Abstract
Purpose.:
To investigate the value of multimodal confocal scanning laser ophthalmoscopy (cSLO) for phenotyping fundus lesions in patients with pseudoxanthoma elasticum (PXE) and to correlate these findings with morphologic alterations detected by spectral domain optical coherence tomography (SD-OCT).
Methods.:
Imaging was performed with a combined SD-OCT-cSLO system (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). OCT scans were placed at locations of interest on near-infrared (NIR) reflectance, fundus autofluorescence (FAF), and fluorescein angiography (FA) images. The instrument allowed for exact topographic correlation of findings on OCT and cSLO images.
Results.:
NIR reflectance imaging showed the highest sensitivity to detect angioid streaks and peau d'orange compared to FAF or FA. On OCT scans, angioid streaks reliably showed breaks in Bruch's membrane. Peau d'orange was associated with alternating reflectivity within Bruch's membrane. Characteristic mid-peripheral chorioretinal atrophies showed hyporeflective spaces involving the outer neurosensory retina. In eyes with pattern dystrophy like alterations, subneurosensory accumulation of material was observed within areas of increased FAF.
Conclusions.:
SD-OCT in combination with cSLO imaging using NIR light locates the primary pathologic formations of angioid streaks and peau d'orange in Bruch's membrane. NIR reflectance imaging may be superior for detecting PXE-related fundus lesions at the level of Bruch's membrane, because the blue laser light that is used in FAF and FA is markedly absorbed by the pigment epithelium and therefore may only detect alterations if this cell layer is also affected. The findings indicate that multimodal cSLO and SD-OCT imaging of the outer retina allows for screening of PXE related retinal alterations.
Pseudoxanthoma elasticum (PXE) is a rare systemic disease mainly affecting the cardiovascular system, skin, and eyes with a variable phenotype.
1,2 The disorder with a prevalence estimated to be 1 in 25,000 to 100,000 is a consequence of mutations in the
ABCC6 gene.
3 Progressive fragmentation and calcification of elastic fibers in connective tissue result in pathologic changes most pronounced in the dermis, Bruch's membrane, and blood vessels.
1,2 Characteristic lesions at the fundus are angioid streaks, peau d'orange, secondary choroidal neovascularization, diffuse chorioretinal atrophy, and chorioretinal atrophic spots in the midperiphery, often with comet tails pointing toward the posterior pole.
1,2 Fundus lesions similar to those observed in pattern dystrophies have also been described.
4 So far, phenotypic investigation has been based mainly on standard imaging methods such as ophthalmoscopy and fundus photography.
2 However, fundus autofluorescence (FAF) imaging was recently found to reveal characteristic changes in patients with PXE.
5,6 Other topographic fundus imaging modalities such as near-infrared (NIR) reflectance have never been used, and the relative value of specific imaging modalities for phenotyping retinal lesions in PXE remains unknown. It also remains to be determined whether such multimodal fundus imaging allows sensitive detection and characterization of fundus lesions in PXE.
Histologic studies of fundus changes due to PXE are rare, and the underlying histologic alterations of such fundus lesions remain largely unknown.
7–12 High-resolution spectral domain optical coherence tomography (SD-OCT) has recently become available and offers a quasi histologic assessment of the posterior ocular fundus in vivo.
13–15 Systems combining SD-OCT with a confocal scanning laser ophthalmoscope (cSLO) allow simultaneous recordings of cross-sectional OCT images with various topographic imaging modes such as NIR reflectance, FAF, and fluorescein angiography (FA) of the cSLO. Exact alignment of the SD-OCT scans with the topographic cSLO images permits to correlate quasi in vivo histology with pathologic features observed on FAF, reflectance, and angiography images.
The purpose of this study was to investigate PXE-related fundus lesions using multimodal cSLO imaging and to study whether SD-OCT reveals underlying morphologic alterations that are detected by specific topographic fundus imaging modalities.
Fifty-six eyes of 28 patients (8 male and 20 female patients) with fundus abnormalities due to PXE were investigated. All patients were seen in the outpatient clinic at the Department of Ophthalmology, University of Bonn, which is a tertiary PXE-referral center in Germany. The diagnosis of PXE was positively confirmed by a skin biopsy, genetic analysis, or characteristic funduscopic pathologic changes in combination with further systemic manifestations typical for PXE.
All patients underwent a complete ophthalmic examination, including best corrected visual acuity, indirect ophthalmoscopy, fundus photography (FF450; Carl Zeiss Meditec, Jena, Germany), and combined cSLO and SD-OCT imaging (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany).
The study was in compliance with the tenets of the Declaration of Helsinki, and informed consent was obtained from every patient.
The cSLO unit of the Spectralis HRA-OCT is similar to the widely used HRA2 (Heidelberg Engineering, Heidelberg, Germany) and uses an optically pumped solid state laser source to generate the blue light excitation wavelength of 488 nm for FA and FAF images. Recorded emission wavelengths are limited by a barrier filter to wavelengths between 500 and 700 nm. A diode laser source of 820 nm wavelength is used for NIR reflectance recordings. With confocal image acquisition, light from a conjugate plane of interest is detected by the image sensor, permitting suppression of light from planes anterior and posterior to the plane of interest and resulting in high-contrast fundus images.
The high-resolution SD-OCT has a 7-μm optical depth resolution and a 14-μm lateral optical resolution. The system acquires 40,000 A-scans per second. In the present study, the B-scan angle was set to 30° with 768 A-scans per B-scan, resulting in a lateral resolution of 11 μm/pixel and a scan rate of 50 B-scans per second.
Using automated eye tracking and image alignment based on cSLO images, the software allows averaging a variable number of single images in real time (ART, [Automatic Real Time] Module; Heidelberg Engineering). The OCT B-scan is then repositioned in the moving eye and thus stabilized and frozen at the selected retinal location. The software computes and compensates for movements between single B-scan images caused by eye movements. Averaging live B-scans improves the signal-to-noise ratio and therefore enhances image quality with increased B-scan contrast and detail.