For questions, contact Elaine Eckheart
Only Residents and Fellows still need to swipe to comply with accreditation requirements for conference attendance. 
Residents and Fellows (who are not Board certified) do not need to obtain CME credits.
Faculty who want to obtain CME credits must text the unique code for each conference.

3. Accreditation Mayo Clinic College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Mayo Clinic College of Medicine designates this live activity for a maximum of  0.75 AMA PRA Category 1 Credits™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.
CME Objectives 1) Identify/summarize/describe concepts related to clinical eye care 2) Apply new knowledge to relevant clinical situations.
As a provider accredited by ACCME, Mayo Clinic College of Medicine, (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities.   Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity.  Safeguards against commercial bias have been put in place.  Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation.  Disclosure of this information will be published in course materials so those participants in the activity may formulate their own judgments regarding the presentation.
Listed below are individuals with control of the content of this program who have disclosed…
Relevant financial relationship(s) with industry:
Raymond Iezzi, M.D. is a consultant to Alcon, Alimera, Vergent
No relevant financial relationship(s) with industry:
Dept. of Ophthalmology Planning Committee includes members of the Education Committee:   Drs. Sophie Bakri, Sanjay Patel, Keith Baratz, Andrew J. Barkmeier, Elizabeth Bradley, William Brown, John Chen, Amir Khan, Sunil Khanna, Leo Maguire, Michael Mahr, Brian Mohney, Wendy Smith, Linda Mrozek, Kari Sczepanski.

4. DISCLOSURE Jonathan M. Holmes
Relevant Financial Relationship(s)
None (only grant funding from NIH)
Off Label Usage
None

5. Presentation Learning Objectives
To understand the current evidence-base for the use of overminus spectacles as a treatment for intermittent exotropia
To identify factors that might predispose to successful treatment of intermittent exotropia with overminus spectacles

6. Question 1 Control of intermittent exotropia should be assessed with:
Standardized timing of the tropic phase
Prism and alternate cover test
Near stereoacuity
Standardized assessment on the synoptophore

7. Question 2 The current evidence suggests
Overminus may be more effective when control is moderate
Overminus may be more effective when control is poor
There is no relationship between the effectiveness of overminus and level of control
Overminus is ineffective as a treatment for intermittent exotropia

8. Index Case 5 year-old boy
Hx - “left eye wanders particularly when tired or at end of day”
VA 20/20 20/20
Full ductions
D 25 X(T) comitant
N 25 X(T)
SLE Fundus Normal
Cret R L

9. Diagnosis – Intermittent Exotropia
One of the most common strabismus disorders of childhood
Other
Accommodative
ET (28%)
Sensory XT (3%)
XT assoc with CNS (4%)
Acquired Non-accomm ET (10%)
CI XT
(5%)
Up to 1% of children under 11y in Olmsted CO MN
ET assoc with CNS (7%)
Intermittent Exotropia (17%)
Sensory ET (4%)
Paralytic
ET (4%)
Congen
ET (5%)

10. IXT treatment options Observe Alternate patching e.g. 3hrs/day
(? Anti-suppression therapy)
Convergence exercises
Surgery

11. Another non-surgical treatment option
Overminus spectacles e.g. adding sphere to each spectacle lens
E.g. Cret sph R sph L
Overminus Rx sph R sph L
E.g. Cret sph R sph L
Overminus Rx sph R sph L

12. Theoretical underpinnings
Overminus stimulates accommodation which then stimulates convergence
(therefore high AC/A ratio may be beneficial)
Fusional vergence stimulates accommodation
(we have a CA/A ratio)
accommodation blurs distance VA requiring overminus for clarity

13. Previous studies of “Overminus”
Small case series
Differing amounts of overminus (-0.50 to -5.00)
Differing methods of prescription (fixed versus titrated to control of IXT)
No control groups
No standardized outcome assessment
No masking of outcome assessment

14. Intermittent Exotropia Study 3 (IXT3)
A Pilot Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia

15. To assess initial short-term response to overminus treatment
Study Objectives
To assess initial short-term response to overminus treatment

16. What is the question ?
Is overminus treatment more effective than non-overminus treatment in the management of childhood intermittent exotropia?

