Treatment of amblyopia: the “eye pad,” or the iPad?
2015-02-28 09:00:04 来源: JAAPOS
For more than 100 years, ophthalmologists have been wagging their fingers at reluctant, amblyopic children, urging them to wear an eye patch that they do not want to wear, while frightened parents have coaxed, begged, bribed, threatened, and cajoled their stubborn little ones to comply. In the current issue of the Journal of AAPOS and in a recent issue of the journal Eye,Birch and colleagues have conducted the first pediatric studies of a binocular therapy for amblyopia that allows parents to offer their children not an eye patch but an iPad. In both studies, children who played games on a handheld tablet computer equipped with red-green glasses had a statistically significant improvement in visual acuity in the amblyopic eye. Vision was gained with as little as 4 hours of treatment in some cases, with a few patients improving to 20/20. Are we ready, then, to abandon the burden of forced monocular occlusion in favor of encouraging our young patients to play binocular video games on their tablet computers? Unfortunately, no, we are not—not just yet, anyway.
While amblyopia has long been referred to as “lazy eye,”recent years have seen increasing evidence of the binocular nature of the disorder. Visual acuity can improve in patients with strabismic amblyopia treated with atropine, even if the atropine does not cause a change in fixation preference.Even more surprising, vision can improve in the amblyopic eye when amblyopic patients with manifest strabismus and a strong fixation preference are treated with spectacles alone.Amblyopia may also improve—without treatment—after successful strabismus surgery.These observations make no sense if one believes that amblyopia is simply the result of cortical suppression of a blurred or disconjugate image.The supposedly “sound” fellow eye also has subtle but demonstrable deficits. The fellow eye may actively interfere with vision in the amblyopic eye, as evidenced by resolution of amblyopia in animals after long periods of binocular deprivation.Meanwhile, deficits in the amblyopic eye extend far beyond a mere reduction in visual acuity, with some degree of binocularity integral to the optimization of visual acuity. Evidence for this includes the discovery of fixation instability in amblyopic eyes reminiscent of fusion maldevelopment nystagmus and improvement in visualacuity after strabismus surgery thanks to binocular summation.We have found that these abnormal binocular interactionsin amblyopic eyes can now be rapidly assessed and quantified using dichoptic tasks in the clinic.
It is with this emerging picture of amblyopia as a disease of the binocular visual system that investigators have begun to explore the benefits of binocular therapy. While treatment with atropine penalization or Bangerter occlusive foils is technically “binocular” therapy, these treatments to not encourage the brain to integrate images from the two eyes into a single percept. Truly binocular treatments use dichoptic presentation, in which one stimulus is presented to the left eye and another stimulus is presented to the right eye. At the onset of testing, an alignment procedure assures that the stimuli will overlap. Contrast of the two images is then adjusted to balance perception of the two images. The dichoptic stimuli are designed so that if they are perceived binocularly, a subject with nascent binocular ability will be able to complete a task. The result should then enhance binocular perception in a patient with otherwise-deep suppression of an amblyopic eye.
Previous explorations of binocular therapy have been performed in a supervised laboratory setting.These studies,while interesting, were performed on visually mature adults,and although there were gains in visual acuity, rarely if ever was the 0.2 logMAR (2 line) threshold exceeded in this age group. The question of great importance is, could binocular treatment ever be used as an equally effective alternative to patching—at home—in children whose visual systems have sufficient plasticity to allow full recovery of vision? The devices used in the adult studies to date were not suitable for testing preschoolers or for home use. They used a lenticular design, which required patients to sustain a precise head position during play, and involved play of the moving, falling puzzle piece game Tetris, which requires dexterity and cognitive abilities above those of most preschool children.To transition the treatment to younger children, the lenticular design was abandoned in favor of a red-green display with chromatically matched goggles, allowing more flexibility of head position. Three simpler games were added to provide variety and make the games more accessible to the youngest subjects. Once the design had been modified accordingly, Birch and her colleagues prescribed treatment in 50 children aged 4-12 years in the Eye study2 (conducted first) and in 