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Appropriate research design for studies of refractive surgery in children
GUEST EDITORIAL
Appropriate research design for studies of refractive surgery in children Surgical methods for the improvement of refractive error (aphakia, anisometropia, and bilateral high ametropia) have migrated gradually from adult ophthalmology to pediatric ophthalmology. Sometimes a particularly exciting technique is adopted before problems in the adult population become evident.1 Commonly described as “late” occurrences in adults, these are only “delayed” in children with decades of life expectancy. When proposing refractive surgery to parents, the ophthalmologist has 2 responsibilities: to relay the unknown nature, severity, and consequences of complications in the pediatric time frame and to distinguish between the optical effects and the desired but uncertain functional benefits without inflating the operation’s advantages over standard conservative therapy. All parties would benefit if research on pediatric refractive surgical techniques reported uniform data obtained with carefully defined methods. When drafting an earlier publication,2 I frequently found this informationdcrucial from the perspective of a pediatric ophthalmologistdof unclear validity or not presented. In addition, the investigation’s purpose must be clearly defined. Although reduction of refractive error and improvement in uncorrected visual acuity are probable outcomes, they are not adequate surgical indications for the reasons enumerated below. Age, cognitive development, and “the mood of the day” affect a child’s ability to cooperate with testing. Investigators treating children must accept some data inaccuracy. A “better number” caused by intrinsic measurement imprecision,3 normal physiological variation,4 a learning effect, older age,5–7 or stronger effort should not be mistaken for true improvement. Investigators who are refractive surgeons should recruit their pediatric ophthalmology colleagues as the surest way to improve study design and data quality. The corrected monocular visual acuity is an important outcome parameter that requires particularly well-defined methods and consistency as it is a challenging test in young children. If the investigators are assessing the effects of surgery on activities of daily living or strabismus, positive and negative binocular summation should be determined by measuring binocular visual acuity with optimum correction for both eyes (including a contact lens, if necessary) and also without correction of the surgical eye(s) before and after surgery. Q 2011 ASCRS and ESCRS Published by Elsevier Inc.
Research on patients with unilateral high myopia often fails to separate the effects of minification and other optical aberrations induced by high-minus spectacle lenses. To fairly measure acuity, stereopsis, and motor fusion before surgery, the myopic eye must be corrected with a contact lens. Rather than being unduly difficult or unnecessary, testing with a contact lens has 2 valuable uses: It can reassure the parents and the surgeon that definite gains can be made through refractive surgery, and it can reveal the true depth of the amblyopia. In either case (marked gains through reduction of minification and/or an urgent need for optical compliance and amblyopia treatment), the purpose of the surgery will be more clearly defined. Investigators should avoid reaching unsupported conclusions based on poorly measured or assumed functional outcomes,8–9 particularly depth perception and educational achievement. Humans use numerous monocular perceptions to determine depth including occlusion, relative height, known size, shadowing, texture, motion parallax, and atmospheric gradient. Surgeons should not overvalue a modest improvement in near stereopsis score.10 Performance of a mundane task (pouring water into a glass) is unaffected by nil stereopsis.11 Coarse near stereopsis of 100 to 400 arc seconds may confer no performance advantage in activities of daily living. Regarding educational achievement, a treatment that does not improve binocular reading acuity12 (maximum reading speed, minimum font size) is unlikely to affect binocular reading ability (fluency, comprehension). Studies have found that amblyopic eyes show a reduction in rate, accuracy, and fluency13–16 that persisted in treated eyes that regained normal visual acuity.15,17 Under binocular conditions, reading speed is reduced14,16 and saccadic eye movements are abnormal16 in amblyopic children. Researchers must guard against naïve enthusiasm based on anecdotal reports affected by optimism bias,18 such as a parental statement of “significant” improvement in educational achievement.10 Studies investigating reading performance should incorporate structured quantitative reading assessment using standard proficiency tests under binocular conditions. Based on present knowledge, it seems unlikely that unilateral refractive surgery would improve learning ability. Intraocular refractive surgery in children with neurobehavioral disorders, bilateral high ametropia, and spectacle intolerance19–20 has unique issues. 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2011.06.016
