Clinical Utility of Multimodal Imaging to Assess Macular Changes in Usher Syndrome: A Transversal Study

doi:10.21203/rs.3.rs-4714838/v1

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Research Article

Clinical Utility of Multimodal Imaging to Assess Macular Changes in Usher Syndrome: A Transversal Study

https://doi.org/10.21203/rs.3.rs-4714838/v1

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Purpose

Usher syndrome (USH) is an autosomal recessive disorder that presents with varying degrees of visual loss related to Retinitis Pigmentosa. In most of the developing countries, initial diagnosis is based on clinical criteria and supported by multimodal imaging. The objective of this study is to identify changes in retinal morphology through retinal imaging that could be a diagnostic parameter of disease’s progression.

Methods

a transversal study was conducted to examine patients referred with a presumed clinical diagnosis of USH using visual acuity, campimetry, retinography and quantitative OCT and OCTA parameters. Eyes were divided into two groups according to visual acuity (BCVA): Group 1 BCVA > 0.5 and Group 2 BCVA < 0.5, allowing comparative analysis between eyes with different degrees of visual loss from the disease.

Results

The final sample consisted of 18 patients. Group 1 showed an increased central macular thickness (p = 0.003, µd 64µm), a decrease in FAZ area and perimeter (p = 0.002, µd -0,43 mm²; p = 0,004 µd -1,45mm); an increase in central, internal and total macular vessel perfusion density (p = 0.002, µd 9.57%; p = 0.001, µd 10.24%; p = 0.001, µd 10.40%). This study compared the difference between the quantitative values between OD and OS, finding a mean difference in FAZ’s circularity index of -0.05µm (p = 0.024).

Conclusion

The OCT and OCTA parameters exhibit notable alterations in USH, which vary based on the patient's visual acuity. Evaluation of retinal quantitative parameters presented in this study can be used as tools for monitoring the evolution and future studies in treatment of USH, especially its complications.

Usher Syndromes

Multimodal Imaging

Tomography

Optical Coherence

Retinitis Pigmentosa

Diagnosis

Deaf-Blind Disorder

Usher syndrome (USH) is an autosomal recessive disorder that involves sensorineural hearing loss and occasional vestibular dysfunction, with varying degrees of visual loss related to Retinitis Pigmentosa (RP) [1]. It is the most common cause of hereditary deaf blindness worldwide [2], with an estimated prevalence of 4 to 17 cases per 100,000 people [2, 3], and 18 genes and loci already described implicated in its pathogenesis [4]. However, a growing list of additional genes has been reported, sometimes associated with a poorly defined clinical subtype called "Atypical Usher Syndrome" that does not meet the canonical criteria for the three recognized subtypes of USH [5].

USH is clinically and genetically heterogeneous and is classified into three subtypes according to age of onset, severity and vestibular characteristics. USH1 corresponds to the form where congenital sensorineural hearing loss is more severe and profound, with vestibular areflexia beginning precociously, in the first decade of life. RP begins in infancy with loss of night vision, reduced visual field and eventually loss of visual acuity, which rapidly progresses to blindness. USH1 accounts for around 35–40% of Usher syndrome cases [6, 7]. USH2, the most prevalent subtype, is characterized by non-progressive moderate sensorineural hearing loss, normal vestibular function and RP from adolescence. USH3 presents with progressive sensorineural hearing loss, sometimes accompanied by vestibular dysfunction, and variable onset of RP [1].

Therefore, the clinical diagnosis of USH is essentially based on the association between hearing loss and RP, where the hearing loss is congenital sensorineural and RP appears in childhood or young adulthood. In most developed countries, the initial diagnosis is still clinical and supported by multimodal tests, followed by genetic confirmation [5]. The identification of genes associated with USH and its pathogenic variants, with the aid of multimodal retinal imaging, enables an adequate correlation between genotype and phenotype [8].

Within multimodal exams, campimetry, retinography and spectral domain optical coherence tomography (SD-OCT) are established and widely accessible retinal imaging techniques for assessing RP and associated complications [1].

Retinography allows to observe changes in the retinal pigmented epithelium (RPE), attenuation of blood vessels, cystoid macular edema, disc pallor and peripheral bone-spicule development that occur at various stages of RP on USH [9].

