Investigation of the normal and pathological development of the macula of the infant human eye using high resolution Optical Coherence Tomography (OCT)

The fovea is a specialised retinal area responsible for high spatial vision. Development of the fovea involves centrifugal migration of inner retinal layers (IRLs) away from the fovea and centripetal displacement of the cone photoreceptors into the fovea and is thought to be complete by 5 years of age. Current understanding of human foveal development is limited to studies of few histological specimens. The recent development of hand-held spectral domain optical coherence tomography (HHSDOCT), can overcome this limitation by facilitating large scale in vivo imaging of the infant human retina, both in controls and in conditions such as achromatopsia and albinism, where foveal development is disrupted. In this thesis, we optimise image acquisition and analysis with HH-SDOCT in young children with nystagmus. We show that HH-SDOCT is reliable in children with and without nystagmus, with an intraclass correlation coefficient of 0.96 for central macular thickness measurements. The non-linear developmental trajectories of each retinal layer modelled in a large cohort of 256 controls suggest that development continues until 12 years of age. A paradigm for the etiological diagnosis of nystagmus using OCT is presented. We describe multiple abnormalities of retinal development in young children with achromatopsia and albinism, including delayed regression of the IRLs from the fovea, diminished elongation of the photoreceptor layers with age and a reduction in perifoveal retinal thickness. This results in significantly increased IRL and decreased photoreceptor thicknesses at the fovea in both conditions (p < 0.05). In contrast, the IRL thickness is significantly decreased at the perifovea in both achromatopsia and albinism (p < 0.01). There is evidence of postnatal development in the achromat and albino retina. In achromatopsia, disruption of photoreceptors is progressive with age. With gene therapy imminent, potentially earlier treatment of these conditions may normalise retinal development and optimise vision

Pediatric Optical Coherence Tomography in Clinical Practice-Recent Progress

PURPOSE: Optical coherence tomography (OCT) has revolutionized the diagnosis and management of adult retinal and optic nerve disease. Children were deprived of this technology until the recent development of handheld spectral-domain OCT (HH-SDOCT). In this article, we review the applications of OCT imaging in pediatric ophthalmology. METHODS: This study was a review of the literature. RESULTS: The acquisition and interpretation of pediatric tomograms differ significantly from those for adults, with adjustments needed to account for the shorter axial lengths, higher refractive errors, and ongoing retinal and optic nerve development in the pediatric eye. Handheld SDOCT is increasingly being used as an adjunctive diagnostic tool in retinopathy of prematurity (ROP) and nonaccidental injury (NAI) by providing additional morphologic information that is not normally clinically discernible. The role of HH-SDOCT in streamlining diagnosis in infantile nystagmus syndrome, retinal dystrophies, and degenerations has been established. Optical coherence tomography can also help differentiate between pediatric intraocular tumors, for example, hamartomas and retinoblastoma; monitor tumor progression; and monitor treatment response. In addition, HH-SDOCT is establishing its role as a noninvasive monitoring tool in children affected by optic nerve pathology such as glaucoma, optic nerve atrophy and hypoplasia, optic pathway glioma, and pseudotumor cerebri. CONCLUSIONS: Handheld SDOCT can provide novel insights into the natural history of retinal and optic nerve diseases in young children. For example, in achromatopsia and albinism, in vivo OCT studies have provided evidence of altered but ongoing retinal development in early childhood, which suggests that potentially targeting treatment at an earlier age may optimize visual function by normalizing retinal development

Handheld Optical Coherence Tomography in a Young Infant With Albinism and Fovea Plana.

We present handheld optical coherence tomography (OCT) diagnosis of Grade 4 foveal hypoplasia (fovea plana) in a 28-day-old infant with albinism. Grade 4 foveal hypoplasia is characterized by the absence of the foveal pit, absence of outer segment lengthening, and absence of outer nuclear layer widening. Binocular visual acuity at 58 months follow-up was 1.2 logarithm of the minimal angle of resolution (logMAR). We describe our handheld OCT acquisition protocol and compare the morphological features with a healthy, age-matched control subject

Characterisation of Abnormal Optic Nerve Head Morphology in Albinism Using Optical Coherence Tomography

