Pediatric Anisometropia: tacles, vision therapy, and occlusion. Case two Case Series and Review is anisometropia caused by organic vision loss from optic neuritis early in life. Case three is John D. Tassinari OD, FAAO, FCOVD an infant with hyperopic anisometropia and Diplomate Binocular Vision esotropia. The esotropia did not respond to Perception and Pediatric Optometry, spectacles and home based vision therapy. American Academy of Optometry Neonatal high bilateral hyperopia that Associate Professor Western converted to anisometropia because of early University of Health Sciences onset cosmetically invisible unilateral esotropia College of Optometry is speculated. Case four describes a boy Pomona, California diagnosed with hyperopic anisometropia at age 11 months coincident with a diagnosis of pseudoesotropia. His compliance with

ARTICLE prescribed spectacles was spotty until age three years. An outstanding visual outcome ABSTRACT was achieved by age five years with spectacles Background only (no occlusion therapy). Case five concerns The etiology and natural course and history a boy who acquired hyperopic anisometropia of pediatric anisometropia are incompletely because one eye experienced increasing understood. This article reviews the literature hyperopia during his toddler years. His regarding pediatric anisometropia with much response to treatment, spectacles and part of the review integrated into a case series. time occlusion with home vision therapy, was The review and case reports are intended to outstanding. Case six is an infant diagnosed elevate clinical understanding of pediatric with 2.50 diopters of hyperopic anisometropia anisometropia including and especially at age six months. Monocular home based treatment outcomes. vison developmental activities, not glasses, were prescribed. Her anisometropia vanished Case Reports three months later. Case one is anisomyopia with amblyopia that resulted in a poor treatment outcome despite Conclusions outstanding compliance with prescribed spec­ Pediatric anisometropia presents and responds to treatment in a variety of ways that challenge Correspondence regarding this article should be emailed to John D. Tassinari, OD, FAAO, FCOVD, at clinical care. Etiology and age of onset, which [email protected]. All statements­ are the author’s usually elude clinicians, can explain this variety. personal opinions and may not reflect the opinions of Additional research is required to improve the College of Optometrists in Vision Development, Vision Development & Rehabilitation or any institution­ clinical outcomes. or organization to which the authors may be affiliated. Permission to use reprints of this article must be obtained from the editor. Copyright 2020 College of Optometrists Pediatric anisometropia may be causative of, in Vision Development. VDR is indexed in the Directory or at the very least associated with, monocular of Open Access Journals. Online access is available at and binocular visual impairment. If anisometropia covd.org. https://doi.org/10.31707/VDR2020.6.1.p32. occurs during the sensitive period of visual Tassinari JD. Pediatric Anisometropia: Case Series and development, is of significant magnitude, Review. Vision Dev & Rehab 2020;6(1):32-56. chronic, and not treated in time, the visual abnormalities are lifelong. The natural course Keywords: Anisometropia, amblyopia, and history of anisometropia and its etiology vision therapy, occlusion are incompletely understood. One important

32 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 but elusive consideration in the longitudinal shifted to anisometropia by age 3-years. course of pediatric anisometropia is age of Another longitudinal study showed that onset. Clinically, it is impossible to document anisometropia in infancy does not correlate age of onset because anisometropia, unlike with anisometropia at age 12-15 years, but age many forms of another amblyogenic condition, 5 year anisometropia correlates with adolescent strabismus, is invisible. Epidemiological anisometropia.6 evidence against neonatal onset persistent Age of onset is of particular interest in cases anisometropia comes from studies showing of non-transient anisometropia with abnormal an anisometropia prevalence among infants vision because of its link to severity of amblyopia and young children near 1%1-4-2%5,6 in and treatment prognosis.14-17 In broad terms, contradistinction to older pediatric populations persistent pediatric anisometropia appears to with an anisometropia prevalence ranging from be a largely acquired condition sometime after 6%6-9%.7,8 Atkinson et. al. acquired refractive age 1 year. For cases of persistent anisometropia data from over 8,000 infants age 6-8 months. that are an exception to this rule, and onset Per a criterion of > 1.50D, the anisometropia early in the first year of life, deep amblyopia prevalence was approximately 1%.1 Another and recalcitrant suppression of binocular vision definitive study of early in life ametropia (see Cases 1 and 3 below) is expected. found four anisometropes > 1.00D among 514 For cases of acquired non-transient ped­ children age 1-48 months.2 The STARS cross ia­tric anisometropia, how does the shift sectional population based study found one to anisometropia occur? Does the lesser child with anisometropia per a definition of ametropic eye begin with high ametropia equal > 2.00D among 615 children age 6-23 months.3 to the fellow eye then shift toward emmetropia Regarding older children, Hu et al’s recent study leaving the more ametropic eye behind (Case of over 6,000 children age 4-18 years found 7% 4 below)? This sequence seems most plausible anisometropia (≥1 diopter).8 given the proclivity for infant/toddler ametropia Another confounding age-of-onset variable to migrate toward emmetropia.1,2,5,13,18 Alter­­ is that transient and reducing anisometropia natively, the shift from isometropia to aniso­ occurs during the first few years of life5,6,9-13 metropia occurs because the ametropia in one (see Case 6 below). Wood, Hodi, and Morgan’s eye worsens while the fellow eye does not. No longitudinal study found that all cases of doubt a 3rd chronological route for acquired anisometropia in infants younger than age 6 pediatric anisometropia is a combination. One months disappeared before age 12 months.5 eye shifts towards emmetropia while the fellow Similarly, Almeder et. al. found that among the shifts away (see Case 5 below). identified non-strabismic anisometropic infant Onset age and antecedent refractive subjects none had persistent anisometropia.11 changes aside, etiology of acquired pediatric Another longitudinal study showed 10% anisometropia remains a quandary. In basic terms, anisometropia prevalence at all age levels pediatric anisometropia is due to mismatched one through four years.10 This prevalence optical eye growth. If each eye functions in the carried through the ages because there same environment and participates in the same were anisometropic children who converted visual experiences, why does one eye stray to isometropia during the study time frame further from the emmetropization path than supplanted by children who acquired its fellow? It may be as simple as the optical anisometropia. Ingram and Barr’s longitudinal elements of the worse eye deviating further study found a similar result.9 Seven of their away from emmetropization per random twelve 1-year old anisometropes converted to biological and genetic variation. The eye and isometropia and eight of their 136 isometropes its attached neurology are structurally sound

33 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 but the individual optical elements of the worse meridian, not the spherical equivalent, registers eye, for benign and idiopathic reasons, comply as the signal for axial elongation.28 Thus, an eye poorly with the rules of emmetropization. saddled with higher astigmatism than its fellow Support for a genetic contribution to eye concludes emmetropization with higher anisometropia etiology can be found in a hyperopia (Case 6 below). Bilateral and equal Vision in Preschoolers (VIP) study showing astigmatism that results in anisometropia may differences in the prevalence of anisometropia be understood as one eye possessing better among different racial/ethnic groups.19 Two emmetropization responsiveness in the face of known causes of faulty emmetropization in one astigmatic blur (Case 5 below). eye and therefore anisometropia are visual- This article presents a retrospective chart input depriving eye diseases18,20 (Case 2 below) review series of six pediatric anisometropia and unilateral strabismus, particularly unilateral cases that raise questions and discussions esotropia (Case 3 below).11,20-26 It is tempting, points regarding anisometropia. In each case, therefore, to view cases of apparently non- the patient has visual abnormalities associated strabismic disease-free anisometropia in this with their anisometropia. The literature review light. Almeder et. al. were among the early continues in the discussion section of each adopters of the hypothesis that “… most adult case. It emphasizes speculations regarding the anisometropia is the result, rather than the natural course and etiology of the anisometropia cause of amblyopia”.11 Barrett, Bradley, and as a backward look to understand clinical Candy provide a recent extensive review of the findings and treatment outcomes in these cases hypothesis that seemingly pure anisometropia and other cases of pediatric anisometropia may actually be a consequence of unilateral encountered by clinicians. The institutional microstrabismus or unilateral occult, possibly review board of the Western University of temporary, disease.20 The first consequence Health Sciences approved inclusion of the case of the disease or strabismus is abnormal series in this article. visual input from the isometropic affected eye.20 Next, the abnormal input interrupts Case 1. MT, Anisomyopia and Poor emmetropization in the affected eye and with Treatment Outcome time anisometropia ensues. Upon clinical MT presented as a calm, healthy, friendly, presentation the trigger for anisometropia, scholastically high achieving 8-year-old 3rd pathology or microstrabismus, is not detected grade boy. His parents wanted to know if and the anisometropia is incorrectly deemed their son would benefit from office based responsible for the amblyopia when indeed vision therapy for a “weak left eye”. Case microstrabismus or disease marred visual input, history and prior records showed that MT which in turn caused anisometropia (Case 2 and was first diagnosed with anisomyopia and 3 below). In this scenario, the anisometropia refractive amblyopia OS at age 6 years. He adds to the original cause of reduced vision or was compliant with the prescribed full time prolongs it if the original abnormality abates.20 eyeglass wear (OD: Plano DS, OS: -4.25DS), Another potential driver of anisometropia, two hours of daily opaque occlusion of the more specifically anisohyperopia, with some right eye, and home vision therapy (video literature support is astigmatism,6,9,10,27,28 even games). Further review of prior records showed when the astigmatism is bilateral and equal.6,9,10 that MT’s best visual acuity OS had improved The astigmatic retinal image, per this hypothesis, from 20/200 at baseline to 20/80. Significant retards post-natal axial elongation to cause case history includes premature birth (30 weeks hyperopia. A speculated specific mechanism gestation age), low birth weight (less than three for this retardation is that the least hyperopic pounds) and incubation during his postnatal