17. Candidate 1o Outcome measures
Angle of deviation?
No – 2 cases can have same angle but very different
Stereoacuity?
No – stereoacuity often preserved
Control?
Yes - that is what others see

18. “Control” ? Proportion of the time the eyes are manifestly exotropic
Ease of recovery when dissociated

19. “Control” ? Proportion of the time the eyes are manifestly exotropic
Ease of recovery when dissociated

20. Mohney/Holmes office control score
Description 5
Constant exotropia during a 30-second observation period (before dissociation) 4
Exotropia >50% of the time during a 30-second observation period (before dissociation) 3
Exotropia <50% of the time during a 30-second observation period (before dissociation) 2
No exotropia unless dissociated (10 seconds): recovery in > 5 seconds (worst of 3) 1
No exotropia unless dissociated (10 seconds): recovery in 1-5 seconds (worst of 3)
Pure phoria: < 1 second recovery after 10-second dissociation (worst of 3)
Phoric Tropic
Control score described in a paper in Strabismus Control rated on 0 to 5 scale……
Scored separately for distance and near
Mohney BG, Holmes JM. An office-based scale for assessing control in intermittent exotropia. Strabismus 2006;14:

21. 30 second observation Constant exotropia – Grade 5
Exotropia > 50% of 30 seconds before dissociation – Grade 4
Exotropia < 50% of 30 seconds before dissociation – Grade 3
Score distance and near fixation separately

22. Three 10-second periods of dissociation
first R, then L, then the eye that deviated longest – estimate how many seconds it takes to recover
Grade by the worst of 3 trials
(R, L, then worst)
>5 seconds – grade 2
1-5 seconds - grade 1
<1 second – grade 0 (pure phoria)

23. But……control can be variable Distance control over the course of day1 2 3 4 5
8:00 -10:30
10:31-13:00
13:01-15:30
15:31-18:00
Tropic
Phoric
46% showed variable control
( >1 level)
during a single day
Control score
There were 3 patients who changed at distance fixation……
All changed between phoria and tropia
Worse level of control was not always later in day
Patient 1
Patient 10
Patient 13
Assessment time

24. Multiple assessments of control
Early am
Late am
Early pm
Late pm
Single
Double
Triple
Mean of one or two or three measures (single, double, triple)
Compared to Day mean (of 12 measures)
2. Subsequent day mean (of 12 measures)
Triple measures (mean of 3) were most representative of the patient

25. Current recommendations for assessing control – 3 assessments
30 sec observation
5 - constant
Visit
4 ->50%
3 - <50%
Mean of three assessments
For Distance
For Near
3 10-sec covers
2 - >5 secs
secs
0 - phoria

26. Back to the Pilot RCT

27. Refining the question in terms of the chosen primary outcome measure

28. Study Objectives
To assess initial short-term response to overminus treatment
Compare:
Study group mean of distance IXT control scores (primary outcome)*
Proportion of patients with improvement >=1 point in distance IXT control score*
Adverse symptoms, near VA, & compliance
*The distance IXT control score is the mean of 3 control tests at the visit.

29. 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 deviation does not exceed distance deviation by >10 ∆ on PACT

30. Major Eligibility Criteria (cont.)
No previous strabismus surgery
No previous substantial overminus (>=1.00D)
No non-surgical treatment for IXT within past 6 months (other than refractive correction)
SE in both eyes between and inclusive
No ADHD drugs or other drugs known to affect accommodation
Wearing appropriate correction for ≥1wk if refractive error meets certain criteria

31. Study Flow Chart Enrollment Randomization Overminus GROUP
Spectacles with full CR plus 2.50D overminus
Observation GROUP
(non-overminus spectacles
or no spectacles)
2-WEEK PHONE CALL (FROM SITE)
8-WEEK Primary outcome exam (masked exam)

32. Study Treatment & Sample Size
58 patients enrolled at 21 sites
We planned 50 patients, knowing that we would have 88% power to detect a 0.75 pt difference with a SD of (1-sided test with alpha of 0.05)
58 patients enrolled and randomized (1:1) to:
Observation (N=31)
Non-overminus spectacles or no spectacles (if correction not needed)
Overminus (N=27)
Spectacles with 2.50D overminus

33. Post-randomization Spectacle Wear in Observation Group

34. Baseline: XT Control at Distance
N/A
N/A
Distance Exotropia Control Score (mean of 3 testings)

35. Baseline: XT Control at Near
Near Exotropia Control Score (mean of 3 testings)

36. Baseline: PACT at Distance
N/A
Magnitude of Exodeviation by PACT at Distance (∆)
Note: PACT at distance had to be at least 15 PD for eligibility.

37. Magnitude of Exodeviation by PACT at Near (∆)
Baseline: PACT at Near
Magnitude of Exodeviation by PACT at Near (∆)

38. Baseline Stereoacuity at Near
Baseline Near Stereoacuity (arcsec)

39. Visit Completion

40. Visit Completion Observation (N=31) Overminus (N=27) 2-week call
Completed
Missed
30 (97%)
1 (3%)
27 (100%)
0 (0%)
8-week outcome visit
31(100%)

41. Weeks of Overminus Spectacle Wear Possible
Treatment Compliance
Weeks of Overminus Spectacle Wear Possible

42. Weeks Overminus Patients Had Overminus Spectacles
Mean = 7 weeks
Range = weeks
Weeks Between Spectacle Receipt and 8-Week Visit

