Alterations to the structure and function of the retina and choroid in an experimental model of progressive myopia

Abstract

Myopia is one of the most common ocular disorders. Its onset and progression are characterized by vitreous chamber elongation that puts mechanical strain on the retina and choroid, potentially compromising the integrity and functioning of its cells and presents an increased risk of developing posterior segment complications. The exact relationship with myopic growth remains unclear since most studies describe correlational rather than causal relationships. This thesis presents a comprehensive evaluation of the gross anatomical, cellular and functional changes in a non-human primate model with 6 months of myopia development to understand the effect of myopic growth on the retina and choroid and detect early biomarkers of myopic growth and susceptibility to ocular complications. The thickness of each individual retinal layer, choroidal biometry, ganglion cell (RGC) and astrocyte densities, function, and interrelationship between all measures were assessed using spectral-domain optical coherence tomography, immunohistochemistry and electroretinogram in marmosets. Aim 1 investigated the cause-effect relationship between myopic growth and individual retinal thickness changes measured using SD-OCT. While untreated controls had an overall age-related retinal thickening, the myopic animals had relative thinning of the GCL, IPL, INL, OPL, ONL and relative RPE thickening. Retinal changes in these layers within the near-mid retinal periphery predicted the compensatory refraction and vitreous elongation observed. Aim 2 employed IHC to explore the effect of myopia on the spatial distribution of RGC and astrocytes, as well as glial reactivity, in the ganglion cell complex. The analysis revealed reduced RGC and astrocyte cell densities in the peripapillary retina as well as an increase in global GFAP coverage and GFAP intensity in myopic eyes compared to controls. These cellular changes were associated with the degree of myopic growth. Aim 3 studied inner retina function using the full-field ERG PhNR, and input from bipolar cells (b- and d-wave) in myopic marmosets. Less than 2 weeks into treatment, when treated marmosets had not developed significant changes in eye size or refraction, the b-, d- and PhNR wave amplitudes had decreased compared to controls. These amplitude reductions disappeared as treated marmosets grew older and developed myopia. In controls, the PhNR was dependent on bipolar cell input. However, this relationship was absent in myopic marmosets. Aim 4 using SD-OCT assessed the effect of myopic growth on choroidal morphology: thickness, area, luminal area, stromal area, vascularity index and luminal/stromal area ratio. All measures were significantly lower in treated marmosets compared to controls and decreased with increasing degree of myopic growth. Aim 5 evaluated the interrelationship between the gross anatomical, cellular and functional effects of myopia on the retina and choroid described in the previous aims. The ppRNFL was thinner in myopic eyes and changed as a function of eye growth. The inner retinal anatomical changes did not affect inner retinal function. Choroidal parameters were significantly associated with the a- and d-wave amplitudes. In summary, this thesis provides evidence of the effect of myopia development and progression on the inner retina and choroid of marmosets. All these changes were associated with myopic elongation. The early attenuation of retinal responses might reflect retinal signal processing mechanisms in response to hyperopic defocus. The choroidal changes confirmed in myopic marmosets were associated with reduced photoreceptor function, which reflects compromised metabolic support to the outer retina. This thesis confirms the effect of myopic growth on the retinal and choroidal structure and describe early biomarkers of altered anatomical changes that will help understand the reduced visual performance of myopic eyes and increased risk of developing secondary myopic complications.