Optical Coherence Tomography and Angiotomography (SD-OCT and OCTA) have revolutionized imaging in ophthalmology, allowing in vivo and non-invasive images of the retina’s layers. It produces high-resolution cross-sectional images of the inner and outer retinal structures, pigment epithelium and clinical choroid, and adds new insights into its pathogenesis and prognosis [10].

The decrease or absence of response from cones and rods is the most notable characteristic of USH, due to the involvement of the outer layer, especially the outer nuclear layer of the retina, which contains the nuclei of the photoreceptors, initially sparing the inner nuclear layer of the retina consisting of amacrine, bipolar and horizontal cells [11].

These alterations can be observed by OCT as concentric loss of the layers of the external limiting membrane (ELM) and the ellipsoid zone (EZ) [12]. The outer hyperreflective layers of the retina represent the structural integrity of the macular photoreceptors [1], so a decrease in layer thickening and width correlates with a decline in visual function [1, 12, 13]. Since shortening of the outer segments of photoreceptors is the earliest histopathological change in RP [14], OCT evaluation for outer retinal rupture is an important diagnostic tool in USH.

Narrowing of larger retinal vessels has been described as a characteristic sign of RP on ophthalmoscopy in contrast to normal subjects. There is limited knowledge about changes in small retinal vessels in the macular area. Multiple retinal dystrophies, including RP on USH, shows changes in the foveal avascular zone (FAZ), a capillary-free zone in the center of the macula, and reduced vascular density (VD) or perfusion when examined with OCTA [15].

Sclerosis and choroidal atrophy are also changes described on USH. Enhanced depth imaging (EDI) is a relatively new technique that allows in vivo examination and quantification of the choroid using particular focusing techniques and a SD-OCT device [16].

Currently, there are no approved treatments available to prevent the visual loss associated with USH. However, with an increasing number of therapeutic trials in progress, a better understanding of how retinal morphology relates to established clinical measures is necessary for the identification of reliable surrogate targets [1].

In this study, we investigated changes in multimodal retinal images in patients with a clinical diagnosis of USH, as well as the relationship between the metrics of these images, such as retinal thickness, vessel density and avascular foveal zone with visual function in order to identify changes in retinal morphology that could be a diagnostic parameter and predictors of disease progression for future interventional studies.

Location

The study was carried out in a tertiary craniofacial anomalies’ hospital, a reference in the care of patients with associated syndromes, and in a private ophthalmology clinic located in the same municipality as the hospital.

Population and sample

The researchers examined patients referred by the hospital's otorhinolaryngology department with a presumed clinical diagnosis of USH, using visual acuity, 10:2 campimetry and multimodal retinal images (retinography, OCT and OCTA), all over the age of 16 years old. One image was obtained from each patient for reasons of time, cost and the difficulty patients had in cooperating with fixation due to their low visual acuity. Patients with alterations suggestive of RP on retinal mapping or retinography were included, as well as those with alterations in the basic pattern of concentric visual field loss. Patients who, after ophthalmic assessment, were assigned a diagnosis other than RP were excluded from the sample.

Methods of data collection

Visual acuity was measured using the Snellen chart at a distance of six meters from the patient; the parameter for low visual acuity was considered to be results below 0.5. Finger counting and hand movement visual acuities were converted into decimals according to Schulze-Bonsel K et al (2006) and Karanjia R et al (2016) [17, 18]. The patients were then divided into two groups according to best-corrected visual acuity (BCVA), into Group 1 BCVA > 0.5 and Group 2 < 0.5, following the parameter used to qualify to drive motor vehicles in Resolution 425/2012 of the National Traffic Council (CONTRAN), a signatory of the Vienna Code since 1968 [19], allowing comparative analysis between eyes at different stages of the disease, with no minimum visual acuity limit, as long as it was possible to carry out the examination and consequently obtain quantitative and qualitative data.

In order to diagnose RP, retinal mapping was carried out using Binocular Indirect Ophthalmoscopy (Vantage Plus Indirect Ophthalmoscopy Enhanced Keeler®) and retinography of the posterior pole of the retina and mid-periphery obtained using the Visucam NM/FA Zeiss® device, assessing the presence of pigmented spicules or other pathological findings.

Campimetry (Humphrey Field Analyzer II-i series Zeiss®) was used to obtain the visual field through light emissions and the patient's response to them. This test depends on the patient's cooperation, but it accurately estimates visual field loss. The visual field was used to segregate visual loss using Mean Deviation (MD) and Pattern Standard Deviation (PSD).