1379
1380
GUEST EDITORIAL
Proponents of the surgery advance the premise that a marked increase in uncorrected visual acuity will enhance life abilities such as environmental awareness, ambulation, and social interaction.21 This is a plausible but unproven hypothesis. The effects of optimism bias cannot be measured or eliminated from parent, teacher, and caregiver reports of improvement.20 In some developmentally delayed children, it may be impossible to accomplish an adequate postoperative assessment in the office. Serial examinations under anesthesia may be required to detect chronic subclinical inflammation,22 pigment dispersion, or elevated intraocular pressure. Alternatively, the ophthalmologist might assume that all is well if the eye is not red and the IOL not obviously dislocated. The first choice involves anesthesia risk and considerable inconvenience and expense. The second choice is far below the standard of care for an adult. To protect these particularly vulnerable patients and attempt to balance the currently unproven benefits against the unknown long-term risks, investigational review boards (and journal editors) should require that such studies include child development experts who assess patient behavior using 1 or more established observation protocols. Hopefully, well-designed clinical trials of pediatric corneal and intraocular refractive surgery will be conducted in the near future. To provide valid information on the effects of these procedures, tremendous collaboration will be needed between refractive surgeons, pediatric ophthalmologists, orthoptists, child development professionals, experts in the design of vision function and disease-specific health-related quality of life surveys, reading education teachers, and parents. Psychovisual assessments such as visual acuity and stereopsis must be standardized and optimized for a sometimes uncooperative patient population. Testing should be performed by examiners with appropriate skills who are unaware of the child’s surgical state (ie, preoperative or postoperative) whenever feasible. Until such trial results are available, ophthalmologists must advise parents that “changing the numbers” on refractive error, visual acuity, stereopsis, and ocular alignment has not been proven to change the child’s quality of life. Sandra M. Brown, MD Rhonda Gentry provided assistance with obtaining reference articles. Drs. Mark Greenwald and David Harper critically reviewed this manuscript.
REFERENCES 1. Buckley EG. Pediatric sutured intraocular lenses: trouble waiting to happen [editorial]. Am J Ophthalmol 2009; 147:3–4
2. Brown SM. Pediatric refractive surgery. Arch Ophthalmol 2009; 127:807–809 3. Holmes JM, Leske DA, Hohberger GG. Defining real change in prism-cover test measurements. Am J Ophthalmol 2008; 145:381–385 4. Adams WE, Leske DA, Hatt SR, Holmes JM. Defining real change in measures of stereoacuity. Ophthalmology 2009; 116:281–285 5. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester following the Amblyopia Treatment Study protocol. J AAPOS 2008; 12:145–149 n L, Frise n M. How good is normal visual acuity? A study of 6. Frise letter acuity thresholds as a function of age. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1981; 215:149–157 7. Hatt SR, Leske DA, Mohney BG, Brodsky MC, Holmes JM. Classification and misclassification of sensory monofixation in intermittent exotropia. Am J Ophthalmol 2010; 150:16–22 8. Ernst E, Canter PH. Investigator bias and false positive findings in medical research. Trends Pharmacol Sci 2003; 24: 219–221 9. Schmoll H-J, Arnold D. When wishful thinking leads to a mistyeyed appraisal: the story of the adjuvant colon cancer trials with edrecolomab [editorial]. J Clin Oncol 2009; 27:1926– 1929. Available at: http://jco.ascopubs.org/content/27/12/ 1926.full.pdf. Accessed June 14, 2011 10. Pirouzian A, Ip KC. Anterior chamber phakic intraocular lens implantation in children to treat severe anisometropic myopia and amblyopia: 3-year clinical results. J Cataract Refract Surg 2010; 36:1486–1493 11. O’Connor AR, Birch EE, Anderson S, Draper H, and the FSOS Research Group. The functional significance of stereopsis. Invest Ophthalmol Vis Sci 2010; 51:2019–2023. Available at: http://www.iovs.org/content/51/4/2019.full.pdf. Accessed June 14, 2011 12. Merrill K, Hogue K, Downes S, Holleschau AM, Kutzbach BR, MacDonald JT, Summers CG. Reading acuity in albinism: evaluation with MNREAD charts. J AAPOS 2011; 15:29–32 13. Repka MX, Kraker RT, Beck RW, Cotter SA, Holmes JM, Arnold RW, Astle WF, Sala NA, Tien DR; on behalf of the Pediatric Eye Disease Investigator Group. Monocular oral reading performance after amblyopia treatment in children. Am J Ophthalmol 2008; 146:942–947 14. Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W. Monocular and binocular reading performance in children with microstrabismic amblyopia. Br J Ophthalmol 2005; 89:1324–1329. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1772895/pdf/bjo08901324.pdf. Accessed June 14, 2011 15. Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W. Evaluating reading acuity and speed in children with microstrabismic amblyopia using a standardized reading chart system. Graefes Arch Clin Exp Ophthalmol 2005; 243:1228–1235 16. Kanonidou E, Proudlock FA, Gottlob I. Reading strategies in mild to moderate strabismic amblyopia: an eye movement investigation. Invest Ophthalmol Vis Sci 2010; 51:3502–3508. Available at: http://www.iovs.org/content/51/7/3502.full.pdf. Accessed June 14, 2011 €rcher B, Lang J. Reading capacity in cases of ‘cured’ strabis17. Zu mic amblyopia. Trans Ophthalmol Soc U K 1980; 100:501–503 18. Chalmers I, Matthews R. What are the implications of optimism bias in clinical research? [comment] Lancet 2006; 367:449– 450 19. Tychsen L, Packwood E, Hoekel J, Lueder G. Refractive surgery for high bilateral myopia in children with neurobehavioral
J CATARACT REFRACT SURG - VOL 37, AUGUST 2011
GUEST EDITORIAL
disorders: 1. Clear lens extraction and refractive lens exchange. J AAPOS 2006; 10:357–363 20. Tychsen L, Hoekel J, Ghasia F, Yoon-Huang G. Phakic intraocular lens correction of high ametropia in children with neurobehavioral disorders. J AAPOS 2008; 12:282–289
1381
21. Tychsen L. Refractive surgery for special needs children. Arch Ophthalmol 2009; 127:810–813 € ell JL. Phakic intraocular 22. Kohnen T, Kook D, Morral M, Gu lenses: part 2: results and complications. J Cataract Refract Surg 2010; 36:2168–2194
J CATARACT REFRACT SURG - VOL 37, AUGUST 2011
Appropriate research design for studies of refractive surgery in children Surgical methods for the improvement of refractive error (aphakia, anisometropia, and bilateral high ametropia) have migrated gradually from adult ophthalmology to pediatric ophthalmology. Sometimes a particularly exciting technique is adopted before problems in the adult population become evident.1 Commonly described as “late” occurrences in adults, these are only “delayed” in children with decades of life expectancy. When proposing refractive surgery to parents, the ophthalmologist has 2 responsibilities: to relay the unknown nature, severity, and consequences of complications in the pediatric time frame and to distinguish between the optical effects and the desired but uncertain functional benefits without inflating the operation’s advantages over standard conservative therapy. All parties would benefit if research on pediatric refractive surgical techniques reported uniform data obtained with carefully defined methods. When drafting an earlier publication,2 I frequently found this informationdcrucial from the perspective of a pediatric ophthalmologistdof unclear validity or not presented. In addition, the investigation’s purpose must be clearly defined. Although reduction of refractive error and improvement in uncorrected visual acuity are probable outcomes, they are not adequate surgical indications for the reasons enumerated below. Age, cognitive development, and “the mood of the day” affect a child’s ability to cooperate with testing. Investigators treating children must accept some data inaccuracy. A “better number” caused by intrinsic measurement imprecision,3 normal physiological variation,4 a learning effect, older age,5–7 or stronger effort should not be mistaken for true improvement. Investigators who are refractive surgeons should recruit their pediatric ophthalmology colleagues as the surest way to improve study design and data quality. The corrected monocular visual acuity is an important outcome parameter that requires particularly well-defined methods and consistency as it is a challenging test in young children. If the investigators are assessing the effects of surgery on activities of daily living or strabismus, positive and negative binocular summation should be determined by measuring binocular visual acuity with optimum correction for both eyes (including a contact lens, if necessary) and also without correction of the surgical eye(s) before and after surgery. Q 2011 ASCRS and ESCRS Published by Elsevier Inc.