34 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 1. Case 1 – MT, Salient exam findings before and after treatment Ametropia BCVAb Monocular visual function Sensory fusion • Saccades, Pursuits 4+c Plano DS a 20/20 • Accommodative Amplitude 15D OD KM: 42.87 • Contrast Sensitivity: 8% @ 20/20d Stereo: 100 seconds contour • Saccades, Pursuits: 2+ No random dot • Accommodative Amplitude: 7D -4.25 DS Worth 4 Dot: Suppress OS at 35cm a 20/80 • Visuoscopy & Hadinger Brush: central OD KM: 43.12 fixation, minor variability • Contrast sensitivity: 32% @ 20/100 • Saccades, Pursuits OS: 4+ Stereo: 70 seconds contour OS • Accommodative Amplitude OS: 12D No random dot Post-VT 20/60 • Visuoscopy & Hadinger Brush OS: Central fixation, steady Worth 4 Dot: Suppress OS at 60cm • Contrast sensitivity OS: 50% @ 20/60 a=average keratometry b=Best Corrected Distance Visual Acuity with single line Snellen optotypes c=SCCO method of scoring29 d=M & S Technologies Smart System 20/20 (Niles, IL)

Box 1. Sample of vision therapy (VT) procedures com­ limited to reduced best corrected visual acuity, pleted by MT (Case 1, OS amblyopia). are present. Sensory fusion was abnormal per Home VT – Monocular Office VT – Monocular OS suppression and reduced stereopsis. MT did Pencil Saccades29,30 Marsden ball bunting29 not have strabismus nor did he have eccentric Hidden Pictures31 Wayne Perceptuomotor Pen29 Near-far charts30,31 Prism jumps31 fixation. All ocular health testing, including a Visual Tracing (Groffman)29 Monocular tachistoscope30 dilated fundus exam, monocular color vision, pupil light reactions, and screening visual field, Home VT – MFBF*/ Office VT – MFBF/ anti-suppression anti-suppression were normal. His manifest subjective refraction Colored filters tracing30,31 Cheiroscopic Tracings29-31 equaled his entering spectacle Rx. Refractive Bar reading29,30 Red Filter Tachistoscope30 29,30 30 amblyopia and binocular dysfunction secondary Pola Mirror Vertical Prism Rotations to anisometropia were diagnosed. Office based Home VT – Binocular Office VT – Binocular vision therapy (VT) in the form of 1-hour weekly Brock String29 Van Orden Star30 office visits coupled with two hours of daily Hand Held Stereoscope29 Four Ball Cards Telebinocular30 Three Dot Card29 Vectograms29,30 occlusion and daily home VT were prescribed. Another treatment instituted after 10 vision *MFBF. monocular fixation binocular field. therapy sessions was applying a 0.2 (20/100) hospital stay. In the hospital and shortly after occlusion foil to the right spectacle lens on MT’s discharge, he was evaluated for retinopathy of back-up glasses. He was instructed to wear prematurity (ROP), but never required any form these glasses with graded translucent occlusion of treatment. They recall a comment from the for a minimum of 12 hours every weekend. His eye doctor at the post-discharge exam that MT parents encouraged him to wear the translucent might be nearsighted at a young age. Parents occlusion rendered glasses to school but MT’s did not comply with planned follow-up after his classroom visual function was untenable. first outpatient eye exam. MT’s weight and size MT demonstrated outstanding attendance caught up during the first 6-7 months of life and compliance with the VT program and and he ultimately met all major early childhood occlusion. A sample of home and office VT developmental milestones on time. procedures he completed are listed in Box 1. The salient evaluation findings can be viewed An emphasized VT procedure category was in Table 1. Anisomyopia magnitude 4.25D and monocular-fixation-binocular-field (MFBF). A abnormal OS monocular vision, including but not rep­resent­ative MFBF VT activity that MT

35 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 completed was red filter tachistoscope.30 In disease causing the subnormal vision OS. The this procedure, the tachistoscope projects a ophthalmological evaluation, which included lit target comprised of black numbers in a red dilated fundus exam, optical coherence background that are exposed for a brief, pre- tomography, corneal topography, wavefront selected and adjustable time interval. This vision aberrometry, and ultrasound, was negative. therapy target is not seen by an eye viewing Other pertinent negatives include monocular through a green filter. MT wore a green filter color vision, visual field, photostress test and in front of his right eye leaving the amblyopic pupil light reactions left eye. The ultrasound left eye to locate, resolve and identify the confirmed that the anisomyopia was due to an briefly flashed projected number sequence. axial length difference which is consistent with The red filter tachistoscope procedure became population studies of anisometropia.7,8,36-39 The more challenging as patient performance eye doctor informed the parents that additional improved via target distance (smaller target amblyopia treatment was futile and that the size), number sequence length (1, 2, 3 or 4) vision therapy program their son completed and speed of presentation (.1 sec, .05 sec, .025 was “a waste of time and money”. sec, .01 sec). This VT procedure recognizes that visual processing speed is a known deficit Case 1. MT, Anisomyopia. DISCUSSION in amblyopia.14 It also is representative of MT’s findings are consistent with amblyopia recommended perceptual learning principles OS secondary to myopic anisometropia. Among in amblyopia therapy.32,33 infants and young children, anisomyopia is MT completed progress evaluations on visit rare and has a much lower prevalence than 10 and 20 of his VT program. Progress was anisohyperopia.1,4,10,12,17 A large study (N = nominal at visit 10. At visit 20 it was concluded 2,298) of young children (age 6-71 months) that MT’s visual function reached a plateau and found 10 children with myopic anisometropia further gains were unlikely. As shown in Table ≥ 1.00D (per spherical equivalent).4 There 1, there were notable gains in monocular visual were 89 children with hyperopic anisometropia skills. Sensory fusion improved but remained per same definition. Among the 10 children abnormal. End of vision therapy visual acuity with myopic anisometropia, only 2 were ≥ OS was unfortunately no better than 20/60 3.00D. Amblyopia from myopic anisometropia using single line presentation of Snellen letters. typically causes a less severe amblyopia than MT remained a regular patient with the hyperopic anisometropia of equal magnitude author until age 20 years. He began wearing and requires a higher inter-ocular difference to contact lenses OU full time at age 12 years when be amblyogenic.31,37,40-45 For example, Tanlami his heretofore-emmetropic OD developed and Goss found a 50% prevalence of amblyopia 1.50D myopia. This pattern of myopic increase among individuals with 4.5D anisomyopia in the less myopic eye with a corresponding while 100% of anisohyperopes at that level decrease in anisometropia matches a literature had amblyopia.43 Levi and colleagues showed based pattern.34,35 MT attempted another that among amblyopic anisomyopes with an course (10 office visits) of vision therapy at inter-ocular difference in the 4-5D range, like age 12 as a contact lens wearer. Visual acuity MT, the visual acuity ranged from 20/32 to and sensory fusion did not improve although 20/80 with most clustered near 20/40 – 20/50.44 there was a modest improvement in contrast They also showed that even with substantial sensitivity. When visual acuity did not improve, anisometropia (up to 10D) 53% of myopic his parents, on their own recognizance, sought anisometropes retain stereo acuity of better an expert opinion at a university based eye clinic than 30 arc seconds,44 noticeably superior to regarding the possibility of an undetected eye MTs 100 seconds pre-VT and 70 seconds post-

36 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 2. Case 1 – MT, speculated and known ametropia levels to account for severity of visual dysfunction. AGE, months AGE, years Age 2 weeks 1 3 6 12 24 36 6b 8 12 – 1.00 + 0.50 + 0.50 + 0.50 + 0.50 + 0.50

A a – 8.00 – 8.00 – 7.50 – 7.00 – 7.00 – 4.25 – 5.50 – 5.00 – 5.00 – 3.50 – 3.50 – 1.00 Plano Plano – 1.50DS B – 6.00 – 6.00 – 6.00 – 5.00 – 5.00 – 4.25 – 4.25DS – 4.25DS – 4.50DS

