Adaptive Optics

Physics and its Application

AO by itself does not produce an image and it must be integrated with an existing imaging device like a fundus camera, SLO or Spectral Domain-OCT (although flood light illumination can be used). All adaptive optics systems have three main elements: a mechanism for wavefront correction, typically a deformable mirror; a wavefront sensor (usually Hartmann Shack type) and a command and control algorithm (software) to integrate the two 4 (Figure 1). A deformable mirror is capable of changing shapes through the use of actuators that push and pull on the mirror. In the case of the Imagine Eyes system, there are 52 actuators that push and pull on an 8 × 8 array, while the system developed by Wavefront Sciences (Advanced Medical Optics, AMO, Santa Ana, California) has 800 centroids. 5 In simple words, the deformable mirror by virtue of its shape changing abilities "cleans up" the aberrations sensed by the wavefront sensor and produces a sharp image despite any defocus.

Figure 1: Principle of Adaptive Optics

Light from the retina is received by the aberrometer which then is sensed by a deformable mirror. A corrected wavefront is thus received as a high resolution retinal image.

Adaptive optics (AO) Retinal Imaging Systems

AO fundus camera: This system has been used mainly for studying the cone mosaic, cone directionality and reflectance. (Figure 2) Apart from photoreceptors; Retinal Pigment Epithelium, White Blood Cells in the vessels, retinal vessel wall and lamina cribrosa can be visualized. Considerable image processing effort is needed including registration, montaging and quantitative analysis. Despite these setbacks, AO fundus imaging has been a major breakthrough in terms of the resolution achieved. 6

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Adaptive optics scanning laser ophthalmoscopy (AO-SLO) -AO integrated with an SLO produces highly magnified, high resolution images. A wide field line scanning laser ophthalmoscope is used which creates an image by detection of a flying spot raster focused on the retina in a confocal arrangement. The confocality aids in better lateral resolution. Eye tracking softwares correct for micro-movements of the eyes and enable imaging even in non-mydriatic states. 7 Adaptive optics Optical coherence tomography (AO-OCT) -The peculiarity in OCT is that the axial and lateral resolution is decoupled. Axial resolution is limited by the coherence properties of light. Lateral resolution is limited by focal spot size, significantly degraded by the eye's aberrations. Thus AO can be used to compensate for the eye's monochromatic aberrations. AO is capable of resolving individual photoreceptors in 3 dimensions. 3D visualization of nerve fibre layer, lamina cribrosa, ganglion cells, as well as RPE photoreceptor mosaic and choriocapillaris is possible using high speed scans using AO-OCT (1,20,000 scans/ second) 6

Clinical Applications

Zhang et al studied the inter and intra-individual variability of cones in the macula in young adults. AOSLO was used in 40 eyes of 20 subjects ranging from 19-29 years. Cone density was assessed on a sampling grid of 2.4 mm X2.4 mm in the central macula. In their study they found that peak density is 168890±21348 cones/ mm 2 (mean± SD) in right eye and 167434±26068 cones/ mm 2 in the left eye. Both right and left eyes exhibited sharp density gradients. At 150 micron eccentricity, the cone density was 55% of the peak and at 1.2mm, it was 10% of the peak. They noted that the AO findings correlated well with the histology findings. 8 The AURA study by Dabir et al studied the cone packing density in emmetropic patients. Cone packing densities were calculated at 2 degrees and 3 degrees from the fovea in the temporal, superior, nasal and inferior quadrants. Mean cone packing densities were highest temporally, followed by superior, nasal and inferior. Mean cone packing densities at 2 degree from the fovea was 25154.67±4777.69 and at 3 degrees was 21.366.28±4167.86. Micro-perimetry revealed that the sensitivity of cones were highest at the fovea and decreased as the distance from the fovea increased. Thus they concluded that the sensitivity correlated with cone packing density. 9 Retinal dystrophies-Wolfing et al studied the cone directionality, sensitivity and density in patients of atrophic Bull's eye lesions. A 6 degree montage was obtained with the AOSLO. They demonstrated larger cones at 1.25 degrees from the fovea and decreased cone density. There was also a 5.5-fold reduction in amplitude evidenced by multi-focal ERG. This report showed that the density and functionality have a correlation and the larger cones indicated that the cones may not be normally functioning. At the foveal centre the patient's cone density was 31,100 cones/ sq mm (normal average-199,200 cones/ sq mm). 10 Studies suggest that diabetic retinopathy could be now considered a neurovascular disorder rather than a microvasculopathy. There has been growing evidence of photoreceptor apoptosis and neural degeneration which in turn lead to vascular drop out. 11 Lombardo et al 11 studied the para foveal cone density in a series of 11 patients diagnosed with type 1 diabetes and studied its correlation with the duration of diabetes, glycosylated hemoglobin level, the presence of retinopathy and the SD-OCT retinal thickness. These parameters were studied in patients of no retinopathy or mild non proliferative retinopathy. The study revealed statistically significant differences in cone densities between diabetics and control healthy subjects (p <0.001). At 230, 350 and 460 microns, the average density in the study group was 91%, 90% and 89% of the average cone density in the control group, respectively. Thus there was a subtle decline in the photoreceptor density and this study revealed structural alterations at the cellular level much before clinical DR manifested. 12 CSCR (Central serous chorioretinopathy) -Ooto and collaeagues used AOSLO to examine CSCR eyes with resolved subretinal fluid. Resolved CSCR have fewer cones per square mm than control subjects. They demonstrated this in patients with 20/20 or better visual acuity as well as in those with a preserved Inner Segment/Outer Segment (IS/OS) junction as seen on SD-OCT. Those patients with gaps in IS/OS junctions had further decline in the number of photoreceptors. Thus they demonstrated the subclinical loss of photoreceptors even after a single episode of CSCR, in patients who recovered excellent visual acuity. 13 Macular holes-Ooto and Hangai used AOSLO to study surgically closed macular holes and their correlation with pre-operative symptom duration and visual acuity. After standard 23 gauge 3-port vitrectomy, they observed large dark areas of photoreceptor loss, the sizes of which correlated with duration of pre-operative visual symptoms. The photoreceptor density was lower even in eyes with