Using SD-OCT and OCTA (OCT-SD and OCTA-SD; Cirrus 5000 Angioplex HD-OCT, Carl Zeiss Meditec Inc, Dublin, USA), with the patients under pharmacological mydriasis obtained one hour after the application in each eye of three drops of 1% tropicamide interspersed for five minutes, we obtained cross-sectional and three-dimensional tomograms of the posterior pole of the eye using low-coherence interferometry, 840nm light beams emitted by a diode, to obtain high-resolution images without emitting radiation and without coming into contact with the eye. The layers were analyzed qualitatively in a non-invasive histological manner to identify alterations in specific retinal cell layers, mainly the outer structure of the foveal retina and alterations in the photoreceptor layer (ellipsoid zone or IS\OS layer).

The quantitative assessment mode for macular thickness was selected from the computer console. The examination was carried out using the "Macular Cube Scan 512x128" scanning protocol for macular image acquisition.

The image was taken with a green cross as an internal fixation target. After saving the image on the computer, the data values were analyzed using the built-in software. The machine-generated report provides the color image of the central macula with the image centered on the fovea. Macular thickness is represented as concentric circles 1, 3 and 6 mm from the center of the fovea (Fig. 1a). All macular thickness and macular volume values were recorded, tabulated and analyzed.

During the 3x3 mm OCT analysis, the quantitative values defined by Sampson DM et al, 2022 were taken into account: i) foveal thickness between the internal limiting membrane and retinal pigment epithelium (µm); ii) foveal volume (mm³); iii) mean macular thickness (µm); iv) choroidal thickness (µm). Choroidal thickness was measured manually from the inner edge of the sclera to the outer edge of the EPR in the subfoveal region.

For 3x3 mm OCTA analysis, the following quantitative values were obtained automatically by the device software, parameters that were taken into account were: i) Vessel Perfusion Density (%) in the ETDRS grid centered in the fovea, divided by central ring, inner ring and total rings (area occupied by vessel pixels divided by the total image area; Fig. 1a); ii) Foveal Avascular Zone (FAZ) in terms of area, perimeter and circularity index (ratio between the measured perimeter and the perimeter of a perfect circular area of the same size; Fig. 1b).

It should be noted that all image acquisition and manual measurements were carried out by the same researcher and followed the OCT data standardization guidelines recommended by the EQUATOR Network and by Sampson DM et al (2022) [20, 21]. It should be noted that when acquiring OCT and OCTA scans of patients with low visual acuity, there is an increase in artifacts and segmentation errors when the software automatically analyzes them. To correct this error, all the exams were checked and the segmentations, where necessary, were corrected according to what was suggested by Enders C et al, 2019.

Analysis and data interpretation

The results were transcribed into a single table and statistically analyzed using the Jamovi Version 2.5® software (The jamovi project 2024, Sydney, Australia). The variables were analyzed using descriptive statistics, and the eyes were compared using the Wilcoxon test for paired samples. Correlations were made using a single correlation matrix using the Kendall Tau test.

In order to stratify the severity of the disease, the eyes were divided into two groups stratified by the AVCC cut-off point of 0.5: Group 1: corrected visual acuity > 0.5; Group 2: corrected visual acuity < 0.5. This separation criterion was created to compare eyes at different stages of the disease, taking as a starting point that USH is initially peripheral and, from the moment that significant quantitative loss of vision is observed, there is already greater severity of the disease and its consequences. By observing groups at different stages of progression, different quantitative metrics can be studied. The groups were compared using the Mann-Whitney U test for Group 1 ≠ Group 2, Group 1 > Group 2 and Group 1 < Group 2.

Among the patients evaluated, one was excluded because, after ophthalmic examination, he was diagnosed with Optic Atrophy, with the diagnosis later confirmed genetically by the OPA1 gene mutation. Retinography was used to confirm retinitis pigmentosa by the triad of bone spicules, vascular thinning and optic nerve pallor (Fig. 2). Thus, 18 patients were included in the final sample. The patients were 37.25±16.92 years old (16–64), 61% male and 39% female.