Myopia OU + 1.00 + 1.00 + 1.00 + 0.50 + 0.50 + 0.50 C + 1.00 + 1.00c Plano – 3.50 – 3.50 – 4.25 Gray=Speculative refractive status. Black=Known refractive status A. MT’s speculated ametropia history explaining depth of amblyopia, poor sensory fusion, and poor VT outcome. B. Favorable ametropia history leading to less severe amblyopia and better sensory fusion. Unlikely in this case. C. Speculated pathological etiology of abnormal emmetropization OS and resultant anisometropia a=myopia OU is assumed per case history. b=age of anisometropia diagnosis c=speculated onset of eye disease OS. Disease causes compromised visual input and abnormal axial elongation OS

VT. Hu et. al. also showed that anisomyopia is in life.14-17,33 MT did not have an eye exam less impactful on stereo acuity than comparable with an eye care practitioner between the first anisohyperopia.8 month of life and age 6 years. Speculations The proffered explanation for better visual regarding his ametropia history are offered in function in anisomyopia is that the more myopic Table 2 toward the goal of understanding the eye is not ignored because it is utilized for near unexpected severity of his visual dysfunctions. vision while the lesser myopic eye dominates All three versions of his speculated ametropia far vision.31,37,41,45,46 In anisohyperopia, the history assume neonatal myopia per the worse eye never dominates because the eye parents’ recollection of the neonatal eye exam with less hyperopia is chosen to view at all results. Version A in Table 2 speculates that OD distances.31,37,45,46 There is an alternative or was much less myopic than OS when MT was a additive explanation for the typically better neonate and shifted rapidly from myopia to low visual function in anisomyopia compared to hyperopia by age 3 months. The left eye did anisohyperopia of a comparable magnitude. not, causing MT to have severe antimetropia The anisometropia magnitude may generally of 8.5 diopters very early in life. This extreme be less in anisomyopia versus anisohyperopia difference repressed natural utilization of OS during the most sensitive amblyogenic years for near vision thereby stunting development early in life.8,46 of monocular vision OS and binocular vision. A In this context, it is puzzling that MT’s speculated cause of the severe myopia OS can 4.25D of anisomyopia caused such a reduced be traced back to his premature birth and low level of pre-treatment BCVA (20/200) and birth weight. Both have been linked to myopia such a marked reduction in stereopsis (100 and anisometropia with the link strengthened if seconds). Moreover, his treatment outcome retinopathy of prematurity (ROP) is present.47-51 despite an intense therapy program for which Perhaps OS had ROP that involuted and OD he exhibited outstanding compliance, was never had ROP. Or, OS had more pervasive and mediocre. These inconsistencies raise the chronic ROP before it regressed. possibility that at one time he had a more Version A further speculates that the powerful amblyogenic mechanism in play than antimetropia reduced to 4.75 by age 36 months 4.25D of anisomyopia, and the amblyogenic hand in hand with myopia decrease left eye mechanism or mechanisms were present early and ultimately reached 4.25D anisomyopia by

37 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 his age of anisometropia diagnosis, 6 years. for eye disease as an older child and found to As the myopia OS declined (and with it, the have none. Thus, the speculated eye disease antimetropia) MT did not convert to habitual would have to be ephemeral or quite elusive. near viewing with OS because of its embedded Note that a temporary disease may trigger reduced vision. Although version A depicts anomalous eye growth for an extended period an extreme level of OS myopia early in life, a after the insult.20 Finally, whichever version in lesser level of myopia may have led to the same Table 2 best represents the veridical course outcome under the correct circumstances. As and history of MT’s ametropia, earlier diagnosis mentioned above, in anisomyopia the eye and treatment would have likely led to a better with higher myopia is assumed to dominate treatment outcome. at near affording protection from amblyopia. There is recent evidence, however, suggesting Case 2. DG, Antimetropia and that children with anisomyopia may focus with Optic Atrophy the less myopic eye at all distances.20 In order DG, age 6 at the author’s first exam, failed to contrast and compare, Version B in Table a school vision screening at age 5 years upon 2 illustrates an ametropia history that would entry into kindergarten. His previous eye lead to milder amblyopia and better sensory care practitioner diagnosed amblyopia OS, fusion because the anisometropia is mild early prescribed glasses for full time wear, and daily in life. In Version B, unaided binocular visual part-time occlusion therapy of OD. DG willingly acuity would be worse than Version A during wore the glasses but was adamantly opposed infancy and it is conceivable that there would to occlusion therapy. His parents presented to have been behavioral signs causing MT to seek the author wanting to know if vision therapy another eye exam sooner than age six years. would benefit their son. Table 3 shows that Thus, version B can be tacitly ruled out. Note best corrected visual acuity (BCVA) OS was that Version A and B involve myopic reduction 20/80 at baseline. Repeated careful unilateral in at least one eye; an established phenomenon cover testing per the suspicion of small angle early in life,9,50,52 including children with a esotropia did not reveal a visible strabismus. history of preterm birth.50 The greatest myopic Microtropia with the degree of strabismus reduction in Versions A and B is intentionally equal to the degree of eccentric fixation29,55 placed at age 2-3 years in accord with Erlich’s was considered but not confidently supported longitudinal study of infant myopia.52 per equivocal results on visuoscopy and 4 base Another explanation for the poor outcome, out test shown in Table 3. DG’s ametropia (OD depicted in Table 2 version C, is a non-ROP +1.75 -025 180, OS -1.75 -0.25 180) had 3.50 early onset occult or temporary disease of the diopters inter-ocular difference that manifested left eye or its visual pathway. In this version, as antimetropia. However, the myopic left eye MT was isometropic until a pathologic insult had the reduced BCVA, not the hyperopic right to the left eye or its visual pathway to the eye. While 3.50 diopters interocular difference cortex occurred. The pathology deprived is amblyogenic,15,16 the more hyperopic eye is development of visual pathway neurons and the expected amblyopia casualty.16,44 responsive cortical cells resulting in reduced Reduced vision in the myopic left eye vision (“organic amblyopia”). Saddled with prompted careful attention to disease testing organic amblyopia, OS eye growth went and DG’s left eye had a positive afferent pupil the way of excessive axial elongation, a defect, abnormal color vision, and paracentral possible sequela of ocular pathology early in visual field defects (Figure 1). Ophthalmoscopy life,18,20,39,53,54 and subsequent anisomyopia. As revealed inferior sector pallor of OS optic mentioned above, MT was thoroughly tested disc and extensive inferior nerve fiber layer

38 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 3. Case 2 - DG, Salient exam findings at initial exam andfollow-up Ametropia BCVAa Monocular visual function Binocular testing • Saccades, Pursuits 3+b Cover Test • Accommodative Amplitude 15D Unilateral: no movement +1.75 -0.25 180 20/20 OD • Normal: color vision, automated screening Alternate: no movement visual field, and pupil light reactions Stereo • Saccades, Pursuits: 1+ 100 seconds contour • Accommodative Amplitude: unresponsive No random dot • Visuoscopy: unsteady variable direction, brief central fixation -1.75 -0.25 180 20/80 possible OS 4 BO test: poor fixation • Color vision: abnormal for red/green • Automated screening visual field: abnormal (see Figure) Worth 4 Dot Suppress • + afferent pupil light reaction defect OS at all distances • Saccades, Pursuits OS 1+ Stereo: 70 seconds contour Post-VT • Accommodative Amplitude: 10D No random dot OS (10 office visits) 20/80 and occlusion Worth 4 Dot Suppress OS at all distances a=BestFigure 1. CorrectedCase 2. Screening Visual Acuity withv singleisual field results line HOTV optotypes b=SCCO method of scoring27

Figure 1: Case 2. Screening visual field results. Figure 2: Case 2. Fundus photo OS showing optic nerve atrophy and inferior retina atrophy. loss as shown in Figure 2. A referral to an eye disease specialist group lead to multiple on the pathological vision loss,39,40,48 office exams with pediatric, retina specialist, and based VT and part time occlusion therapy were neuro ophthalmologists. The exams confirmed prescribed. The occlusion methods included OS optic atrophy and inferior retina atrophy. conventional opaque occlusion and a trial of Another relevant finding was OS axial length graded occlusion (0.2 filter to right spectacle approximately 1 mm longer than OD. The lens of his spare pair of glasses). Compliance ultimate diagnosis was optic atrophy from a with office based VT, including monocular in- previous episode of idiopathic optic neuritis OS. office VT, was satisfactory while home based Given the possibility that DGs monocular vision part-time occlusion remained impossible. OS and binocular vision could improve because Sensory fusion improved somewhat after 10 he had a functional amblyopia superimposed VT office visits as shown in Table 3. DG’s visual

39 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 4. Case 3-AB, Salient Exam Findings AGE in months: 11 13 24 Monocular VA 1. Teller Cards 1. unable 1. unable 1. 20/80 OD 20/200 OS 2. Fix/Follow 2. Fail OS 2. Fail OS 2. Not tested 3. Resistance to occlusion 3. Not tested 3. Fail OS 3. Not tested 4. 10 vertical prism 4. Not tested 4. Fail OS 4. Brief alternation, prefers OD Binocular VA 20/200 20/100 20/60 Teller Cards Ocular alignment 1. Kappa/Hirschberg/Krimsky 1. CLET; 50^BO 1. CLET; 30^BO 1. CLET* 40^BO 2. Unilateral cover test 2. CLET 2. CLET 2. CLET* 3. Alternate cover test 3. Unable 3. Unable 3. 40^BO Distance and near *No strabismus at 4-6cm with +3.00 add in place

+5.00 -0.50 180 +5.00DS Cycloplegic Retinoscopy +9.00 -1.00 180 +9.00DS Versions: Full, deviation concomitant in horizontal gazes Ductions: full horizontally. Other Tests Stereopsis (age 24 months with +3.00 add in place): none per Lang and Keystone Visuoscopy (age 24 months): unable to test either eye acuity did not improve after 10 VT office visits nerve disease. While occluded, he suffered prompting termination of vision therapy and much more than reduced acuity. Contrast the conclusion that there was not a functional sensitivity, color vision, and visual field were overlay to the organic vision loss. also compromised.

