A Reflectivity Measure to Quantify Bruch's Membrane Calcification in Patients with Pseudoxanthoma Elasticum Using Optical Coherence Tomography

Abstract

Purpose: Progressive calcification of Bruch's membrane (BM) causes considerable visual morbidity in patients with pseudoxanthoma elasticum (PXE). Since calcification is hyperreflective on optical coherence tomography (OCT), our aim was to measure BM calcification with OCT imaging.

Methods: Case-control study with 45 patients with PXE under 40 years (range, 11-39) and 25 controls (range, 14-39). Spectralis HRA-OCT imaging consisted of seven macular B-scans with 250-µm spacing. Retinal segmentation was performed with the IOWA Reference Algorithms. MATLAB was used to extract and average z-axis reflectivity profiles. Layer reflectivities were normalized to the ganglion cell and inner plexiform layers. Both median and peak layer reflectivities were compared between patients with PXE and controls. The discriminative value of the retinal pigment epithelium (RPE)-BM peak reflectivity was analyzed using receiver operating characteristic analysis.

Results: The reflectivity profile of patients with PXE differed from controls in the outer retinal layers. The normalized median RPE-BM reflectivity was 41.1 (interquartile range [IQR], 26.3-51.9) in patients with PXE, compared with 22.5 (IQR, 19.3-29.5) in controls (P = 2.09 × 10^-3). The normalized RPE-BM peak reflectivity was higher in patients with PXE (67.5; IQR, 42.1-84.2) than in controls (32.7; IQR, 25.7-38.9; P = 2.43 × 10^-5) and had a high discriminative value with an area under the curve of 0.85 (95% confidence interval, 0.76-0.95). In patients with PXE under 40 years, increasing age did not have a statistically significant effect on the RPE-BM peak reflectivity (patients under 20 years: 44.2 [IQR, 40.5-74.6]; 20-30 years: 66.0 [IQR, 45.1-83.8]; 30-40 years: 70.8 [IQR, 49.0-88.0], P = 0.47).

Conclusions: BM calcification can be measured as increased RPE-BM reflectivity in young patients with PXE and has a high discriminative value.

Translational relevance: In patients with PXE, the OCT reflectivity of Bruch's membrane may be the first biomarker for Bruch's membrane calcification and a valuable ophthalmologic endpoint in clinical trials.

Keywords: Bruch's membrane; calcification; pseudoxanthoma elasticum; quantification; reflectivity.

Figure 1.

Reflectivity profiles of patients with PXE and controls. Averaged reflectivity profiles of patients with pseudoxanthoma elasticum (PXE) (n = 45) and controls (n = 25). The normalized reflectivity is plotted against the retinal depth. On the right side, the corresponding retinal layers are noted. The GCL-IPL layer was used as the reference layer for normalization. The fourth root of the normalized reflectivity was used for better visualization.

Figure 2.

Receiver operating characteristic curve. ROC curve of the RPE-BM peak reflectivity and RPE-BM median reflectivity (normalized to the GCL-IPL layer). Reflectivity values were averaged per person.

Figure 3.

The effect of age. RPE-BM peak reflectivity of patients with PXE and controls, plotted by their age category. The RPE-BM reflectivity is normalized to the GCL-IPL layer. The horizontal bars represent the median value, and the boxes represent the interquartile range. Per person, the reflectivity values were averaged. The number of patients per category is listed at the bottom of the figure.

Figure 4.

Within-eye and within-subject correlation. Within-eye (A) and within-subject (B) correlation of RPE-BM peak reflectivity of patients with PXE and controls. Within-eye correlation is measured with horizontally and vertically orientated OCT scans. For within-eye correlation, there were 101 comparisons for patients with PXE and 36 comparisons for controls. For within-subject correlation, there were 29 pairs of observation in patients with PXE and 19 pairs of observation in controls. The diagonal line represents the perfect correlation. In the top-left corner, the Spearman correlation coefficients (ρ) are shown for patients with PXE (black) and controls (gray).