The Detrimental Effect of Noisy Visual Input on the Visual Development of Human Infants.

We followed visual development in a rare yet large sample of patients with congenital bilateral cataract for 4 years. We divided the patients into two groups: a complete deprivation group with no response to a flashlight pointing to either of their eyes and otherwise an incomplete deprivation group. All the patients received cataract surgery at age of 3 months. From 27 months onward, the complete deprivation group showed better developmental outcomes in acuity and eyeball growth than the incomplete deprivation group. Such a seemingly counterintuitive finding is consistent with research on visually deprived animals. Plasticity is better preserved in animals receiving a short period of complete visual deprivation from birth than in animals who saw diffuse light. The current finding that plasticity in visual development is better preserved in human infants with complete visual deprivation than in those who can see diffuse light but not patterned visual input has important clinical implications.

Introduction

Patterned visual input early in life has been crucial for the development of a wide range of visual functions (Maurer et al., 1999, Kalia et al., 2014). Human infants who experience transient early visual deprivation as a result of congenital cataracts have permanent deficits in visual acuity, perception of high spatial frequency information, global motion, and face perception and have abnormal patterns in multisensory integration (Chen et al., 2017; de Heering and Maurer, 2014, Gandhi et al., 2017, de Heering et al., 2016, Collignon et al., 2015). The visual system retains considerable plasticity despite the visual deprivation, as improvements in many basic visual functions are seen after restoring normal visual input. There is a substantial individual difference in the developmental outcome of early visually deprived patients (Kalia et al., 2014). What determines a patient to have a better or worse developmental outcome after receiving normal visual input is a very important question; one that not only speaks to developmental plasticity in the visual system, but also has practical implications for recovery of visual functions in early visually deprived patients.

Results

To answer this question, we longitudinally followed the visual development of a large sample of patients with congenital cataract for 4 years (N = 28, details in Transparent Methods). All these patients were born with bilateral dense central cataracts, which blocked all patterned visual inputs. Importantly, although such patients cannot see any patterned visual input, they may still sense diffused light through their cataractous lenses. Therefore, right before the cataract surgery, we assessed their responsiveness to light using a standard light chasing procedure based on the 11th Revision of the International Classification of Diseases (ICD-11) (WHO, 2010). Based on their responsiveness to light, we divided the patients into two groups: those who failed to show any response in the light chasing procedure (complete deprivation group, N = 11) and those who did show some signs of light chasing (incomplete deprivation group, N = 17) (detailed records are tabulated in Table S1).

All the patients had their cataracts surgically removed at the age of 3 months. After surgery, the infants received spectacle lenses so visual input could be focused on their retina. As previous studies have shown that the length of visual deprivation is correlated with the final visual acuity (Bonaparte et al., 2016, Birch et al., 2009), having all the infants operated at the same age allowed us to compare the subsequent recovery process among patients. After visual input was restored, we tracked the development of their vision at the ages of 9, 15, 27, and 48 months (i.e., 6, 12, 24, and 45 months post surgery, respectively). For each visit, we measured their visual acuity with the Teller acuity card and the refractive status of their eyeballs (details in Transparent Methods).

As shown in Figure 1, variability in visual acuity increased among the patients as a function of age. Interestingly, some infants developed consistently better over time than the others. Did cataract density predict recovery? Surprisingly, the better recoverers were from the complete deprivation group, who even failed to show any response to light before the cataract surgery. More specifically, as shown in Figure 2A, the two groups of infants did not differ in their visual acuity at the age of 9 months (1.32 ± 0.76 versus 1.60 ± 1.02 cy/d, p = 0.436) or at the age of 15 months (3.87 ± 2.88 versus 3.03 ± 2.38 cy/d, p = 0.449). However, a significant difference emerged at the age of 27 months (7.55 ± 1.97 versus 4.40 ± 2.10 cy/d, p = 0.0008). Such a difference even increased at the age of 48 months (13.47 ± 2.90 versus 7.71 ± 3.10 cy/d, p = 8.27 × 10−5). Therefore, from the age of 27 months onward, the infants from the complete deprivation group had substantially better recovery in visual acuity than the infants from the incomplete deprivation group. The lack of difference at the age of 9 and 15 months between the two groups could have been due to a floor effects, given that the range of visual acuity is relatively narrow.

Figure 1

Development of Visual Acuity in Patients with Congenital Cataract after Restoring Visual Input

We longitudinally followed 28 patients with congenital cataract for 4 years. All these patients were born with bilateral dense central cataracts, and they received cataract surgery at 3 months of age. After surgery, we tracked the development of their vision at the ages of 9, 15, 27, and 48 months. Normal acuity values were presented as a reference (black line). The mean values for complete (yellow triangle) and incomplete (green triangle) deprivation subgroups were presented. We saw two interesting patterns. First, with age, we saw increasing variability in visual acuity among the patients. Second, when we classified these patients based on their responsiveness to light, the complete deprivation group (red and yellow curves) showed a faster improvement of visual acuity than the incomplete deprivation group (green and blue curves). Notes: cy/d = cycle/degree.

Figure 2

Comparison of Visual Acuity and Eyeball Growth between the Complete and Incomplete Deprivation Groups

(A) Based on the responsiveness to light, we classified the infants into complete deprivation or incomplete deprivation subgroups. The VA development of the complete group (n = 11, yellow bars) is significantly better than that of the incomplete group (n = 17, green bars) at the age of 27 (7.55 ± 1.97 versus 4.40 ± 2.10 cy/d, p = 0.0008) and 48 months (13.47 ± 2.90 versus 7.71 ± 3.10 cy/d, p = 8.27 × 10−5) but not at the age of 9 (1.58 ± 1.14 versus 1.41 ± 0.71 cy/d, p = 0.663) and 15 months (3.87 ± 2.88 versus 3.03 ± 2.38 cy/d, p = 0.449).