50 children aged 3-7 years in the J AAPOS study.1 Both studies included sham arms, with 25 sham patients in the Eye study and 5 the J AAPOS study. Data from 10 subjects were included in both studies (E. Birch,personal communication), meaning that in total, 90 children and 30 controls aged 3-12 were enrolled in the two studies.In the Eye study, visual acuity in “compliant” children (who reported playing more than 4 of the 16 prescribed hours—just 1 hour of treatment per week) improved by an average of one line (0.1 logMAR) after 4 weeks. Beyond that, there was no correlation of time playing the game with amount of improvement. In the J AAPOS study, the threshold for compliance was 8 total hours of game play over 4 weeks; in that group, visual acuity improved by 1.5 lines. These improvements were statistically significant,but are they clinically important? To place 1 to 1.5 lines of improvement in 4 weeks in context, consider that in the original amblyopia treatment study, the atropine penalization group improved by 1.4 lines after 5 weeks of treatment.In another PEDIG study, 2 hours of patching gave 1.1 lines of improvement after 5 weeks in patients patched for 2 hours per day (and this was after a spectacle run-in phase of at least 5 weeks.) Thus, a gain of 1 to 1.5 lines in 4 weeks with dichoptic therapy is exciting and potentially clinically significant, but with a major caveat: in the Eye study, the improvement in visual acuity plateaued after 4 weeks, with no further improvement after an additional 4 weeks of treatment. Contrast that with the PEDIG studies,in which the ultimate improvement was 3 lines at 6 months in the original ATS trial.The J AAPOS study, which included subjects in the exact age range of the ATS trial,did not report results after more than 4 weeks of dichoptic therapy, so the potential for further improvement over a longer treatment episode remains to be seen. Although improvement in the Eye study patients plateaued at 4 weeks,consider that the PEDIG studies excluded patients who had undergone extensive prior amblyopia therapy, whereas the children in the Eye study had patched on average 1.9 years and those in the J AAPOS study had patched for 3-18 months prior to enrollment. Therefore, there remains a possibility that binocular therapy might prove to be as effective as patching or atropine in previously untreated children.
Treatment was not limited to game playing in all patients;many had concurrent eye patching of about 2 hours per day. The study authors make a convincing argument that patching was not a confounding factor and did not contribute to the observed improvements in visual acuity.
What additional studies will be required before we can consider offering tablet computers and red/green glasses as a first line of treatment for amblyopia? PEDIG has now initiated a prospective, randomized, controlled study comparing binocular therapy with patching in children 5-17 years of age.Until such studies are performed and evaluated, ophthalmologists will have to continue wagging their fingers at guilty parents, and parents will need to continue to chase their amblyopic children around the house wielding eye patches and dropper bottles in an effort to treat their amblyopia.
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References
1. Birch EE, Li SL, Jost RM, et al. Binocular iPad treatment for amblyopia in preschool children. J AAPOS 2015;19:6-11.
2. Li SL, Jost RM, Morale SE, et al. A binocular iPad treatment for amblyopic children. Eye (Lond) 2014;28:1246-53.
3. Pediatric Eye Disease Investigator Group. The course of moderate amblyopia treated with atropine in children: experience of the amblyopia treatment study. Am J Ophthalmol 2003;136:630-39.
4. Writing Committee for the Pediatric Eye Disease Investigator Group. Optical treatment of strabismic and combined strabismic-anisometropic amblyopia. Ophthalmology 2012;119:150-58.
5. Lam GC, Repka MX, Guyton DL. Timing of amblyopia therapy relative to strabismus surgery. Ophthalmology 1993;100:1751-6.
6. Blais BS, Frenkel MY, Kuindersma SR, et al. Recovery from monocular deprivation using binocular deprivation. J Neurophysiol 2008;100:2217-24.
7. Duffy KR, Mitchell DE. Darkness alters maturation of visual cortex and promotes fast recovery from monocular deprivation. Curr Biol 2013;23:382-6.
8. Birch EE, Subramanian V, Weakley DR. Fixation instability in anisometropic children with reduced stereopsis. J AAPOS 2013;17:287-90.
9. Pineles SL, Demer JL, Isenberg SJ, Birch EE, Velez FG. Improvement in binocular summation after strabismus surgery. JAMA Ophthalmol Jan 2 2015. Epub ahead of print.
10. Kwon M, Lu Z-L, Miller A, Kazlas M, et al. Assessing binocular interaction in amblyopia and its clinical feasibility. PLoS One 2014;9:e100156.
11. Abrams MS, Duncan CL, McMurtrey R. Development of motor fusion in patients with a history of strabismic amblyopia who are treated part-time with Bangerter foils. J AAPOS 2011;15:127-30.