Case 2. DG, Antimetropia and optic atrophy. Case 3. AB, Infant Hyperopic Discussion Anisometropia and Esotropia DG’s case exemplifies the clinical adage AB presented as a healthy normally devel­ that functional amblyopia is a diagnosis of op­ing 11-month-old girl. Pregnancy, birth and exclusion.45,46 Reduced best corrected visual perinatal history were unremarkable. AB was acuity may be due to disease even if an not crawling. Her caregiver described her as amblyogenic condition (eg anisometropia) is “not that active” during floor time and that present. In DG’s case, it is plausible that the she preferred to be held. The chief complaint disease process OS caused the anisometropia. was constant misalignment of the left eye. The Early onset diseases and conditions that impair inward crossing progression was described visual input are known triggers for axial elongation as worsening and its onset was 10 days prior. myopia as discussed previously.18,20,39,53,54 For Salient exam findings are shown in Table 4. DG, the likely sequence of events was acquired She was diagnosed with a basic concomitant idiopathic optic neuritis OS followed by optic constant left esotropia of approximately 50 atrophy leading to vision loss. The dulling of prism diopters. Unaided binocular visual acuity visual input from OS to cortex dysregulated was reduced for her age per preferential emmetropization in the direction of aberrant looking to grating patterns with the Teller excessive axial elongation. Thus, the reduced Cards test.56 Cycloplegic retinoscopy following vision in one eye caused anisometropia as instillation of 0.5% cyclopentolate and 1.0% opposed to the other way around. Another tropicamide drops revealed marked bilateral comment is that DGs repudiation of occlusion hyperopia and 4.00D of anisometropia (OD of the sound eye can be viewed in light of optic +5.00 -0.50 180, OS +9.00 -1.00 180) as shown

40 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 in Table 4. The full cycloplegic hyperopia the likelihood that an accommodative esodev­ result, sans the cylinder, was prescribed and iation will not respond fully to spectacle AB accepted and wore the glasses without correction”.57 Weakley and Birch postulate that resistance. At follow-up two months later, anisometropia disrupts binocularity such that she presented wearing her glasses and her the debut of accommodative esotropia is more caregivers reported that AB had become more likely to be constant versus intermittent and active since the glasses including vigorous subsequently unresponsive to spectacles.57 In crawling. AB continued to exhibit constant left this chronology, it can be speculated that ABs esotropia with the glasses in place although anisometropia onset early in her life and was the magnitude was less by approximately present long enough, say six months, to impair 20-prism diopters base-out. Amblyopia was binocularity. The anisometropia came first present per lack of strabismus alternation followed by esotropia at age 10.5 months. This and her failure OS on the 10 vertical prism, version of her ametropia course and history is fix-follow and resistance to occlusion tests. A depicted in Table 5, version A. In contention to repeat cycloplegic refraction, this time with this speculation is that it lacks a defined cause two drops of cyclopentolate 1.0% five minutes of the severe anisometropia and assumes the apart, failed to divulge additional hyperopia. esotropia had nothing to do with its etiology. The author and a pediatric ophthalmologist An alternative to the parsimonious ‘version followed her simultaneously for 18 months. A’ explanation for AB’s disappointing clinical Passive treatment during that time included response to spectacles is provided in Table binasal occlusion with the tape narrower on the 5, versions B and C. A key element of this left spectacle lens,31 direct opaque occlusion speculation is that cosmetically invisible left of OD, and a +3.00 add bifocal prescribed esotropia preceded the cosmetically obvious at age 24 months. Through the bifocal add, esotropia by several months and caused a centration range of 4-6cm was observed. anisometropia. The notion that frank esotropia Home based vision therapy procedures were follows the breakdown of a pre-existing assigned that included monocular saccades/ microtropia has been reported.23,55 Moreover, pursuits emphasizing abduction and binocular anisometropia as sequelae of esotropia, viewing and reaching for small targets in the including microtropia, is a known phenomenon centration range. The esotropia increased reported in the literature.11,20-26,58 Note that to 40 prism diopters by age 2 years while at presentation AB had both left esotropia the ametropia remained unchanged. At age and significant hyperopic anisometropia. The 29 months, parents heeded the pediatric cosmetically obvious esotropia was, per case ophthalmologist recommendation to proceed history, present for 10 days and unlikely to with eye muscle surgery. Following that, she cause four diopters of anisometropia in that was lost to follow-up. time frame. The appeal of this speculated ametropia history is that a defined cause Case 3. AB, Infant Hyperopic Anisometropia of the marked anisometropia, unilateral and Esotropia. DISCUSSION esotropia, exists. Version B in Table 5 portrays Despite the fact that AB’s esotropia was of non-strabismic bilateral, high, isometropic putatively short duration and associated with hyperopia that was poised for a bilateral high hyperopia it did not ameliorate with the reduction. At the speculated age three months full hyperopic compensation. Thus, she did onset of cosmetically invisible left esotropia, not have purely accommodative esotropia. OS emmetropization ceased because of the This outcome is consistent with Weakley and esotropia while OD proceeded. Casting doubt Birch’s report that anisometropia “… increases on Version A is the low probability 10 diopters

41 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 5. Case 3 – AB, speculated and known ametropia and strabismus findings. AGE (months) 1 3 6 9 10.5b 11d 13 24 + 9.00 + 8.00 + 6.00 + 5.50 + 5.00 A + 9.00 + 9.00 + 9.00 + 9.00 + 9.00 No Strabismus CLETc + 10.00 + 9.00 + 6.50 + 5.00 + 5.00 + 5.00 B + 10.00 + 9.00a + 9.00 + 9.00 + 9.00 + 9.00

+ 5.00 + 5.00 + 5.00 + 5.00 + 5.00 C + 5.00 + 5.00a + 6.00 + 7.00 + 8.00 CLET CLET CLET CLET No Strabismus Cosmetically invisible CLET ~ 50^e ~ 30^f ~ 40^f Gray=Speculative binocular and refractive status. Black=Known binocular and refractive status Top number: Most hyperopic meridian right eye Bottom number: Most hyperopic meridian left eye A. Anisometropia precedes esotropia B. CLET precedes and causes anisometropia via cessation of hyperopia reduction OS C. CLET precedes and causes anisometropia via hyperopic increase OS a: speculated onset of cosmetically invisible constant left esotropia interfering with emmetropization OS b: known onset of cosmetically visible constant left esotropia per case history c: CLET, constant left esotropia d: first eye exam / age of diagnosis e: uncorrected f: SRx in place. SRx = age 11 mos refractive findings. of bilateral hyperopia at age one month. there was motor impetus for complete Version B presents a more likely neonatal divergence to bi-foveal fixation. AB’s sensory refractive status but adds the doubtful four fusion was not capable of supporting it and diopter increase in hyperopia OS. Perhaps the she activated anomalous fusional convergence veridical course of AB’s ametropia is a blend of leading to persistent esotropia. the two versions. Both versions make the point A more granular look at the specific vision that it is difficult to account for nine diopters of losses in this case could provide support for hyperopia OS at age eleven months. Another Version A, primarily anisometropic amblyopia salient point is that clinical evidence for a pre- with esotropia onset after anisometropia, existing microtropia per a reliable diagnosis of or versions B/C in which the amblyopia is eccentric fixation of the non-fixating eye could predominantly strabismic because the esotropia not be obtained due to the patient’s age. preceded and caused the anisometropia. A Additional support for an early onset clear-cut differential would be a measurement esotropia (age 3 months) versus age 10 months of stereopsis. Reduced stereopsis is tightly is the behavior of the esotropia immediately associated with strabismic amblyopia versus post spectacles and over time. One might anisometropic amblyopia.17,40,44,59 If stereopsis expect a unilateral esotropia of short duration was found to be absent or greatly reduced while and high hyperopia to reduce in magnitude by tested with the angle of deviation compensated more than the 20^ AB enjoined. An esotropia (eg a major amblyscope), the case for versions that had been present for eight months, on the B/C, predominantly strabismic amblyopia due to other hand, may have prompted development eight months of constant unilateral strabismus, of abnormal sensory fusion such as anomalous would be strengthened. Contrast sensitivity also correspondence (AC). Upon wearing the glasses differentiates strabismus from anisometropic and curtailing five diopters of accommodation, amblyopia but in the reverse relationship. If

