Observations on the relationship between anisometropia, amblyopia and strabismus

Abstract

We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the co-existence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.

Keywords: Amblyopia; Anisometropia; Emmetropization; Eye growth; Hyperopia; Myopia; Refractive error; Strabismus.

Figure 1

Interocular differences in refractive error (treated eye – fellow eye) for individual macaques reared with negative-powered, soft, extended-wear contact lenses on their treated eyes. The data were obtained at the end of the lens-rearing period for the animals in the Crewther et al. (1988), Hung & Smith (1996) and Smith et al. (1994) studies. The data from the Kiorpes’ lab (Kiorpes & Wallman, 1995, Kozma & Kiorpes, 2003) were obtained well after the end of the rearing period and a long period of unrestricted vision. The fellow control eyes of the animals from Hung & Smith III (1996), Kiorpes & Wallman (1995), Kozuma & Kiorpes (2003), and one −6 D animal from Crewther et al. (1988) were fitted with plano zero-powered lenses. The fellow control eyes of all the remaining monkeys from Crewther et al. (1988) and 6 of the 8 monkeys from Smith et al. (1994) were untreated.

Figure 2

Effects of zero-powered, soft, extended-wear contact lenses on refractive development. (A) Longitudinal refractive errors for the fellow “control” eyes of individual rhesus monkeys that were fitted with zero-powered contact lenses (Hung & Smith III, 1996). The treated eyes of these monkeys were fitted with either +3 or −3 D contact lenses. Mean (±SEM) interocular differences (treated eye – fellow eye) in refractive error (B) and corneal power (C) plotted as a function of age for marmosets reared with zero-powered lenses on the treated eyes (Whatham & Judge, 2001b). The fellow control eyes were untreated. In all plots, the filled and open symbols represent data obtained during and after the lens-rearing period, respectively.

Figure 3

Grating acuity versus anisometropia in lens-reared macaques. (A) Interocular grating acuity ratios (treated eye/fellow eye) plotted as a function of the degree of optically imposed anisometropia (treated eye – fellow eye) during the treatment period for individual animals. The black and white symbols represent monkeys reared with spectacle and extended-wear contact lenses, respectively. The grey symbols represent normal monkeys reared with unrestricted vision. (B) Interocular grating acuity ratios plotted as a function of the degree of anisometropia that existed at the time that the behavioral data were obtained for individual monkeys. These animals were reared with either −3, −6, or −9 D spectacle lenses in front of their treated eyes and plano lenses in front of their fellow control eyes. In panel A, the data represented by the open circles were from the Kiorpes’ lab at New York University (NYU) (Kiorpes & Wallman, 1995, Kozma & Kiorpes, 2003). The other data were from Smith III et al. (1997b, 1985b, 1999) and Tao et al. (2014) at the University of Houston (UH) or were previously unpublished.

Figure 4

Interocular differences in refractive error (treated eye – fellow eye) obtained at the end of the treatment period for individual macaques reared with monocular form deprivation produced by eyelid closure (A), diffuser spectacle lenses (B), and (C) black opaque contact lenses or diffuser contact lenses. The published data in panel A were unpublished (dark red) or obtained from Harwerth et al. (red, 1983), Smith et al. (green, 1987), Wiesel and Raviola (cyan, 1977), Raviola and Wiesel (dark green, 1990), Tigges et al. (grey, 1990), and von Noorden and Crawford (dark cyan, 1978). In panel B, the data were obtained from Smith and Hung (2000) and Smith et al. (2012). In panel C, the data were obtained from Iuvone et al. (1991), Tigges et al. (1999), and Bradley et al. (1996).

Figure 5

Interocular differences in refractive error (treated eye – fellow eye) for monocularly formed-deprived marmosets. (A) Mean (±SD) anisometropia obtained at the end of the treatment period for marmosets reared with monocular eyelid closure. Data are shown for 4 different treatment groups; the average onset age and duration of treatment for each group are shown in the symbol legend (from Troilo and Judge (1993)). The green bars represent the mean anisometropias after compensating for the average treatment-induced flattening of the anterior corneal surface. To make this adjustment, we assumed that the fellow control eyes had anterior corneal radii equivalent to normal, age-matched marmosets and used the growth-curve equation for age-related corneal changes in Troilo and Judge (1993) to calculate the corneal power of the fellow control eyes using an assumed refractive index of 1.333. Using the interocular differences in corneal curvature reported by Troilo and Judge (1993), we then calculated the refracting power of the treated eye cornea and adjusted the measured anisometropia by the interocular differences in anterior corneal power. (B) End-of-treatment anisometropias for individual marmosets reared with diffuser spectacle lenses over their treated eyes; their fellow control eyes were untreated. The data are from Group 1 in Troilo and Nickla (1999).

Figure 6

Interocular differences in refractive error (treated eye – fellow eye) obtained from individual monkeys that had undergone monocular foveal ablation and subsequently allowed unrestricted vision (red boxes) and normal control monkeys (green boxes, n = 34). The laser ablations were performed at 3 weeks of age and the data were collected at biweekly or monthly intervals over the next 1–2 years. The horizontal lines in the box plots represent the medians, the bottoms and tops of the boxes represent the 25th and 75th percentiles, respectively. The whiskers that extend vertically from the tops and bottoms of the boxes represent the 90th and 10th percentiles, respectively. The diamond symbols represent outliers. The majority of data were taken from Smith et al. (2007); some results were previously unpublished.