Research on patients with unilateral high myopia often fails to separate the effects of minification and other optical aberrations induced by high-minus spectacle lenses. To fairly measure acuity, stereopsis, and motor fusion before surgery, the myopic eye must be corrected with a contact lens. Rather than being unduly difficult or unnecessary, testing with a contact lens has 2 valuable uses: It can reassure the parents and the surgeon that definite gains can be made through refractive surgery, and it can reveal the true depth of the amblyopia. In either case (marked gains through reduction of minification and/or an urgent need for optical compliance and amblyopia treatment), the purpose of the surgery will be more clearly defined. Investigators should avoid reaching unsupported conclusions based on poorly measured or assumed functional outcomes,8–9 particularly depth perception and educational achievement. Humans use numerous monocular perceptions to determine depth including occlusion, relative height, known size, shadowing, texture, motion parallax, and atmospheric gradient. Surgeons should not overvalue a modest improvement in near stereopsis score.10 Performance of a mundane task (pouring water into a glass) is unaffected by nil stereopsis.11 Coarse near stereopsis of 100 to 400 arc seconds may confer no performance advantage in activities of daily living. Regarding educational achievement, a treatment that does not improve binocular reading acuity12 (maximum reading speed, minimum font size) is unlikely to affect binocular reading ability (fluency, comprehension). Studies have found that amblyopic eyes show a reduction in rate, accuracy, and fluency13–16 that persisted in treated eyes that regained normal visual acuity.15,17 Under binocular conditions, reading speed is reduced14,16 and saccadic eye movements are abnormal16 in amblyopic children. Researchers must guard against naïve enthusiasm based on anecdotal reports affected by optimism bias,18 such as a parental statement of “significant” improvement in educational achievement.10 Studies investigating reading performance should incorporate structured quantitative reading assessment using standard proficiency tests under binocular conditions. Based on present knowledge, it seems unlikely that unilateral refractive surgery would improve learning ability. Intraocular refractive surgery in children with neurobehavioral disorders, bilateral high ametropia, and spectacle intolerance19–20 has unique issues. 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2011.06.016
1379
1380
GUEST EDITORIAL
Proponents of the surgery advance the premise that a marked increase in uncorrected visual acuity will enhance life abilities such as environmental awareness, ambulation, and social interaction.21 This is a plausible but unproven hypothesis. The effects of optimism bias cannot be measured or eliminated from parent, teacher, and caregiver reports of improvement.20 In some developmentally delayed children, it may be impossible to accomplish an adequate postoperative assessment in the office. Serial examinations under anesthesia may be required to detect chronic subclinical inflammation,22 pigment dispersion, or elevated intraocular pressure. Alternatively, the ophthalmologist might assume that all is well if the eye is not red and the IOL not obviously dislocated. The first choice involves anesthesia risk and considerable inconvenience and expense. The second choice is far below the standard of care for an adult. To protect these particularly vulnerable patients and attempt to balance the currently unproven benefits against the unknown long-term risks, investigational review boards (and journal editors) should require that such studies include child development experts who assess patient behavior using 1 or more established observation protocols. Hopefully, well-designed clinical trials of pediatric corneal and intraocular refractive surgery will be conducted in the near future. To provide valid information on the effects of these procedures, tremendous collaboration will be needed between refractive surgeons, pediatric ophthalmologists, orthoptists, child development professionals, experts in the design of vision function and disease-specific health-related quality of life surveys, reading education teachers, and parents. Psychovisual assessments such as visual acuity and stereopsis must be standardized and optimized for a sometimes uncooperative patient population. Testing should be performed by examiners with appropriate skills who are unaware of the child’s surgical state (ie, preoperative or postoperative) whenever feasible. Until such trial results are available, ophthalmologists must advise parents that “changing the numbers” on refractive error, visual acuity, stereopsis, and ocular alignment has not been proven to change the child’s quality of life. Sandra M. Brown, MD Rhonda Gentry provided assistance with obtaining reference articles. Drs. Mark Greenwald and David Harper critically reviewed this manuscript.