Conflict of interest: None declared

maintained IS-OS junctions. Lower cone density correlated with poorer post-operative visual acuity. The dark areas corresponded to lower foveal sensitivities and thinner inner and outer segments. Darker areas on AO were larger in eyes with pre-operative cuff of fluid. AOSLO was thus valuable even in eyes with good anatomical closure seen on SD-OCT. This study gives insight into the possible pathogenesis of macular holes, which they suggest is formed by avulsion of focal neural tissue by antero-posterior traction. 14 Epiretinal membranes-the structural abnormalities underlying vision changes are not known in ERMs. Only ILM folds larger than 50 microns are detectable on SDOCT or colour fundus photographs. AOSLO has revealed microfolds 5-20 microns in size. A study has shown the correlation of metamorphopsia with these microfolds. Thus, AOSLO in patients of metamorphopisa with a normal looking fundus or a normal SDOCT may be able to provide evidence of structural abnormalities in the photoreceptor layer. 15 The pathophysiologic significance of paravascular opacification seen by AO may be either cellular infiltration or parietal thickening. AO imaging may even identify subclinical retinal vasculitis, which is not detected by ophthalmoscopy or Fundus Fluorescein Angiography. This may contribute to the diagnosis and workup of a variety of general inflammatory diseases. AO imaging may also contribute to a better understanding of the process leading to vascular occlusion, thereby helping to identify patients at risk of severe visual loss. Therefore, AO imaging may be a useful tool for the detection, early diagnosis, and management of retinal vasculitis. 16 Normal blood vessels are depicted in (Figure 3). Lamina Cribrosa-The number of pores in the lamina cribrosa has been seen to be larger and of better quality in AOSLO imaging than conventional (Figure 4). Pore area has also been studied and found to be larger in glaucomatous eyes. Thus, AOSLO is a useful imaging technology for assessing laminar pore number and area.

The laminar pore area may be affected by axial length and IOP. 17

Conclusion

Thus we see that AO has far-reaching clinical applications. However, the lengthy analyses and algorithms for image acquisition, montaging and processing and patient fixation problems are some established drawbacks of AO technology. Moreover, the cost makes it prohibitive for a clinical office setting. In spite of this, recent years have seen an explosion of data on the various applications of AO in clinical research and experimental ophthalmology. The quantitative measurement of cone density based on eccentricity from the fovea, its correlation with cone functionality based on micro-perimetry and its accurate agreement with histopathology, all the while being a non-invasive technique, makes it a formidable tool in the armamentarium of a clinical researcher. It can be used to test newer treatments and surgical methods and can be used for long term longitudinal monitoring. 18

Figure 4: AO image showing pores in the lamina cribrosa

Techniques