12. Li J, Thompson B, Deng D, Chan LY, Yu M, Hess RF. Dichoptic training enables the adult amblyopic brain to learn. Curr Biol 2013;23:R308-9.
13. The Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for treatment of moderate amblyopia in children.Arch Ophthalmol 2002;120:268-78.
14. Pediatric Eye Disease Investigator Group Public Web Site.ATS18—study of binocular computer activities for treatment of amblyopia. http://pedig.jaeb.org/Studies.aspx?RecID5235. Accessed February 5, 2015.
While amblyopia has long been referred to as “lazy eye,”recent years have seen increasing evidence of the binocular nature of the disorder. Visual acuity can improve in patients with strabismic amblyopia treated with atropine, even if the atropine does not cause a change in fixation preference.Even more surprising, vision can improve in the amblyopic eye when amblyopic patients with manifest strabismus and a strong fixation preference are treated with spectacles alone.Amblyopia may also improve—without treatment—after successful strabismus surgery.These observations make no sense if one believes that amblyopia is simply the result of cortical suppression of a blurred or disconjugate image.The supposedly “sound” fellow eye also has subtle but demonstrable deficits. The fellow eye may actively interfere with vision in the amblyopic eye, as evidenced by resolution of amblyopia in animals after long periods of binocular deprivation.Meanwhile, deficits in the amblyopic eye extend far beyond a mere reduction in visual acuity, with some degree of binocularity integral to the optimization of visual acuity. Evidence for this includes the discovery of fixation instability in amblyopic eyes reminiscent of fusion maldevelopment nystagmus and improvement in visualacuity after strabismus surgery thanks to binocular summation.We have found that these abnormal binocular interactionsin amblyopic eyes can now be rapidly assessed and quantified using dichoptic tasks in the clinic.
It is with this emerging picture of amblyopia as a disease of the binocular visual system that investigators have begun to explore the benefits of binocular therapy. While treatment with atropine penalization or Bangerter occlusive foils is technically “binocular” therapy, these treatments to not encourage the brain to integrate images from the two eyes into a single percept. Truly binocular treatments use dichoptic presentation, in which one stimulus is presented to the left eye and another stimulus is presented to the right eye. At the onset of testing, an alignment procedure assures that the stimuli will overlap. Contrast of the two images is then adjusted to balance perception of the two images. The dichoptic stimuli are designed so that if they are perceived binocularly, a subject with nascent binocular ability will be able to complete a task. The result should then enhance binocular perception in a patient with otherwise-deep suppression of an amblyopic eye.
Previous explorations of binocular therapy have been performed in a supervised laboratory setting.These studies,while interesting, were performed on visually mature adults,and although there were gains in visual acuity, rarely if ever was the 0.2 logMAR (2 line) threshold exceeded in this age group. The question of great importance is, could binocular treatment ever be used as an equally effective alternative to patching—at home—in children whose visual systems have sufficient plasticity to allow full recovery of vision? The devices used in the adult studies to date were not suitable for testing preschoolers or for home use. They used a lenticular design, which required patients to sustain a precise head position during play, and involved play of the moving, falling puzzle piece game Tetris, which requires dexterity and cognitive abilities above those of most preschool children.To transition the treatment to younger children, the lenticular design was abandoned in favor of a red-green display with chromatically matched goggles, allowing more flexibility of head position. Three simpler games were added to provide variety and make the games more accessible to the youngest subjects. Once the design had been modified accordingly, Birch and her colleagues prescribed treatment in 50 children aged 4-12 years in the Eye study2 (conducted first) and in 50 children aged 3-7 years in the J AAPOS study.1 Both studies included sham arms, with 25 sham patients in the Eye study and 5 the J AAPOS study. Data from 10 subjects were included in both studies (E. Birch,personal communication), meaning that in total, 90 children and 30 controls aged 3-12 were enrolled in the two studies.In the Eye study, visual acuity in “compliant” children (who reported playing more than 4 of the 16 prescribed hours—just 1 hour of treatment per week) improved by an average of one line (0.1 logMAR) after 4 weeks. Beyond that, there was no correlation of time playing the game with amount of improvement. In the J AAPOS study, the threshold for compliance was 8 total hours of game play over 4 weeks; in that group, visual acuity improved by 1.5 lines. These improvements were statistically significant,but are they clinically important? To place 1 to 1.5 lines of improvement in 4 weeks in context, consider that in the original amblyopia treatment study, the atropine penalization group improved by 1.4 lines after 5 weeks of treatment.In another PEDIG study, 2 hours of patching gave 1.1 lines of improvement after 5 weeks in patients patched for 2 hours per day (and this was after a spectacle run-in phase of at least 5 weeks.) Thus, a gain of 1 to 1.5 lines in 4 weeks with dichoptic therapy is exciting and potentially clinically significant, but with a major caveat: in the Eye study, the improvement in visual acuity plateaued after 4 weeks, with no further improvement after an additional 4 weeks of treatment. Contrast that with the PEDIG studies,in which the ultimate improvement was 3 lines at 6 months in the original ATS trial.The J AAPOS study, which included subjects in the exact age range of the ATS trial,did not report results after more than 4 weeks of dichoptic therapy, so the potential for further improvement over a longer treatment episode remains to be seen. Although improvement in the Eye study patients plateaued at 4 weeks,consider that the PEDIG studies excluded patients who had undergone extensive prior amblyopia therapy, whereas the children in the Eye study had patched on average 1.9 years and those in the J AAPOS study had patched for 3-18 months prior to enrollment. Therefore, there remains a possibility that binocular therapy might prove to be as effective as patching or atropine in previously untreated children.