Figure 7

Recovery from experimentally induced ametropias in amblyopic macaques. Interocular differences in refractive error (treated eye – fellow eye) plotted as a function of age for individual monkeys reared with monocular diffuser spectacles (A, from Qiao-Grider et al. (2004) and unpublished), monocular negative-powered, extended-wear contact lenses (B, from Smith et al. (1994)), and monocular powered spectacle lenses (C, from Smith and Hung (1999) and unpublished). All of these monkeys had behaviorally confirmed amblyopia in their treated eyes. The mean (SD), median and range of interocular grating acuity ratios are 0.24 ± 0.22, 0.15, and 0.04 to 0.66 for the animals in panel A; 0.50 ± 0.24, 0.49, and 0.23 to 0.80 for the animals in panel B; and 0.58 ± 0.23, 0.66, and 0.17 to 0.89 for the animals in panel C. In panel D (from Smith et al. (2005) and unpublished), refractive error is plotted as a function of age for individual animals that were reared with binocular peripheral form deprivation produced by diffuser spectacles. At the end of the period of form deprivation, the fovea of the represented eye was ablated with a thermal laser and the animals were allowed unrestricted vision. The green box plot to the right in panel D represents the ametropias over an equivalent period of time for age-matched normal monkeys. In all plots, the first symbol of each individual function represents the onset of unrestricted vision and the recovery period.

Figure 8

Frequency distributions of refractive errors from the right eyes of normal control monkeys (A, from Qiao-Grider et al. (2007) and previously unpublished), the fellow and deviating eyes of monkeys with surgically or neurotoxin induced esotropia (B and C, respectively, from Kiropes and Wallman (1995), Kozma and Kiorpes (2003), Harwerth et al. (1997) and previously unpublished), and the right and left eyes of monkeys reared with optically induced strabismus (D and E, respectively, from Smith et al. (1997b) Watanabe et al. (2005), and Wensveen et al. (2001, 2011)). Only data from macaques are shown. Only the refractive errors that were obtained at the oldest ages for each subject were included. The prism-rearing procedures for the monkeys in panels D and E were initiated at 3–4 weeks of age. For the esotropic monkeys in panels B and C, the strabismus was induced before 4 months of age.

Figure 9

Interocular differences in refractive error (deviating eye – fixating eye) for individual monkeys reared with experimentally induced strabismus. The left panel (A) includes macaques with naturally occurring esotropia (Kiorpes & Boothe, 1981, Wong, Burkhalter & Tychsen, 2005) and those with esotropia induced by extraocular muscle surgeries (Harwerth et al., 1997, Kiorpes & Wallman, 1995, Kozma & Kiorpes, 2003) and previously unpublished) or by botulinum injections (Kiorpes & Wallman, 1995). The experimental esotropias were induced or observed before 4 months of age. The right panel (B) includes macaques (Smith III et al., 1997b, Watanabe, Bi, Zhang, Sakai, Mori, Harwerth, Smith III & Chino, 2005, Wensveen, Harwerth & Smith III, 2001, Wensveen, Smith III, Hung & Harwerth, 2011) and marmosets (Whatham & Judge, 2007) reared with optically imposed strabismus. The onset of prism rearing was 3–4 weeks of age for both macaques and marmosets. In both plots, only the refractive errors that were obtained at the oldest ages for each subject were included. The dotted lines in both graphs represent the ±2 standard deviations from the mean anisometropia in normal monkeys.

Figure 10

Refractive development in normal macaques (left) and macaques reared with surgically (Harwerth et al., 1997, Kiorpes & Wallman, 1995, Kozma & Kiorpes, 2003, and previously unpublished) and neurotoxin induced esotropia (Kiorpes & Wallman, 1995) (right). In the top plots (A and B), refractive error is plotted as a function of age for the right or deviating eyes of individual monkeys. The bottom plots (C and D) show the interocular differences in refractive error (right or deviating eye – left or fellow eye) plotted as a function of age.

Figure 11

Nature of ametropias in macaques with surgically and optically induced esotropia. In panels A and B, interocular differences in refractive error (treated or right eye – fellow or left eye) are plotted as function of interocular differences in vitreous chamber depth (treated or right eye – fellow or left eye) for monkeys with experimentally induced esotropia and optically imposed strabismus, respectively. In panel C interocular differences in vitreous chamber depth are shown as a function of interocular differences in corneal power for monkeys with experimentally induced esotropia (deviating eye – fellow eye). The small solid symbols in each plot represent normal control monkeys. The control data were not included in the regression calculations.

Figure 12

(A) Interocular ratio of grating acuities (deviating eye/fellow eye) plotted as a function of the deviating eye’s ametropia and (B) interocular difference in refractive error (deviating eye – fellow eye) for individual monkeys with esotropia. See the legend for Figure 9 for the sources of the data.