Visual acuity and campimetry parameters (MD and PSD) in the right eye were 0.34±0.30 (0.005–1.00), -23.19±10.61 (-34.89 – -1.11) and 5.72±3.31 (0.89–12.45), respectively. In the left eye, it was 0.31±0.28 (0.005–0.8), -23.52±10.57 (-35.05 – -1.67), showing different degrees of visual loss in the sample, but a uniformly reduced visual field between the points tested. In addition, there was no significant difference between the right and left eyes (VA p = 0.624; MD p = 0.157; PSD p = 0.896; Wilcoxon's W for paired samples), in the other parameters, there was also no difference between the eyes, for this reason and to avoid analysis bias, they were statically compiled into a single group. The main patient data can be found in Table 1.

Table 1

Epidemiological data of the sample.
Patient	Age (years)	Sex	BCVA OD (decimal)	BCVA OS (decimal)
1	44.9	Female	1.000	0.630
2	64.5	Male	0.320	0.800
3	23.4	Male	0.800	0.800
4	17.6	Female	0.800	0.800
5	17.2	Male	0.630	0.630
6	27.1	Male	0.630	0.630
7	17.8	Male	0.500	0.320
8	44.5	Male	0.500	0.100
9	16.2	Male	0.500	0.500
10	33.8	Female	0.400	0.320
11	57.4	Female	0.320	0.320
12	18.8	Male	0.200	0.250
13	51.5	Male	0.100	0.100
14	46.1	Female	0.050	0.100
15	28.8	Male	0.032	0.050
16	45.1	Male	0.050	0.050
17	64.7	Female	0.016	0.016
18	51.6	Female	0.016	0.016

^{BCVA. Best Corrected Visual Acuity}.

Tomografia de Coerência Óptica (OCT) e Tomografia de Coerência Óptica Angiografia (OCTA)

The quantitative parameters of the OCT and OCTA can be found in Table 2. In this study, the difference between the quantitative values between the left and right eyes was also compared using the Wilcoxon W test for paired samples, which found a significant difference in the circularity index of the avascular zone of the fovea between the eyes of the same individual, showing an average circularity of -0.05µm between OD and OE (p = 0.024, OD < OE).

Table 2

Quantitative parameters in the sample.
	Total (n = 36) Mean ± Standard Deviation (IC 95%)	Comparison of Paired Samples (Wilcoxon W, for OD ≠ OE)	Group 1 (n = 16) Mean ± Standard Deviation (IC 95%)	Group 2 (n = 20) Mean ± Standard Deviation (IC 95%)	Mann Whitney U Test (p; mean difference)
Age (years)	37.2±16.7 (31.6–42.9)	–	28.2±14.2 (20.7–35.8)	44.4±15.2 (37.3–51.6)	< 0.001^***; -19.00^††
Best Corrected Visual Acuity	0.37±0.30 (0.27–0.47)	P < 0.001^***	0.66±1.61 (0.57–0.74)	0.14±0.12 (0.08–0.19)	< 0.001^***; 0.51^†
Foveal Thickness (µm)	229±65.3 (207–251)	p = 0.500	261±49.6 (235–287)	204±66.3 (173–235)	0.003^**; 0.52^†
Foveal Volume (mm³)	8.87±1.38 (8.40–9.34)	p = 0.442	9.13±1.69 (8.23–10.0)	8.66±1.08 (8.16–9.17)	0.288; 0.20^†
Mean Macular Thickness (µm)	246±38.7 (233–259)	p = 0.394	253±47.3 (228–278)	241±30.2 (226–255)	0.300; 5.00^†
Choroidal Thickness (µm)	224±45.8 (209–240)	p = 0.777	226±41.5 (204–248)	223±50.0 (200–247)	0.418; 3.85^†
Central Vessel Perfusion Density (%)	11.20±9.76 (7.86–14.50)	p = 0.495	15,2±6,41 (11,8–13,1)	7.96±10.9 (2.86–13.1)	0.002^**; 9.57^†
Internal Vessel Perfusion Density (%)	23.60±9.10 (20.50–26.70)	p = 0.865	27,9±5,0 (25,1–30,6)	20.2±10.2 (15.4–25.0)	0.001^***; 10.24^†
Total Vessel Perfusion Density (%)	22.30±9.09 (19.30–25.40)	p = 1.000	26,5±4,90 (23,9–29,1)	19.0±10.3 (14.2–23.8)	0.001^***; 10.40^†
Foveal Avascular Zone (mm²)	0.65±0.61 (0.44–0.86)	p = 0.981	0,30±0,17 (0,21–0,39)	0.93±0.69 (0.60±1.25)	0.002^**; -0.44^††
Foveal Avascular Zone Perimeter (mm)	3.22±1.50 (2.71–3.73)	p = 0.347	2,43±0,77 (2,02–2,85)	3.85±1.66 (3.07–4.63)	0.004^**; -1.45^††
Foveal Avascular Zone Circularity Index	0.64±0.09 (0.61–0.68)	p = 0.047^*	0,61±0,11 (0,55–0,67)	0.67±0.07 (0.64–0.70)	0.065; -0.06 ^††

^{*Significance Level; †Test for Group 1 > Group 2; ††Test for Group 1 < Group 2}.