43. Compliance with Overminus*
*Based on parental report and discussion with investigator.

44. Primary Outcome

45. 8-week Mean Distance Control
Difference = (-1.42 to -0.07)
P = 0.03 for one-sided test
Observation
(N=31)
Overminus
(N=27)

46. 8-week: Mean Distance Control
Difference = (-1.42 to -0.07)
P = 0.03 for one-sided test
8-wk Distance Control Score (mean of 3 testings)

47. 8-week Change in Distance Control Percentage of Patients
Worse
Mean change = -0.4
Mean change = -1.2
N/A
N/A
N/A
N/A
Better
Percentage of Patients

48. 8-week Distance Control Treatment Response (≥ 1 point improvement)
Difference = 20% (-6% to 45%)
P = 0.07 for one-sided test

49. Improvement in control by level of baseline control
Does improvement depend on baseline control?

50. 8-week Mean Change in Distance Control According to Baseline Control
Observation
Overminus N
Mean Change
(points)
2 to <3 13
0.1 pt 12
-0.5
3 to < 4 7 6
-0.7
4 to <5 11
-1.0 9
-2.5

51. >=1 point improvement in distance control
8-week Distance Control Treatment Response According to Baseline Control
Baseline
Distance
Control
Observation
Overminus N
>=1 point improvement in distance control
2 to <3 13
3 (23%) 12
6 (50%)
3 to < 4 7
4 (57%) 6
3 (50%)
4 to <5 11
4 (45%) 9
7 (78%)

52. Variability and regression to the mean
Start study here
Patient only enrolled if worse than threshold for inclusion
Worse
Parameter X
Threshold
Better
Visit 1
Visit 4
Visit 2
Visit 3
If you only enroll with “X worse than…” then you will see “apparent improvement” – due to variability and regression to mean

53. But in an RCT … Regression to the mean will be equal between groups

54. So this effect of baseline control is likely to be real
Distance
Control
Observation
Overminus N
Mean Change
(points)
2 to <3 13
0.1 pt 12
-0.5
3 to < 4 7 6
-0.7
4 to <5 11
-1.0 9
-2.5

55. Safety Data

56. Safety Observation N=31 Overminus N=27 Esodeviation* 0 (0%) 1 (4%)
Reduction of ≥ 2 lines distance VA**
2 (8%)
Reduction of ≥ 2 lines binocular near VA***
*Overminus: 3PD esodeviation
**Observation: 20/16 to 20/25 OS
Overminus: 20/20 to 20/32 OS, 20/ 20 to 20/40 OS
***Observation: 20/20 to 20/32

57. Symptom Survey Data

58. Has your child had headaches?
8-week Parental Report of Symptoms

59. Has your child had eyestrain?
8-week Parental Report of Symptoms

60. Has your child avoided reading or doing things up close?
8-week Parental Report of Symptoms

61. Has your child reported blurry vision?
8-week Parental Report of Symptoms

62. Has your child looked over his/her spectacles?
8-week Parental Report of Symptoms

63. Has your child taken spectacles off when should be wearing them?
8-week Parental Report of Symptoms

64. Has your child complained that spectacles hurt ears and/or nose?
8-week Parental Report of Symptoms

65. Limitations Pilot study, small sample size
Generalizable only to children 3 to 7 yrs with similar characteristics
Includes hyperopia only up to D
We don’t know if works over wider range of refractive error
Likely overestimated % with response
1-line of control improvement within test-retest. Expected ~20% to ‘respond’ by chance alone.

66. Conclusions
Overminus spectacles improve distance control (after 8 weeks)
Overminus spectacles appear to improve distance control particularly well in patients with very poor control (with a control score of 4 to 5)

67. How pilot study results pertain to possible full-scale, long-term RCT

68. IXT5 – possible full-scale longer term overminus study

69. Timing of outcome visits?
Children XX years old with IXT (with control score of 2 or worse)
Overminus
Observation
? Should there be escape clauses
If so, what should they be?
Long-term f/u ON treatment
? 12 mo
Final f/u OFF treatment
? 18 mo

70. Question 1 Control of intermittent exotropia should be assessed with:
Standardized timing of the tropic phase
Prism and alternate cover test
Near stereoacuity
Standardized assessment on the synoptophore

71. Question 1 Control of intermittent exotropia should be assessed with:
Standardized timing of the tropic phase
Prism and alternate cover test
Near stereoacuity
Standardized assessment on the synoptophore

72. Question 2 The current evidence suggests
Overminus may be more effective when control is moderate
Overminus may be more effective when control is poor
There is no relationship between the effectiveness of overminus and level of control
Overminus is ineffective as a treatment for intermittent exotropia

73. Question 2 The current evidence suggests
Overminus may be more effective when control is moderate
Overminus may be more effective when control is poor
There is no relationship between the effectiveness of overminus and level of control
Overminus is ineffective as a treatment for intermittent exotropia

74. Thank you