Combined retinal imaging using OCT and adaptive optics

Introduction and background

Current advanced non-invasive retinal imaging instruments permit to detect and measure accurately small focal changes of the retina in patients[PSt1] . These findings can help in determining the cause of unexplained visual symptoms and visual loss. For example, the macula of patients with vitreomacular traction may show only subtle changes detectable by ophthalmoscopy. However, optical coherence tomography (OCT) images allow a precise classification supporting treatment decision and prognosis.1 Additional improvements in OCT technology have permitted to obtain an axial resolution of approximately 3 to 5 µm.2,3 This high resolution allows excellent tomographic visualization of the retinal architecture and helps to indicate pathologic changes in the microstructure of the retina, especially the photoreceptor layer.

Despite the high axial resolution, the relatively low transverse resolution remains a constraint in OCT imaging. Generally, the transverse resolution of OCT is approximately 20 µm, which exceeds the cone [PSt2] mosaic spacing of 5 to 10 µm. The main reasons [PSt3] inducing this limitation are the ocular optical aberrations and the saccadic eye movements. 4,5

Adaptive optics (AO) systems are designed to overcome these optical limitations[PSt4] . An AO system consists of a wavefront sensor to measure ocular aberrations and a deformable mirror to compensate for these aberrations. Correcting the ocular aberrations with the AO system yields a transverse resolution of less than 2 µm, which is required to visualize individual cone photoreceptors [PSt5] in the living retina.6,7 This enables accurate detection and measurement of small anatomical lesions. In contrast to OCT imaging, the limitation of the AO system is its low axial resolution. It is larger than 100 µm in conjunction with conventional flood-illumination fundus photography.6

Because Fourier-domain [PSt6] (FD) OCT provides a high axial resolution enabling visualization of retinal lamination, and the AO system delivers a high transverse resolution allowing direct visualization of the cone photoreceptor mosaic5,8, we think it is valuable to study the [PSt7] retinal architecture in parallel using both instruments.

Recently, the advent of ocriplasmin (JetreaÒ) introduced pharmacological vitreolysis as a new treatment modality for diseases of the vitreomacular interface (VMI)9. This has created the need to obtain data on the incidence of these pathologies in the adult population. Although OCT allows accurate diagnosis and classification of diseases of the VMI1,10 , little is known about the epidemiology. An epidemiological study examining a group of almost 500 visitors using OCT at the ‘Dag van de Wetenschap’ on November 24th 2013 was organized.

Adaptive Optics can visualize individual retinal cones and analysis of the obtained images allows determination of cone density. In addition, spatial distribution of cones can be described by determining spacing and packing arrangement[PSt8]  (number of nearest neighbours). Obtaining normative data of these parameters is crucial for further analysis in diseased retina. Healthy volunteers will be examined with a flood-illumination Adaptive Optics camera (rtx 1TM, Imagine Eyes[JJ9] , France). Limited data on cone density, spacing and packing are available. Although some authors report data in SLO-Adaptive Optics systems11,12,13,14, and Lombardo’s group15 report data in a flood-illumination camera, quantitative analysis in different age groups have not been reported using a flood-illumination camera. Since there is no standardized analyzing method available, we designed a novel technique [PSt10] that we value as also useful for comparison purposes in diseased retinas.

General hypothesis and specific aims of the project

The first project includes an epidemiological study on the incidence of diseases of the vitreomacular interface in the adult population. This study was organized on November 24th 2013 with a total of almost 500 visitors. OCT data recorded from these healthy volunteers will allow to determine the incidence of VMI abnormalities and to create a normative database with data obtained from this study population.

The second project targets a description of the cone photoreceptor density, spacing and packing arrangement in 2[PSt11]  different age groups of healthy volunteers. This will allow the creation of a normative database, useful for referencing purposes in a wide variety of retinal pathologies. Adaptive optics is a novel technology that has been used to address a range of basic science questions and has been able to detect even minor changes in the cone mosaic in eyes that appeared healthy by standard clinical tests.16 Early detection of modest structural changes at the cellular level can be beneficial for patients by shortening the diagnostic lag time of treatment effects and selection of optimal patients to test emerging treatments.17

In addition to this project, patients with various retinal pathologies affecting the outer retina will be examined with AO as to determine and measure morphological changes in the pathologic retina and subsequently these data will be compared to the obtained normative data.