42 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 AB’s monocular contrast sensitivity left eye was of OS or leads to hyperopic increase, a known reduced in proportion to her monocular visual phenomenon reported in the literature,22 acuity at age eleven months, anisometropic, not resulting in the triumvirate clinical picture strabismic, amblyopia is implicated.60 Another of anisohyperopia, unilateral esotropia, and visual function, Vernier acuity, has the same amblyopia. For further reading on the various pattern. In anisometropic amblyopia, Vernier permutations of anisometropia etiologies and acuity is worse than expected compared to chronology, see Barrett, Bradley, and Candy’s the level of ordinary optotype acuity than in review of three scientifically sound hypotheses strabismus amblyopia.60 regarding the co-occurrence of anisometropia While these visual functions were clinically and amblyopia.20 impossible to measure in this case, measurement The second discussion point is the note­ of them may be useful in older individuals with worthy zero change in the hyperopia and anisometropia. Anisometropic children with anisometropia from age 11 months to age 24 satisfactory stereo, reduced contrast sensitivity, months. This halting of emmetropization fits a and a notable drop-off in Vernier acuity pattern reported by Ingram, Gill, and Lambert in compared to their optotype acuity probably do which highly hyperopic infants with strabismus not have, or never had, strabismus, including failed to emmetropize.23 The unchanging microtropia. This conclusion may aid prognosis anisometropia is consistent with Abrahamsson determination or aid analysis of treatment and Sjostran’s conclusion that anisometropia outcome. Electrophysiological testing is ≥ 3.00D at age 1 years tends to persist.12 another option for differentiating anisometropic Finally, the prescription glasses at age 11 from strabismic amblyopia. Multifocal visually months are implicated as an emmetropization evoked potential (VEP) response latencies are impediment.64 more delayed in anisometropic amblyopia.61 Likewise, VEP based parvocellular deficits Case 4. CR, Hyperopic Anisometropia alongside normal magnocellular pathway and Pseudoesotropia function is consistent with anisometropic CR presented as a healthy but very amblyopia not strabismic.62 apprehensive 13 month old with his parents who There are two final discussion points germane requested a 2nd opinion on their son’s need for to this case. First, an occult pathology could glasses. Pregnancy, birth, and developmental account for the anisometropia20,63 and/or the milestone achievement were all unremarkable. strabismus.20,46,63 In hyperopic anisometropia His first comprehensive eye exam occurred two due to pathology, the organic vision loss OS months prior with another eye care practitioner interferes with emmetropization not in the form when his parents sought an explanation for of increasing myopia due to axial elongation as their son’s apparently crossing eyes. That exam described previously in Cases One and Two. resulted in a diagnosis of pseudoesotropia Rather, it halts emmetropization of a highly and hyperopic anisometropia. Glasses were hyperopic left eye. There is some evidence prescribed but the parents chose not to fill the that the onset age of the pathology and the written prescription (OD +1.25D, OS +4.25DS) type of image degradation it gives rise to will shown in Table 6. The case history at the cause anisohyperopia not anisomyopia.20,39 An author’s first exam of CR included a persistent alternative sequence involving occult path­ concern that CR’s eyes were crossing and doubt ology as the trigger, inculpates organic vision regarding their son’s need for glasses given his loss OS leading to sensory strabismus in seemingly normal day-to-day visual function. the form of constant left esotropia. The left His parents staunchly declined diagnostic esotropia, in turn, prevents emmetropization eye drops per a bad experience at CR’s age

43 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 6. Case 4 – CR, salient exam results ages 11 – 22 months. 13 months 11 months 18 months 22 months 22.25 months (first exam with author) b Pseudoesotropia Dry Retinoscopy Dry Retinoscopy Cycloplegic (< >, fluctuating) retinoscopy Written SRx Dry Retinoscopy – 0.25DS OD: Plano < > -0.75. +1.50 DS + 1.25DS & Final SRx + 3.00DS OS: +3.00 < > +4.00 +5.50 DS + 4.25DS Per very brief views a Plano DS Stereo present New SRx +3.00DS. SRx Plano DS Plano DS +4.00 DS Did not fill SRx +3.00 DS Prescription filled No eye disease, no strabismus. Testing compromised because of apprehension and poor cooperation. a=Lang b=1% atropine ointment instilled by parents night prior to exam

11-month eye exam. Exam number one with the eyeglass prescription shown in Table 6, 18 author (age 13 months, Table 6) confirmed both months column. of the previous diagnoses of pseudoesotropia Four months later at the age 22 months and hyperopic anisometropia. Glasses were exam, case history revealed that CR refused prescribed (OD plano DS, OS +3.00DS) and a to wear the glasses regularly. Non-cycloplegic follow-up was scheduled to gauge the impact static distance retinoscopy and near of the glasses on visual function and attempt to retinoscopy were difficult to interpret because extend the testing. CR’s parents chose not to of significant fluctuation and very poor fixation fill the prescription and sought a third opinion, and cooperation. An encouraging result was which delayed the planned follow-up. At the that CR demonstrated random dot stereo with age 18 months exam, the patient’s parents compensatory lenses in place. While being held had questions as to why three eye doctors in the arms of father, the Lang stereo card,65 had three different spectacle prescriptions. which does not require polarized or red/green (Two of the three spectacle prescriptions glasses, was presented to CR and his behavior contained convex lenses prescribed for OD. did not change while unaided. With SRx lenses in The author prescribed Plano DS for OD which place via a flipper trial lens holder CR exhibited prompted parents to resume care with the a positive reaching response to the truck target author.) They also inquired if patching OD on the Lang stereo card. The trial lens holder would be efficacious and mitigate the need was used because CR became angry and turned for eyeglasses. Indeed, they had attempted away upon trying to place the glasses on his occlusion of OD but CR immediately removed face. Given the variable retinoscopy results, a the patch following every attempt. At this cycloplegic refraction was urged. CR’s parents second exam with the author, like the first, CR expressed disdain for eye drops and predicted exhibited poor cooperation, which included that their son would powerfully resist eye drop incessant crying, head turning and eye closures. instillation and inordinate physical restraint Minimal testing was accomplished other than would be required to complete the instillation. confirming approximately 3.00 diopters of An alternative method of at home instillation of hyperopic anisometropia per non-cycloplegic a mydriatic/cycloplegic ointment was offered. retinoscopy. Mydriatic/cycloplegic eye drops The proposed plan was for his parents to instill were again recommended and subsequently 1% atropine ointment at bedtime the night declined. Communication was successful to the before his scheduled exam to which the parents point that his parents agreed to fill the written acquiesced. The instillation was successful

44 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 7. Case 4 – CR, salient exam results ages 30-45 months Age 30 months 37 months 45 months

SRx: OD Plano DS / OS + 4.00 DS

Almost full time since prior exam. SRx Compliance 2 - 10 hours per week. Parents attempt occlusion of OD. CR refuses. Retinoscopy OD Distance Near (SRx in place) Distancec Near (SRx in place) OS Plano DS + 0.50 + 1.00 DS + 0.50 + 4.00 DS + 0.50 + 5.00 DS + 0.50 Other Tests. Binocular VAa 20/30 Monocular VAb Monocular VAb Stereod All are with Monocular VA: OD 20/25 OD 20/25 252 seconds correction in place refused occlusion OS 20/63 OS 20/32 Worth 4 Dot No suppression a=VA (visual acuity, corrected) with Face Dot Test c=cycloplegic retinoscopy b=Lea symbols, matching method d=random dot E matching method

Table 8. Case 4 – CR, salient exam results ages 5-10 years Age 5 years 6 years 10 years

SRx: OD Plano DS / OS + 4.00 DS

SRx Compliance Full time Part time. As needed for school work. Retinoscopy OD/OS Distance Plano/+4.00DS +1.00DS / +5.00DSa Subj Refraction Near +0.50 / +0.50 OD: Plano DS 20/15 Other Tests. Monocular VAb Monocular VAb OS: +3.75DS 20/20 + 3/6 All are with OD 20/25 OD 20/20 correction in place OS 20/40+2/4 OS 20/20 Vergence ranges, NRA, PRA, accommodative Stereo: Stereo: amplitudes, stereo all at or above expected 40 seconds contour 40 seconds contour 252 seconds random dotc 252 seconds random dotc Worth 4 Dot: Suppress Worth 4 Dot: Suppress OS at 2 meters OS at 2 meters a=cycloplegic retinoscopy b=VA (visual acuity, corrected) with HOTV single line c=random dot E and at the 22.25 months exam, CR presented recognition visual acuity was determined. The with only a sliver ring of iris showing in each results (Table 7) were OD: 20/25 and OS: 20/63 eye because of potent mydriasis. Cycloplegic with Lea symbols. Upon observing CR perform retinoscopy showed zero fluctuation, four worse with left eye, his parents appealed for diopters of anisometropia, and bilateral latent a repeat of the test, including unaided, and hyperopia. The spectacle prescription was amplified the test instructions per a belief that updated to match the full anisometropia as lack of effort caused the reduced visual acuity. shown in Table 6. Repeat testing did not change the outcome. Tables 7 and 8 show the salient exam Their concern elevated and they redoubled findings over time. CR’s parents reported their efforts to instigate and maintain CR’s great difficulty placing and maintaining the utilization of the glasses. As compliance with glasses on CR’s face. As shown in Table 7, he the glasses improved, monocular and binocular wore them sparingly until age three years. It visual function improved to normal by age six. was not until age 37 months that monocular Of note, CR never did occlusion therapy. He

