Visual Function and Central Retinal Structure in Choroideremia

Hèon, Elise; Alabduljalil, Talal; McGuigan, David B.; Cideciyan, Artur V.; Li, Shuning; Chen, Shiyi; Jacobson, Samuel G.

doi:10.1167/iovs.15-18421

Cited by 69 publications

(76 citation statements)

References 71 publications

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“…1, P1, vertical arrow ) of attenuation and then loss of the IZ signal in nasal retina with approximation of the EZ to the RPE and mild ONL thinning, consistent with photoreceptor outer segment shortening (POS) and cell loss. 8,10,42-44 Further nasal to this point there is increased backscattering posterior to the RPE/BM. The structural change co-localizes with a transition of the NIR-REF signal from normal to a brighter signal near the nerve (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…1, P2 & P3). 7,8,10 At the TZ there is an outward evagination of the ELM and EZ layers (Fig. 1, P3, yellow outline ).…”

Section: Resultsmentioning

confidence: 99%

“…Similar high frequency of ORT has been previously reported in CHM. 10 The ONL that separates the ORT from the central TZs and that surrounds this lesion is markedly thin. By the third decade of life centripetal progression of the central retinal disease leads to residual islands of relative normal pigmentation with scalloped perimeters surrounded by depigmented RPE/choroid and a thickened fovea causing an abnormal foveal contour (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Natural History of the Central Structural Abnormalities in Choroideremia

et al. 2017

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Purpose To describe in detail the central retinal structure of a large group of patients with Choroideremia (CHM). Design prospective, cross-sectional, descriptive study. Subjects Patients (n=97, age 6-71 years) with CHM and subjects with normal vision (n=44; ages 10-50 years) were included. Methods Subjects were examined with spectral domain optical coherence tomography (SD-OCT) and near infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n=24) with automated static perimetry within the central regions (±15°) examined with SD-OCT. Main outcome measures VA and visual thresholds, total, inner and outer nuclear layer (ONL) thicknesses, and the horizontal extent of the ONL and of the photoreceptor outer segment (POS) interdigitation zone. Results Earliest abnormalities in regions with normally appearing RPE were the loss of the POS and EZ zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, non-atrophic retina in the majority (69%) of patients. In general, retinal pigment epithelium (RPE) abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning. Conclusions Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until late disease. TZ migration to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.

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Section: Resultsmentioning

confidence: 97%

“…1, P2 & P3). 7,8,10 At the TZ there is an outward evagination of the ELM and EZ layers (Fig. 1, P3, yellow outline ).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Natural History of the Central Structural Abnormalities in Choroideremia

et al. 2017

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“…[2, 3] Affected males typically experience nyctalopia and peripheral visual field loss by the second decade of life; central vision is usually affected later in the course of the disease. [4] Early peripheral pigmentary mottling of the fundus develops into choroidal and retinal atrophy, typically beginning in the midperiphery and expanding both centrally and peripherally. [5] Previous histological and optical coherence tomography (OCT) studies have led to various models of degeneration, including 1) a diffuse and independent degeneration of the choriocapillaris, retinal pigment epithelium (RPE), and neural retina,[6, 7] 2) a primary photoreceptor degeneration followed by RPE and choroidal atrophy,[6, 8] and 3) a primary RPE degeneration followed by photoreceptor loss and choroidal atrophy.…”

Section: Introductionmentioning

confidence: 99%

“…[5] Previous histological and optical coherence tomography (OCT) studies have led to various models of degeneration, including 1) a diffuse and independent degeneration of the choriocapillaris, retinal pigment epithelium (RPE), and neural retina,[6, 7] 2) a primary photoreceptor degeneration followed by RPE and choroidal atrophy,[6, 8] and 3) a primary RPE degeneration followed by photoreceptor loss and choroidal atrophy. [9–11] Additional OCT-documented characteristics of choroideremia include the presence of interlaminar bridges[8] (ILBs, wedge-shaped hyporeflective structures bridging the inner and the outer retina) and outer retinal tubulations[4, 12] (ORTs, structures in the outer retina composed of deteriorating photoreceptors and remnant external limiting membrane (ELM) that typically appear on OCT as hyperreflective ovaloid structures with a hyporeflective lumen[13]). Finally, Lazow et al report a relatively abrupt termination of the inner segment/outer segment ellipsoid zone (EZ) and ELM that frequently coincide with ILBs.…”

Section: Introductionmentioning

confidence: 99%

Multimodal Imaging of Photoreceptor Structure in Choroideremia

et al. 2016

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PurposeChoroideremia is a progressive X-linked recessive dystrophy, characterized by degeneration of the retinal pigment epithelium (RPE), choroid, choriocapillaris, and photoreceptors. We examined photoreceptor structure in a series of subjects with choroideremia with particular attention to areas bordering atrophic lesions.MethodsTwelve males with clinically-diagnosed choroideremia and confirmed hemizygous mutations in the CHM gene were examined. High-resolution images of the retina were obtained using spectral domain optical coherence tomography (SD-OCT) and both confocal and non-confocal split-detector adaptive optics scanning light ophthalmoscope (AOSLO) techniques.ResultsEleven CHM gene mutations (3 novel) were identified; three subjects had the same mutation and one subject had two mutations. SD-OCT findings included interdigitation zone (IZ) attenuation or loss in 10/12 subjects, often in areas with intact ellipsoid zones; RPE thinning in all subjects; interlaminar bridges in the imaged areas of 10/12 subjects; and outer retinal tubulations (ORTs) in 10/12 subjects. Only split-detector AOSLO could reliably resolve cones near lesion borders, and such cones were abnormally heterogeneous in morphology, diameter and density. On split-detector imaging, the cone mosaic terminated sharply at lesion borders in 5/5 cases examined. Split-detector imaging detected remnant cone inner segments within ORTs, which were generally contiguous with a central patch of preserved retina.ConclusionsEarly IZ dropout and RPE thinning on SD-OCT are consistent with previously published results. Evidence of remnant cone inner segments within ORTs and the continuity of the ORTs with preserved retina suggests that these may represent an intermediate state of retinal degeneration prior to complete atrophy. Taken together, these results supports a model of choroideremia in which the RPE degenerates before photoreceptors.

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Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Morgan

Vergilio

et al. 2022

JAMA Ophthalmol

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Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells. OBJECTIVE To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTSThis longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 10 10 vector genome per eye) or high-dose (1 × 10 11 vector genome per eye) AAV2-hCHM. Analysis began February 2015. MAIN OUTCOMES AND MEASURESThe macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point. RESULTSNine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM-injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment-related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO.CONCLUSIONS AND RELEVANCE Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.

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Visual Function and Central Retinal Structure in Choroideremia

Cited by 69 publications

References 71 publications

Natural History of the Central Structural Abnormalities in Choroideremia

Natural History of the Central Structural Abnormalities in Choroideremia

Multimodal Imaging of Photoreceptor Structure in Choroideremia

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

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