Methodology

The data capturing of the epidemiological study on the incidence of vitreomacular diseases in an adult population has taken place on the 24th of November 2013 during the ‘Dag van de Wetenschap’. After an information session on the increased interest of the vitreomacular interface due to the advent of a new pharmaceutical treatment modality, visitors were given the opportunity to have an OCT scan taken of the macular area from both eyes after signing the informed consent form. Five similar OCT machines (Cirrus 5000 HD OCT, Carl Zeiss Meditec, Germany) were operated by experienced technicians of the department of Ophthalmology UZ Leuven. Residents in training from the same department provided information on the results of the examination and took a short history (general and ophthalmologic history), as well as the objective refraction of both eyes. Visitors were given a print of their OCT scans along with some relevant explanation.

This study was approved by the  Ethics Committee of the UZLeuven (study S55784). The obtained OCT scans will be viewed and interpreted by Dr J. Jacob and Prof Dr P. Stalmans. If required to build a normative database, additional OCT imaging from healthy subjects may be necessary, which in that case will be performed in an additional clinical study.[PSt12]

The second project [PSt13] consists of Adaptive Optics images on healthy adult subjects of different ages. Subjects without ocular history will be recruited among the hospital staff of the Department of Ophthalmology at Hôpital Lariboisière (AP-HP), Paris. Comprehensive information will be provided and an informed consent will be obtained. For[JJ14]  a better interpretation of Adaptive Optics images other measurements and multimodal imaging of the retinal fundus will also take place: measurement of visual acuity, refractometry, axial length, OCT and fundus photography (Spectralis, Heidelberg engineering, Germany). Adaptive optics images will be obtained using a commercially available flood-illumination camera (rtx1TM, Imagine Eyes, France). Multiple images will be obtained on the horizontal axis and the vertical axis at different eccentricities focused on the photoreceptor layer. Treatment of the images and analysis of density, spacing and packing arrangement will be effected with the use of following software: AO-CK, AO-detect, i2k, GIMP and Powerpoint. Single-frame AO images will be stitched into a montage, and superimposed on a standard clinical fundus photograph, showing the cone mosaic at high resolution and the corresponding area within the wide field image. To[JJ15]  better understand changes, AO imaging of patients with various retinal pathologies will be performed similarly.

Acquisition, treatment and analysis of the images will be performed by Dr J. Jacob, Prof Dr R. Tadayoni and Prof Dr A. Gaudric.

This[JJ16]  institutional clinical study was registered in clinicaltrials.gov (NCT01546181) and the procedures conformed to the tenets of the Declaration of Helsinki. Approval of the Ethics Committee of the Saint-Antoine hospital (AP-HP, Paris, France) was obtained.

Milestones and timing of the PhD-project

Part-time PhD project

Our six-year project can be divided in 7 work packages (WP):

WP 1: analysis of OCT data obtained during ‘dag van de wetenschap’

WP 2: recruitment of patients for AO and acquisition of images

WP 3: reporting results of OCT data from ‘dag van de wetenschap’, possibly designing an additional clinical trial for data collection in healthy subjects

WP 4: treatment of AO images and counting procedure

WP 5: preparation of progress report

WP 6: reporting results AO images

WP 7: writing PhD manuscript

Conclusion

Recent advances in retinal imaging instruments are able to provide noninvasive in vivo images of the retina with unprecedented resolution. Ultra-high resolution OCT with its high axial resolution allowing visualization of retinal lamination and Adaptive Optics with its high transverse resolution allowing direct visualization of the cone mosaic, are complementary in imaging the retinal architecture. These techniques enable detection of subtle structural changes in the retina in eyes that appear healthy by standard clinical tests. Data obtained from a population of healthy eyes are fundamental in determining the density, distribution, and appearance of normal retinal tissue, more specifically photoreceptor cells in vivo. This will allow determination of the normal physiological range in retinal cellular structure, which permits comparison with the diseased retina, even in an early stage. Earlier detection of structural changes at the cellular level of the retina could improve the understanding of physiopathology, accelerate the assessment of treatment effects, hence may allow better selection of patients likely to benefit from treatment. The potential clinical applications are extensive and would involve both common retinal diseases such as diabetic retinopathy, age-related macular degeneration, vitreomacular interface pathologies, as well as rare retinal disorders.