45 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 remained a patient throughout his childhood age 22 months and later exams. Higher levels and teen years. CR converted to as needed part of anisometropia are associated with worse time eyeglass wear at age 10 years continuing stereo and poor treatment outcome.40,41,59,68 to have normal visual function with glasses in Further support for a gentler anisometropia place. Contact lenses, prescribed at age 13 natural course and history is the relatively good years, were never worn regularly per a preference 20/63 monocular BCVA at age 37 months. By to wear spectacles part time and a preference comparison, the PEDIG study found a mean to perform sports unaided. His hyperopia BCVA of 20/80 (0.6 logMAR) in their study decreased bilaterally and symmetrically over population of 84 anisometropes at diagnosis, time leaving the anisometropia magnitude, 62% of whom had smaller anisometropia than four diopters, unchanged during the 17-year CR.66 Granet et. al.’s study population, older span he was followed which is consistent with a than PEDIG’s population, had 88% of the pattern reported in the literature.35 CR followed > 4.00D anisometropes 20/100 or worse.67 another pattern reported by Abrahamsson and Rutstein and Corliss’ study found an average Sjostrand whereby anisometropia that equals or interocular difference of 0.7 logmar with four exceeds three diopters at age one year persists diopters of anisometropia.41 CR’s difference throughout childhood.12 (20/25 compared to 20/63) was 0.4. Table 9 shows two refractive development Case 4. CR, Hyperopic Anisometropia histories that would ostensibly cause less severe and Pseudoesotropia. DISCUSSION amblyopia because anisometropia remained CR attained an outstanding treatment near 1.00D until age nine months. Pathway B outcome despite the fact that he did not wear in Table 9 is noteworthy because it assumes a glasses regularly until age three years for his hyperopic increase during the first 22 months four diopters of hyperopic anisometropia and of life, which has been reported.5,9,10,13,18,21,23 In never performed occlusion or vision therapy. pathway B, the destined to be worse eye not This favorable outcome was found in only 8% only was equal to its fellow early in life it was of amblyopic children age 3 to < 7 years with > relatively close to emmetropia. Time spent 4.00D of anisometropia who were treated with closer to emmetropia may have imparted spectacles only in a well-designed prospective an advantage when treatment commenced. study by the Pediatric Eye Disease Investigator Another presupposition is that pathway A or Group (PEDIG).66 In another study of aniso­ B would be less amblyogenic if CR had good hyperopia none of the children with a 3.25- accommodative function to compensate for his 4.50 difference achieved 20/20 with glasses hyperopia early in life to maximize retinal image only.67 The exceptional treatment outcome clarity. CRs outstanding visual outcome may also with spectacles-only in CRs case (and the 8% be attributed to the brief periods of spectacle in the aforementioned study66) may simply be wear that occurred when CR was younger a function of robust intrinsic neuroplasticity than age 3 years when his neuroplasticity was – an unknown and clinically unmeasurable peaking. Version C in Table 9 is provided to capacity. It may also reflect pure anisometropia compare and contrast a refractive history that due to random biological variation without a would have led to a more severe amblyopia complicating etiology such as microtropia or and binocular dysfunction. pathology. An alternate or additive speculation A final remark is that the prompt for CR to is that CR’s anisometropia onset was relatively seek an exam with an eye care practitioner at late and gradual so that he was isometropic for age 11 months was pseudoesotropia. True to the majority of his first year of life. In support form, his anisometropia was invisible to parents, of this speculation is his good stereo per the pediatrician, and other caregivers. Without

46 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 9. Case 4 – CR, speculated and known refractive levels at certain ages. AGE in Months 1 4 7 9 11a 13b 18b 22c 6 years + 5.50 + 5.50 + 5.50 + 4.25 Planob A + 5.50 + 5.50 + 5.50 + 5.50 + 5.50 + 2.50 + 2.50 + 2.50 + 2.50 + 1.25 Plano – 0.25 + 1.50 B + 2.50 + 3.00 + 3.00 + 3.50 + 4.25 + 3.00 + 3.00 + 5.50 + 2.00 + 2.00 + 2.00 + 1.50 + 1.00c C + 7.00 + 7.00 + 7.00 + 6.50 + 5.00c Grey=Speculated refractive status. Black=Known refractive status Top number: Hyperopia right eye, all are spherical equivalent Bottom number: Hyperopia left eye, all are spherical equivalent a=from written eyeglass prescription – previous eye care practitioner b=non-cyclplegic retinoscopy c=cycloplegic retinoscopy A & B: Speculated hyperopia early in life leading to less severe amblyopia that responds readily to treatment. C: Anisohyperopia early in life leading to more severe, less treatable amblyopia. Unlikely in this case. pseudoesotropia, he may very well have been the normal range for an infant,2 normal visual diagnosed at a later age with a less favorable function, and no ocular disease per testing outcome. that included a dilated fundus exam. The astigmatism present at the age seven months Case 5. PV, Isometropia Converts to exam (2.00D with-the-rule OU) was outside the Anisometropia with Amblyopia normal range of 0-1.50D69 but not considered PV presented at age 5 years following a clinically significant. A routine repeat failed visual acuity test OD at his pediatricians’ comprehensive eye exam was recommended office. His past ocular history included a at age three years, which did not occur. The comprehensive eye exam with the author at age five years comprehensive eye and vision age seven months. That exam, see Table 10, examination was a different story (Table 10). PV revealed isometropia, hyperopia well within had 4.50D hyperopic anisometropia, OD worse,

Table 10. Case 5 – PV, salient exam findings at age 7 months, 5 years, and 20 years Age 7 Months Age 5 Years Age 20 years Cycloplegic Retinoscopy Cycloplegic Retinoscopy Keratometry Subjective refraction + 3.25 - 2.00 180 + 6.00 -1.00 180 43.25 x 42.00 @180 +3.50 -1.00 180 + 3.25 - 2.00 180 + 1.00 DS 43.00 x 42.50 @180 Plano DS Refractive Dataa Near Retinoscopy, unaided Final SRx Near Retinoscopy, Final SRx +0.75 OD/OS, vertical in place meridian (only) +5.00 -1.00 180 + 0.25 DS Plano DS + 0.25 DS Best Corrected VA Accommodative Best Corrected VA Normal per fix/follow, Monocular Distanceb Nearc Amplitude Distance Near resistance to occlusion Vision 20/50 20/80 8 diopters 20/20+ 20/20 and 10 vertical prism tests 20/20 20/25 12 diopters 20/15 20/20 No strabismus, orthophoria Orthophoria Stereo: 500 seconds random dot Normal stereo, Binocular No strabismus Worth 4 Dot: suppress OD at 1.25 meters no suppression Vision Bruckner: normal NPC: 6cm, OD out and suppress Prism bar vergence ranges. BI: X/14/8 BO: X/30/10 a=top number = OD b=6M with HOTV Single line c=40cm with HOTV full chart d=Random Dot E test

47 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 11. Case 5 – PV, selected visual functions at baseline and follow-ups Accommodative Best Corrected VA OD Random Dot Stereo Worth 4 Dot Amplitude OD D: 20/50 Suppress OD at Baseline Age 5 years 8 diopters 500 seconds N: 20/80 1.25 meters Follow-up 4 D: 20/20 252 seconds months later N: 20/32 13 diopters No suppression Follow-up 13 months D: 20/20 125 seconds after baseline N: 20/20 moderate amblyopia OD along with mild degree. This pattern of declining hyperopia in suppression OD. OD also displayed poorer the formerly amblyopic eye in the presence of monocular accommodative amplitude than OS. good motor alignment and sensory fusion has Some encouraging findings with the tentative been reported in the literature.70 spectacle prescription in a trial frame (OD +5.00 -1.00 180, OS Plano DS) were the presence of Case 5. PV, Isometropia Converts random dot stereopsis, good vergence ranges, to Anisometropia with Amblyopia. and good near point of convergence (NPC). DISCUSSION Strabismus and eccentric fixation were absent. Two remarkable findings in this case are Another relevant exam finding was nearly docu­mented hyperopic increase OD and equal keratometry values (see discussion). the outstanding swift response to treatment. Glasses were prescribed for full time wear. Per The two may not be coincidental but rather an internet search, PV’s parents anticipated the cause and effect. If the refractive changes amblyopia diagnosis and were eager to proceed producing anisohyperopia, increase OD / with occlusion therapy. Occlusion therapy of OS decrease OS, were measured causing later with a clip-on occluder was prescribed per a onset of an amblyogenic level of inter-ocular schedule of 15 hours per week minimum. While difference, then the monocular and binocular occluded, PV was instructed to engage in eye- vision impairments are expected to be less hand activities such as coloring books, puzzles, severe.14-17,33 Table 12 portrays speculated building blocks, and snap-together toys. At a gradual longitudinal refractive changes filling follow-up four months later, PV presented with the gap between two known ametropia levels. his parents reporting excellent compliance with The portrayed developmental sequence the treatment plan. He demonstrated much results in weak amblyogenic forces per an age improved monocular and binocular vision 3-year onset of 2.25D anisometropia preceded as shown in Table 11. A tapered occlusion by milder anisometropic levels. Comparing therapy regimen was prescribed along with the least hyperopic meridian OD to OS, the continued full time eyeglasses. His next follow- anisometropia at age 3-years drops to 1.50D. up revealed no regression in visual function Table 12 also posits the astigmatic changes over despite complete cessation of occlusion per the time that led to two diopters of iso-astigmatism parents’ passive decision to forgo the tapering transforming to 1.00D of aniso-astigmatism at plan. PV was followed until age 20 years and age 5-years. Note that at all ages the aniso- retained normal monocular and binocular astigmatism was generally at or less than the vision throughout that period. He became a amblyogenic level of 1.50D.71,72 Note also part time / as needed spectacle wearer at age that the aniso-astigmatism is associated with 10 years without any regression in monocular moderate hyperopia and is due to a difference and binocular vision. OD remained emmetropic in corneal astigmatism between OD and OS while OS shifted to less hyperopia by a minor (Table 10). Both of these clinical findings match