(B) The structural overgrowth magnitude (SOM) has been identified as an adverse outcome (myopic shift) with poor prognosis. The SOM of the complete group (blue bars) is significantly less than that of the incomplete subgroup (purple bars) at ages 15 (5.86 ± 1.24 versus 7.65 ± 1.92 diopters (D), p = 0.008), 27 (7.57 ± 1.59 versus 11.35 ± 2.58 D, p = 8.81 × 10−5), and 48 months (11.55 ± 1.75 versus 14.96 ± 1.75 D, p = 8.84 × 10−5) but not at age 9 months (4.66 ± 2.69 versus 5.24 ± 2.08 D, p = 0.571). VA, visual acuity; cy/d, cycle/degree; D, diopters. All comparisons were analyzed by using the independent sample t test.

Eyeball growth (refractive status) followed a similar pattern as for visual acuity. It has been shown that axial elongation occurs when the eye is deprived of patterned visual input in human infants as a result of eyelid closure (Hoyt et al., 1981, Liu et al., 2016, O'Leary and Millodot, 1979) as well as in animal models with visual deprivation (Wilson and Sherman, 1977, Yinon et al., 1980, Wiesel and Raviola, 1977). We identified eyeball overgrowth (also named myopic shift) as an adverse outcome with poor prognosis. As shown in Figure 2B, the complete deprivation group exhibited less overgrowth than the incomplete deprivation group at the age of 15 months (5.86 ± 1.24 versus 7.65 ± 1.92 diopters [D], p = 0.008), with no difference between two groups at the age of 9 months, 4.66 ± 2.69 versus 5.24 ± 2.08 D, p = 0.571. This difference became more pronounced with age at 27 (7.57 ± 1.59 versus 11.35 ± 2.58 D, p = 8.81 × 10−5) and 48 months (11.55 ± 1.75 versus 14.96 ± 1.75 D, p = 8.84 × 10−5).

In the current patient sample, there were six cases of nystagmus (Table S1). Five of them were from the complete deprivation group. A chi-square test or Fisher's exact test suggested a link between the occurrence of nystagmus and completeness of deprivation (χ2 = 6.212, p = 0.013, Table S2). There were also six cases of strabismus. Four of them were from the complete deprivation group, but the chi-square test did not reach significance (χ2 = 3.187, p = 0.074, Table S2). Given the small sample size and low number of occurrences of nystagmus and strabismus, we are not making any strong claim on relation between completeness of deprivation and manifestation of nystagmus and strabismus. Instead, we report the recovery results of these individuals having nystagmus and strabismus, in comparison with the others without these manifestations in Table S3.

Taken together, these results suggest a counterintuitive but consistent pattern in both functional and structural development in infants who experienced 3 months of early visual deprivation: those who were completely deprived of any visual input in the first 3 months of life had better outcomes up to 4 years after normal visual input was restored than those who received diffused light input.

Discussion

Our findings are consistent with research on visual development in animals reared in darkness or having their eyelids sutured. Kittens reared in complete darkness for up to 4 months of age achieved normal acuity after 4 months of exposure to normal visual input (Timney et al., 1978), whereas this was not the case for kittens subjected to bilateral lid suture (Mitchell, 1988). Physiological data showed that, after prolonged dark rearing, most cells in cat visual cortex were still binocularly activated and had non-specific receptive field properties, leaving the cortex in a state that can be modified by subsequent visual experience. On the other hand, prolonged binocular suture resulted in a high proportion of unresponsive cells, as well as cells with unmappable receptive fields, and a low proportion of binocularly responsive cells (Mower et al., 1981). In addition, the cats (Cynader and Mitchell, 1980; Cynader, 1983;) and rats (Fagiolini et al., 1994; Guire et al., 1999) that received monocular deprivation with dark rearing were found to present prolonged sensitivity. As Jampolsky suggested, dark-rearing may leave a “clean slate” for the development of the visual cortex (Jampolsky, 1994).

The finding that complete deprivation but not diffused input may preserve plasticity for the subsequent development of visual acuity and eyeball growth has important clinical implications. For patients with congenital bilateral cataract, bilateral patching might prevent diffused light input, thereby preserving plasticity for subsequent development after normal visual input is restored. One the other hand, it is important to consider the interactions between visual development and the development of other senses. Recent studies have found abnormalities in cross-modal perception (Chen et al., 2017; de Heering et al., 2016, Collignon et al., 2015) in adults who were visually deprived early in life as a result of congenital bilateral cataracts. Such abnormality in cross-modal perception raises the possibility that the unstimulated visual cortex can be recruited by other sensory modalities. It would be important for future studies to investigate whether cross-modal recruitment is dependent on the nature of deprivation, namely, complete deprivation versus incomplete deprivation with diffused light input. Moreover, the extent of bilateral deprivation is reported to affect strabismus and nystagmus after surgery (Birch et al., 2009). It would be interesting to investigate the recovery of these eye manifestations with sufficient sample size in the future.

In summary, the current findings suggest that, in addition to missing patterned visual input, receiving diffused light can also have a detrimental effect on the subsequent development of vision. Preventing such diffused input (i.e., by ensuring complete deprivation) for a short period early in life may lead to a better outcome in visual development.

Limitations of the Study

Owing to the current samples, we were currently unable to have sufficient statistical power to overcome the potential floor effects in the time point of 9 and 15 months. Also, the relation between completeness of deprivation and manifestation of nystagmus and strabismus remains unclear because of the limited samples with nystagmus and strabismus.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.