Visual acuity and quantitative parameters of the sample

After stratifying the patients by Best Corrected Visual Acuity (BCVA), the 36 eyes of the 18 patients were divided into the two groups described in the methodology, namely Group 1: N = 16 and Group 2: N = 20. Group 1 showed that the patients were 19 years younger (p < 0.001; Mann Whitney U Test for Group 1 < Group 2) and that the OCT showed greater central macular thickness (p = 0.003, mean difference 64µm; Mann Whitney U Test for Group 1 > Group 2). The OCTA showed a reduction in the area and perimeter of the foveal avascular zone (FAZ) when comparing Group 1 with Group 2 (p = 0.002, mean difference − 0.43 mm2; p = 0.004, mean difference − 1.45mm, respectively; Mann Whitney U Test for Group 1 < Group 2). There was also an increase in central, internal and total vessel perfusion density in Group 1 (respectively, p = 0.002 mean difference of 9.57%; p = 0.001, mean difference of 10.24%; p = 0.001 mean difference of 10.40%; Mann Whitney U Test for Group 1 > Group 2). The details of the data can be found in Table 2.

Three patients examined in this study had intraretinal cystic fluid, characteristic of macular edema (Fig. 3a), and two patients had epiretinal membrane (Fig. 3b). All in Group 1, therefore with little clinical alteration; however, these alterations may be possible predictors of progression of the syndrome in the future [22, 23].

When correlating the quantitative parameters with visual acuity, it was observed that visual acuity was positively correlated with foveal thickness (p = 0.004, τ = 0.351), internal and total central vascular perfusion density (respectively, p = 0.006, τ = 0.334; p < 0.001, τ = 0.410; p < 0.001, τ = 0.420). Visual acuity was also negatively correlated with the area and perimeter of the FAZ (respectively, p = 0.001, τ = -0.374; p = 0.005, τ = -0.343). In the remaining variables, there was no difference or correlation between the quantitative parameters. In addition, visual acuity in the sample was inversely correlated with patient age (p = 0.002, τ = -0.387), the younger the patient, the higher the visual acuity.

This study evaluated patients with a clinical diagnosis of USH using multimodal exams. Initially, the quantitative parameters of the OCT and OCTA were studied descriptively and, subsequently, the variation and correlation between these parameters according to the BCVA.

This study included relatively young patients, with a mean age of 37 years, but with a wide range, 16 to 64 years, making it possible to analyze individuals at different stages of the disease. The assessment of campimetry and acuity showed different degrees of visual loss in the sample, which was also negatively correlated with age, meaning that older patients had worse vision, probably due to the progression of USH. Despite the visual difference, campimetry was uniformly reduced between the points tested bilaterally, which are common characteristics of patients with syndromic or non-syndromic RP at different ages and stages of the disease. However, we only used campimetry as diagnostic support, since the morphological changes seen on OCT are more sensitive for detecting the progression of the disease in central vision [24].

In Group 1, eyes with improved BCVA, a greater central macular thickness was observed, reinforcing the other qualitative changes observed in this study: i) loss of the outer retinal structure, sparing the fovea in the early stages (Fig. 4) and ii) alteration of the photoreceptor layer, especially in the ellipsoid zone. This corroborates the findings of other studies [25–27].

In this study, when Group 1 was compared with Group 2, an increase in the area and perimeter of the foveal avascular zone (FAZ) was observed in the group with worse visual acuity, as well as a decrease in the central, internal and total vessel density and the same parameters were observed in the central, internal and total perfusion density. Changes in FAZ metrics and vascular density, used to indicate the micro-circulatory state of the fovea [10], are probably related to the evolution of macular ischemia.