Purpose: To characterise abnormalities in three-dimensional optic nerve head (ONH) morphology in people with albinism (PWA) using spectral domain optical coherence tomography (SD-OCT) and to determine whether ONH abnormalities relate to other retinal and clinical abnormalities. Methods: SD-OCT was used to obtain 3-dimensional images from 56 PWA and 60 age- and gender-matched control subjects. B-scans were corrected for nystagmus associated motion artefacts. Disc, cup and rim ONH dimensions and peripapillary retinal nerve fibre layer (ppRNFL) thickness were calculated using Copernicus and ImageJ software. Results: Median disc areas were similar in PWA (median=1.65mm2) and controls (1.71mm2, p=0.128) although discs were significantly elongated horizontally in PWA (p<0.001). In contrast, median optic cup area in PWA (0.088mm2) was 23.7% of that in controls (0.373mm2, p<0.001) with 39.4% of eyes in PWA not demonstrating a measurable optic cup. This led to significantly smaller cup: disc ratios in PWA (p<0.001). Median rim volume in PWA (0.273mm3) was 136.6% of that in controls (0.200mm3). ppRNFL was significantly thinner in PWA compared to controls (p<0.001), especially in the temporal quadrant. In PWA ppRNFL thickness was correlated to ganglion cell thickness at the central fovea (p=0.007). Several ONH abnormalities such as cup/disc ratio were related to higher refractive errors in PWA. Conclusions: In PWA ocular maldevelopment is not just limited to the retina but also involves the ONH. Reduced ppRNFL thickness is consistent with previous reports of reduced ganglion cell numbers in PWA. The thicker rim volumes may be a result of incomplete maturation of the ONH

Retinal and optic nerve changes in microcephaly: An optical coherence tomography study.

OBJECTIVE: To investigate the morphology of the retina and optic nerve (ON) in microcephaly. METHODS: This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. RESULTS: Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients with microcephaly compared to controls, nasally (307 ± 44 vs 342 ± 19 μm, p = 0.001) and temporally (279 ± 56 vs 325 ± 16 μm, p < 0.001). There was thinning of the ganglion cell layer and the inner segments of the photoreceptors in microcephaly. Total peripapillary retinal thickness was smaller in patients with microcephaly compared to controls for both temporal (275 vs 318 μm, p < 0.001) and nasal sides (239 vs 268 μm, p = 0.013). CONCLUSIONS: Retinal and ON anomalies in microcephaly likely reflect retinal cell reduction and lamination alteration due to impaired neurogenic mitosis. OCT allows diagnosis and quantification of retinal and ON changes in microcephaly even if they are not detected on ophthalmoscopy

Abnormally Small Neuromuscular Junctions in the Extraocular Muscles From Subjects With Idiopathic Nystagmus and Nystagmus Associated With Albinism

PURPOSE: Infantile nystagmus syndrome (INS) is often associated with abnormalities of axonal outgrowth and connectivity. To determine if this manifests in extraocular muscle innervation, specimens from children with idiopathic INS or INS and albinism were examined and compared to normal age-matched control extraocular muscles. METHODS: Extraocular muscles removed during normal surgery on children with idiopathic INS or INS and albinism were immunostained for neuromuscular junctions, myofiber type, the immature form of the acetylcholine receptor, and brain-derived neurotrophic factor (BDNF) and compared to age-matched controls. RESULTS: Muscles from both the idiopathic INS and INS and albinism groups had neuromuscular junctions that were 35% to 71% smaller based on myofiber area and myofiber perimeter than found in age-matched controls, and this was seen on both fast and slow myosin heavy chain isoform-expressing myofibers (all P < 0.015). Muscles from subjects with INS and albinism showed a 7-fold increase in neuromuscular junction numbers on fast myofibers expressing the immature gamma subunit of the acetylcholine receptor. The extraocular muscles from both INS subgroups showed a significant increase in the number and size of slow myofibers compared to age-matched controls. Brain-derived neurotrophic factor was expressed in control muscle but was virtually absent in the INS muscles. CONCLUSIONS: These studies suggest that, relative to the final common pathway, INS is not the same between different patient etiologies. It should be possible to modulate these final common pathway abnormalities, via exogenous application of appropriate drugs, with the hope that this type of treatment may reduce the involuntary oscillatory movements in these children

Retinal Development in Infants and Young Children with Achromatopsia.

Normally, postnatal development of the human retina involves centrifugal displacement of the inner retinal layers (IRLs) from the fovea, centripetal migration of the cone photoreceptors into the fovea, and elongation of the photoreceptors with age. It is not clear whether retinal development in infants and young children with achromatopsia (ACHM) occurs in a similar way and whether any retinal changes that occur are progressive in early childhood. [opening paragraph