48 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 12. Refractive levels and ocular biometry, known and speculated, first 5 years of life to account for outstanding gains in visual function. For all data, top number is OD. Age 7 months 1 year 2 years 3 years 4 years 5 years Refractive + 3.25 - 2.00 180 +3.75 - 2.00 180 +4.50 - 2.00 180 +4.75 -1.50 180 +5.25 -1.25 180 +6.00 -1.00 180 Status + 3.25 - 2.00 180 +3.00 - 1.00 180 +2.50 - 0.50 180 +1.75DS +1.25DS +1.00 DS ( )a (0.25D) (1.25D) (2.25D) (3.375D) (4.50D) A B A B A B A B A B A = B Axial 20.0 19.5 20.4 19.5 20.6 19.5 20.7 20.0 20.8 20.7 21.0 Length 20.0 20.0 20.5 20.6 21.0 21.0 21.5 21.5 22.0 22.0 22.5 (mm) Crystalline 37 39 35.5 38.5 34 37 32 34 29 30 28 Lens 37 37 35.5 35.5 34 34 32 32 29 29 28 (diopters) Mean 44.00 43.00 42.75 42.62 KM 44.00 43.00 42.75 42.75 a=Anisometropia Bold=known ametropia and keratometry Grey=speculated ametropia and keratometry A=speculated ocular biometry parameters at each age level showing a difference in axial elongation as the sole cause of the age 5 year anisometropia B=speculated ocular biometry parameters in which abnormally high OD crystalline lens convex power early in life stunts axial elongation experimental results reported in the Sydney average74 and OS early in life. Specifically, at Myopia Study.73 age 7-months in Version B crystalline lens OD While the initial refractive levels in Table exceeds OS by two diopters causing it to be 12 and the OS ametropia changes over time relatively less hyperopic than OS per this optical are recognizable, the longitudinal course of element. Axial length OD in this speculation OD, increasing hyperopia, is not. Longitudinal is 0.5mm shorter than OS. Their differences, studies of ametropia early in life, however, do OD crystalline lens higher dioptric power and indeed show a small minority of young children shorter axial length, cancel such that the net experience hyperopic increase.5,9,10,13,18,21,23 In refractive status is typical and isometropia PV’s case, the hyperopic increase OD may be ensues. Subsequently, OD crystalline lens explained by a slower rate of axial elongation dioptric power remains abnormally high for the OD that did not keep pace with the ordinary first two years of life causing OD to compensate loss of convex dioptric power in crystalline lens with slowed axial elongation. At age two years, and cornea. A further speculation is that OD the crystalline lens OD begins to correct its was prone to the hyperopia-causing effects course and catch up with OS with a rapid phase of astigmatism while OS was not.6,9,10 Table 12 of convex power decline. OD axial length, Version A portrays a developmental optical however, cannot accelerate growth to match the sequence in which axial lengths and crystalline rapid ‘catch-up’ convex power loss because OD lenses are equal and typical74 at age 7-months. has aged out of much of its emmetropization Beginning at this age, slower axial elongation responsiveness.9,13 The accelerated rate of OD becomes the sole cause of the hyperopic crystalline lens convex power loss OD continues increase OD over time and ultimately 4.50D of until it finally matches OS at age five years. As anisometropia at age 5-years. it does so, hyperopia OD increases due to an An alternative and intriguing speculation embedded shorter axial length. for retarded axial elongation OD is Version B Infantile unequal crystalline lens dioptric in Table 12. The fulcrum of this speculation is a power with a “late release” of convex power crystalline lens OD dioptric power that exceeds in the eye with more crystalline lens convexity

49 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 13. Case 6 – LF, speculated and actual refractive findings over time Age 0 – 1 month 6 months 9 months Age 3 years

Cycloplegic +5.50 - 2.00 180 +5.50 - 1.50 180 +3.00 - 1.00 180 +1.00 - 0.50 180 Retinoscopy +5.00 - 0.50 180 +2.50 - 0.50 180 +2.00 - 0.50 180 +1.00 - 0.50 180. Resultsa 0.25D 2.50D 0.75D a=top number = OD Grey=speculated Black, actual Anisometropia per spherical equivalent has not been reported in the scientific in accordance with comprehensive studies of literature reviewed for this article rendering this refractive correction as the sole treatment for speculation a bit fanciful. A supporting piece of amblyopia.66 As mentioned, parents were eager evidence can be found in the Cass and Tromans’ to begin maximum treatment and proactively study.58 Among their hyperopic anisometropia requested guidance on occlusion. study subjects, the eye with more hyperopia had a crystalline lens dioptric power 1.80D Case 6. Vanishing Infantile Anisometropia (+/-5.83) greater than the less hyperopic eye.58 LF presented as a 6-month-old healthy, This finding raises the distinct possibility that it normally developing girl for a comprehensive may not simply be an axial length difference at eye exam. Her father had anisomyopia without all ages and stages driving the development of amblyopia and normal binocular vision. He anisometropia. There is another entreaty for the self-described his worse eye as “lazy” and hypothesis that an abnormally high crystalline present “all my life”. He wanted to be sure lens dioptric power early in life retards axial that his daughter did not have his condition. elongation. It mirrors the oft reported animal The examination showed that LF had abnormal studies result showing slowed axial elongation visual function OD per 2 tests; fix/follow and when convex power is artificially and externally resistance to occlusion. Bruckner test was added to the eye including when only one eye also abnormal. Cycloplegic retinoscopy (OD is treated.75 Note that both versions in Table +5.50 -1.50 180, OS +2.50 -0.50 180) revealed 12 result in an ultimate anisohyperopia due 3 diopters of anisometropic hyperopia in the to axial length differences, which is consistent horizontal meridian or, stated another way, with the literature.7,8,36-39,58 2.50D anisohyperopia per spherical equivalent Adding credulity to the unequal crystalline (see Table 13). LF was diagnosed with an lens power hypotheses in Version B is the fact amblyogenic level of anisohyperopia16,71,72 that slight differences in the optical variables and an abnormal level2 of spherical equivalent of the high convex powered infant crystalline hyperopia OD for her age. She also had reduced lens (35D-40D74); thickness, index of refraction, unaided vision OD albeit by gross measures of and radii of posterior/anterior curves, could visual function. easily account for 2-3 diopters error difference Glasses were not prescribed given the (a 6 -8% error) between the eyes. Moreover, distinct possibility that the anisometropia would morphologic properties of the crystalline lens self-correct.5,6,9-13 Toward the goal of prompting early in life are vastly different from its age self-correction, the parents were educated 6-year iteration.74 A similar argument cannot regarding home based visual developmental be made for corneae because they undergo a activities for their daughter. Namely, they were much smaller percentage change from age 7 instructed to occlude OS with their hand and months to 5 years.74 present small colorful toys to capture LF’s A final clinical note is that the gains in visual visual attention. The toy was to be moved in function PV realized may have occurred with all directions; in and out (accommodation) and full time wear of the glasses without occlusion, in the X -Y plane (pursuits). The instructions