REFERENCES 1. Buckley EG. Pediatric sutured intraocular lenses: trouble waiting to happen [editorial]. Am J Ophthalmol 2009; 147:3–4
2. Brown SM. Pediatric refractive surgery. Arch Ophthalmol 2009; 127:807–809 3. Holmes JM, Leske DA, Hohberger GG. Defining real change in prism-cover test measurements. Am J Ophthalmol 2008; 145:381–385 4. Adams WE, Leske DA, Hatt SR, Holmes JM. Defining real change in measures of stereoacuity. Ophthalmology 2009; 116:281–285 5. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester following the Amblyopia Treatment Study protocol. J AAPOS 2008; 12:145–149 n L, Frise n M. How good is normal visual acuity? A study of 6. Frise letter acuity thresholds as a function of age. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1981; 215:149–157 7. Hatt SR, Leske DA, Mohney BG, Brodsky MC, Holmes JM. Classification and misclassification of sensory monofixation in intermittent exotropia. Am J Ophthalmol 2010; 150:16–22 8. Ernst E, Canter PH. Investigator bias and false positive findings in medical research. Trends Pharmacol Sci 2003; 24: 219–221 9. Schmoll H-J, Arnold D. When wishful thinking leads to a mistyeyed appraisal: the story of the adjuvant colon cancer trials with edrecolomab [editorial]. J Clin Oncol 2009; 27:1926– 1929. Available at: http://jco.ascopubs.org/content/27/12/ 1926.full.pdf. Accessed June 14, 2011 10. Pirouzian A, Ip KC. Anterior chamber phakic intraocular lens implantation in children to treat severe anisometropic myopia and amblyopia: 3-year clinical results. J Cataract Refract Surg 2010; 36:1486–1493 11. O’Connor AR, Birch EE, Anderson S, Draper H, and the FSOS Research Group. The functional significance of stereopsis. Invest Ophthalmol Vis Sci 2010; 51:2019–2023. Available at: http://www.iovs.org/content/51/4/2019.full.pdf. Accessed June 14, 2011 12. Merrill K, Hogue K, Downes S, Holleschau AM, Kutzbach BR, MacDonald JT, Summers CG. Reading acuity in albinism: evaluation with MNREAD charts. J AAPOS 2011; 15:29–32 13. Repka MX, Kraker RT, Beck RW, Cotter SA, Holmes JM, Arnold RW, Astle WF, Sala NA, Tien DR; on behalf of the Pediatric Eye Disease Investigator Group. Monocular oral reading performance after amblyopia treatment in children. Am J Ophthalmol 2008; 146:942–947 14. Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W. Monocular and binocular reading performance in children with microstrabismic amblyopia. Br J Ophthalmol 2005; 89:1324–1329. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1772895/pdf/bjo08901324.pdf. Accessed June 14, 2011 15. Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W. Evaluating reading acuity and speed in children with microstrabismic amblyopia using a standardized reading chart system. Graefes Arch Clin Exp Ophthalmol 2005; 243:1228–1235 16. Kanonidou E, Proudlock FA, Gottlob I. Reading strategies in mild to moderate strabismic amblyopia: an eye movement investigation. Invest Ophthalmol Vis Sci 2010; 51:3502–3508. Available at: http://www.iovs.org/content/51/7/3502.full.pdf. Accessed June 14, 2011 €rcher B, Lang J. Reading capacity in cases of ‘cured’ strabis17. Zu mic amblyopia. Trans Ophthalmol Soc U K 1980; 100:501–503 18. Chalmers I, Matthews R. What are the implications of optimism bias in clinical research? [comment] Lancet 2006; 367:449– 450 19. Tychsen L, Packwood E, Hoekel J, Lueder G. Refractive surgery for high bilateral myopia in children with neurobehavioral
J CATARACT REFRACT SURG - VOL 37, AUGUST 2011
GUEST EDITORIAL
disorders: 1. Clear lens extraction and refractive lens exchange. J AAPOS 2006; 10:357–363 20. Tychsen L, Hoekel J, Ghasia F, Yoon-Huang G. Phakic intraocular lens correction of high ametropia in children with neurobehavioral disorders. J AAPOS 2008; 12:282–289
1381
21. Tychsen L. Refractive surgery for special needs children. Arch Ophthalmol 2009; 127:810–813 € ell JL. Phakic intraocular 22. Kohnen T, Kook D, Morral M, Gu lenses: part 2: results and complications. J Cataract Refract Surg 2010; 36:2168–2194
J CATARACT REFRACT SURG - VOL 37, AUGUST 2011