A significant difference was also found between the circularity index of the FAZ between the right and left eye of the same individual, showing that the index was − 0.05µm lower in the left eye. In normal eyes, this index is closer to 1, i.e. the shape of the FAZ is closer to a perfect circle. However, articles have shown that, with ischemic suffering from various retinal diseases, the FAZ undergoes morphological and geographical deformations, becoming increasingly larger and less circular, evidenced by an increase in area and perimeter with a decrease in the circularity index [28–30]. Studies show that USH is either slightly asymmetrical or symmetrical and bilateral [24], however, the use of this index can show that, despite being symmetrical, the progression of the disease can occur at a different rate between the eyes.

Measurements of the OCT and the OCTA, with the exception of choroidal thickness, were obtained automatically using the device's software because it was more convenient, faster and avoided variability between different observers. Although there may be errors in the design and measurement of the parameters by the algorithms, which would lead to inaccurate metrics [10], this method allowed data acquisition in all patients in a uniform and faster way. To minimize segmentation errors, when necessary, this parameter was corrected manually [31].

However, it should be noted that quantitative parameters can also be altered by ocular complications common in USH, such as subcapsular cataracts, optic nerve drusen, epiretinal membranes and cystoid macular edema [1]. In this study, only three patients examined had intraretinal cystic fluid, characteristic of macular edema and two patients with epiretinal membrane, all in Group 1, with better visual acuity, therefore, with little visual impact and in the quantitative analyzes, data also observed in another study [32], however, these alterations found in the early stages of RP may, in the future, be possible predictors of progression of the syndrome [22, 23].

Some studies have indicated a reduction in choroidal thickness in patients with USH [33], although this study demonstrated an apparently normal choroidal thickness and no discernible difference between the groups. The thinning of the choroid observed in RP is not well understood, and it is possible that the characteristic progressive photoreceptor degeneration results in this thinning [33]. In addition, the choroidal thickness is influenced by a range of factors, including age, axial length, refractive error, blood pressure, and the chronicity of choroidal pathology. This makes it challenging to ascertain the precise thickness of the choroid. One limitation of this technique is the inability to assess the thickness of the choroid in all eyes due to an indistinct posterior boundary of this structure, specifically at the choroid/sclera junction.

It is important to note that variations between different OCT and OCTA devices can lead to differences in the metric analysis of images. Vessel density measurement and FAZ are quantifiable metrics of posterior pole vascularization that can also change physiologically with advancing age or secondary to ocular pathologies [10]. Other potential causes for this discrepancy include a suboptimal number of B-scan OCT scans, a lack of eye-tracking software, and the possibility of eye movement during imaging, which could result in image degradation [33].

Several studies have assessed the repeatability and reproducibility of quantitative OCTA metrics in healthy eyes, which have been observed to differ between different examiners. However, these differences have been observed to be less than 1%, for which clinical significance has yet to be determined, suggesting that the selected parameters may be feasible in a trial or clinical setting [10].

Another limitation of this study was that the diagnosis was only clinical and imaging, without genetic evaluation. However, it should be noted that in Brazil and in developing countries, due to high costs and difficult access to genetic tests, these end up being reserved for a small number of individuals [34]. Nevertheless, the limitation had a minimal impact on the results, as studies showed a 97% correlation between the clinical and genetic diagnoses [35].

The evaluation of retinal metrics, thickness, vascular density and the foveal avascular zone presented here proved to be fundamental to collaborate as quantitative and qualitative analysis tools for monitoring the evolution and treatment of USH. This approach allows for new research that considers the preservation of central vision, leading to a better quality of life for these patients.

The potential to characterize retinal alterations and, most importantly, their complications allow for a more favorable evolution and final visual prognosis. This is due to the fact that interventional trials aimed at RP in USH are underway, with the promising prospect of a treatment for at least some USH subtypes, even though they are not yet available.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JS, LES, EHY and LFML. The first draft of the manuscript was written by JS and LES, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (date 06/06/2022, protocol number 5.504.706).

Consent to participate

Written informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Figure(s) 1, 2, 3 and 4.

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Clinical Utility of Multimodal Imaging to Assess Macular Changes in Usher Syndrome: A Transversal Study

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Abstract

Purpose

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Results

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INTRODUCTION

METHODS

Location

Population and sample

Methods of data collection

Analysis and data interpretation

RESULTS

Tomografia de Coerência Óptica (OCT) e Tomografia de Coerência Óptica Angiografia (OCTA)

Visual acuity and quantitative parameters of the sample

DISCUSSION

CONCLUSIONS

Declarations

References

Additional Declarations

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