50 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 included placing the toy close enough to LF to with human studies linking anisometropia and encourage visually guided motor activities via astigmatism.6,9,10,27 Results of an animal study28 reaching and head/body movement directed support the hypothesis that axial length in LF’s by the abnormally ametropic right eye. Another more astigmatic OD responded to the least instruction in the monocular vision therapy hyperopic meridian and slowed its elongation plan was to place an item of interest such as in comparison to typical and her fellow eye. eye contact or a toy at a far distance and use Another interesting discussion point is LF’s sound or movement to prompt a shift of her hyperopic reduction of 2.25D in a 3-month visual attention to it, and then back to the near period. It seems dramatic at first glance, toy (accommodative facility and saccades). especially for eye care practitioners accustomed Specifically, one parent was instructed to speak to refractive changes in adults. A 2.25D or make a noise to obtain visual attention at far hyperopic reduction may be unremarkable if for a moment then the other parent moved the one takes into account that it can result from near toy to activate a shift in visual attention as small a change in axial elongation as 0.5 to and fixation to nearpoint. These monocular 0.7mm in the small; infant eye.77 is required to activities were to be carried out for brief periods effect the refractive change. For context, axial 25-30x per day. length growth of 2.7mm is typical for the first Three months later at a follow-up exam, 12 months of life.78 1.1mm is typical from age LF showed a beneficial refractive change. OD 3 to 6 months.74 The 0.5 -7mm speculation may hyperopia declined 2.25D while OS reduced be an overstatement if some of the hyperopic 0.25D rendering her hyperopic anisometropia to reduction stems from slowing in the rate of an amblyopia invulnerable level of 0.75D.16,71,72 flattening of crystalline lens or cornea. This trend continued and at her age 3-year The discussion point with high clinical exam, her refractive status was symmetrical and rele­­vance is the influence of the home based normal as shown in Table 13. monocular visual activities in the OD ame­ tropia reduction. Longitudinal studies of infant Case 6. Vanishing Infantile Anisometropia anisometropia clearly demonstrate spon­ DISCUSSION taneous self-correction without monocular LF presented with both anisohyperopia and vision therapy.5,6,9-13 Thus the passage of aniso-astigmatism. The unequal astigmatism time, not monocular vision therapy, may have may provide a clue to the etiology of the minimized the anisometropia. Evidence that the anisohyperopia. It is conceivable that each eye monocular vision therapy played a beneficial was near 5 diopters in one meridian during role can be found in research linking deficits the first month of life as shown in Table LF. in accommodation to poor emmetropization This amount of age 1-month hyperopia is among infants.26,79 The monocular activities within 1 standard deviation of the mean in one facilitated periods of accurate accommodation study76 and within the 95% prediction limits2 OD which would not have occurred without in another, and, it approximates her known occlusion. These arranged conditions may level of hyperopia OD at age 6 months. The have prompted an emmetropization response. standout abnormality, perhaps due to simple Whatever the reason for her normalization, LF’s anatomical variation in the highly convex case touches on the larger question of why neonatal cornea, is the speculated 1.50D aniso- some young children with abnormal ametropia astigmatism OD early in LF’s life.4,69 The higher (one or both eyes) emmetropize and others do astigmatism OD slowed axial elongation OD not. Clinicians diagnosing infants and young and caused the anisohyperopia. This proposed children with abnormal ametropias are eager to cause-effect sequence of events is consistent prescribe treatments that spur emmetropization

51 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 to augment the fatalistic management strategy ganglion cells. The interference, perhaps of watchful waiting for time and nature to take retinal/macula edema or hemorrhage during a favorable turn. birth, plants a pathological seed at the very A final comment in this case is that LF may beginning of life. Assuming permanent not have seen an eye doctor as an infant if her anisometropia onset is not during the first year father did not have non-amblyopic anisomyopia. of life,1- 6,12 the anisometropia-causing seed lays dormant and sprouts later when a flawless CONCLUSIONS & SUMMARY retino-geniculate-cortico pathway is required The etiologies and natural course and history to fine tune emmetropization. of pediatric anisometropia are incompletely In the clinical care of pediatric aniso­ understood. There is a complex mix of metropia, its magnitude and patient age at variables that explain the wide range of clinical first diagnosis are crucial elements in prognosis presentations and response to treatment. This (see Table 14 for a summary). An important article did not explore in-depth the contribution premise of this review are two extant but of genetics,19,80 ocular dominance81 and higher unknowable questions clinicians may ask order aberrations (HOAs)82 to anisometropia upon diagnosing anisometropia for the first etiology but these may have clinical merit. time. First, what was the ametropia in the An unexplored linkage is ocular dominance / months and years preceding first diagnosis, HOAs to anisometropia that arises subsequent including and especially the age at which the to bilateral and equal astigmatism.6,9,10 Perhaps anisometropia became amblyogenic? Second, the eye that ultimately has the higher ametropia was the anisometropia due to innocent random is non-dominant and/or has more pernicious biologic, genetic, or epigenetic variation in the HOAs. One or both of these factors cause optics of the eyes versus an organic root (occult it to succumb to astigmatic blur with poor disease, physical difference such as small nerve emmetropization while its fellow does not. or abnormally high HOAs) or microstrabismus? Bolstering the hypotheses that a difference in In the very least, presumptions can be made HOAs causes anisometropia is the statistically about antecedent ametropia and etiology significant association between pediatric based on depth of amblyopia/sensory fusion unilateral nasolacrimal duct obstruction (NLDO) abnormalities and their subsequent response and higher ametropia in the afflicted eye.83 to treatment as evinced in the case reports The authors speculate that NLDO induced herein. Turning to the literature, in Tomac abnormal tear film degrades the retinal image and Birdal’s case series, one of their subjects and interferes with emmetropization while the (no. 7) had a scant 0.50D anisometropia with unaffected eye moves closer to emmetropia deep amblyopia (6-line difference) and greatly causing anisometropia. reduced stereo (1,980 seconds of arc).88 Another Anatomical and physiologic differences (subject no. 18) had 3.25D anisometropia and such as thickness of retinal nerve fiber layer only one line difference with 240 seconds of (RNFL),84,85 vasculature of optic disc/macula,86 arc stereo. Subject seven experiencing a more and optic nerve size87 may also prove to be severe anisometropia early in life, an earlier insightful regarding pediatric anisometropia onset, or a more impactful anisometropia etiology, its sequelae, and response to etiology may explain this stark difference. treatment. RNFL, thicker in anisometropia but Zaka-ur-Rab’s prospective study of previously not strabismus amblyopia, is a particularly untreated anisometropic amblyopes found intriguing association. It implies an event or a significant correlation between depth of circumstances pre-natal or early in life that amblyopia and degree of anisometropia.37 interfered with normal apoptosis of retinal There were numerous exceptions, however, that

52 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 Table 14. Prognosis determination. Note that Magnitude, Type, and Patient age at first diagnosis are the only charac­ ter­­istics that are known clinically in many cases. Anisometropia Characteristic Prognosis Better Prognosis Worse Simple random biological variation Occult disease, physical Etiology in optical development defect, or microstrabismus Age at which anisometropic causing Older Younger disease or microstrabismus onsets If disease, severity of disease Less severe More severe Patient age when anisometropia magnitude Older Younger reaches amblyogenic magnitude Time elapsed between onset of anisometropia and/or anisometropia causing Short Long condition and initiation of treatment Worse eye begins with lower Worse eye begins high and is Progression ametropia and gradually worsens unchanging or worsening Magnitude Low High Type Myopic Hyperopic Patient age at first diagnosis Younger Older give clinicians pause. For example, hyperopic study subject 39 had 0.86D difference in REFERENCES refraction and a visual acuity difference of 1. Atkinson J, Braddick O, Nardini M, Anker S. Infant 0.48 log MAR units. 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55 Vision Development & Rehabilitation Volume 6, Issue 1 • March 2020 84. Yen MY, Cheng CY, Wang AG. Retinal nerve fiber layer thickness in unilateral amblyopia. Invest Ophthalmol Vis AUTHOR BIOGRAPHY: Sci 2004: 45: 2224-2230. John D. Tassinari, OD, FCOVD Street Pomona, California 85. Yoon SW, Park WH, Baek SH, Kong SM. Thickness of macular retinal layer and peripapillary retinal nerve fiber Dr. Tassinari is a 1987 SCCO graduate layer in patients with hyperopic anisometropic amblyopia. and residency trained in VT and pediat- Korean J Ophthalmol 2005: 19: 62-67. rics at SUNY Optometry in 1987-88. Dr. 86. Sobral I, Rodrigues TM, Soares M, et. al. OCT angiography Tassinari ran a private optometry practice findings in children with amblyopia. J AAPOS 2018: 22: in Pasadena CA from 1988 to 2015. His 286-289. practice specialized in VT and pediatric optometry. During that same period, Dr. Tassinari served as 87. Lempert P. The axial length/disc area ratio in anisometropic a part time faculty member for SCCO. In 2016, Dr. Tassinari amblyopia. A hypothesis for decreased unilateral vision joined the Western University of Health Sciences College of associated with hyperopic anisometropia. Ophthalmology Optometry full time and serves as the chief of pediatrics in 2004: 111: 304-308. the Eye Care Institute. 88. Tomac S, Birdal E. Effects of Anisometropia on Binocularity. J Ped Ophthalmol Strab 2001: 38: 27-33. 89. De Vries J. Anisometropia in children: analysis of a hospital population. Br J Ophthalmol 1985: 69: 504-507.

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