Treatment was not limited to game playing in all patients;many had concurrent eye patching of about 2 hours per day. The study authors make a convincing argument that patching was not a confounding factor and did not contribute to the observed improvements in visual acuity.
What additional studies will be required before we can consider offering tablet computers and red/green glasses as a first line of treatment for amblyopia? PEDIG has now initiated a prospective, randomized, controlled study comparing binocular therapy with patching in children 5-17 years of age.Until such studies are performed and evaluated, ophthalmologists will have to continue wagging their fingers at guilty parents, and parents will need to continue to chase their amblyopic children around the house wielding eye patches and dropper bottles in an effort to treat their amblyopia.
查看原文
References
1. Birch EE, Li SL, Jost RM, et al. Binocular iPad treatment for amblyopia in preschool children. J AAPOS 2015;19:6-11.
2. Li SL, Jost RM, Morale SE, et al. A binocular iPad treatment for amblyopic children. Eye (Lond) 2014;28:1246-53.
3. Pediatric Eye Disease Investigator Group. The course of moderate amblyopia treated with atropine in children: experience of the amblyopia treatment study. Am J Ophthalmol 2003;136:630-39.
4. Writing Committee for the Pediatric Eye Disease Investigator Group. Optical treatment of strabismic and combined strabismic-anisometropic amblyopia. Ophthalmology 2012;119:150-58.
5. Lam GC, Repka MX, Guyton DL. Timing of amblyopia therapy relative to strabismus surgery. Ophthalmology 1993;100:1751-6.
6. Blais BS, Frenkel MY, Kuindersma SR, et al. Recovery from monocular deprivation using binocular deprivation. J Neurophysiol 2008;100:2217-24.
7. Duffy KR, Mitchell DE. Darkness alters maturation of visual cortex and promotes fast recovery from monocular deprivation. Curr Biol 2013;23:382-6.
8. Birch EE, Subramanian V, Weakley DR. Fixation instability in anisometropic children with reduced stereopsis. J AAPOS 2013;17:287-90.
9. Pineles SL, Demer JL, Isenberg SJ, Birch EE, Velez FG. Improvement in binocular summation after strabismus surgery. JAMA Ophthalmol Jan 2 2015. Epub ahead of print.
10. Kwon M, Lu Z-L, Miller A, Kazlas M, et al. Assessing binocular interaction in amblyopia and its clinical feasibility. PLoS One 2014;9:e100156.
11. Abrams MS, Duncan CL, McMurtrey R. Development of motor fusion in patients with a history of strabismic amblyopia who are treated part-time with Bangerter foils. J AAPOS 2011;15:127-30.
12. Li J, Thompson B, Deng D, Chan LY, Yu M, Hess RF. Dichoptic training enables the adult amblyopic brain to learn. Curr Biol 2013;23:R308-9.
13. The Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for treatment of moderate amblyopia in children.Arch Ophthalmol 2002;120:268-78.
14. Pediatric Eye Disease Investigator Group Public Web Site.ATS18—study of binocular computer activities for treatment of amblyopia. http://pedig.jaeb.org/Studies.aspx?RecID5235. Accessed February 5, 2015.
