Author: Alessandro Arrigo (Italy)
Co-authors: Maurizio Battaglia Parodi, Emanuela Aragona, Francesco Bandello, Robert E MacLaren
Choroideremia (CHM) is a X-linked inherited retinal dystrophy characterized by a progressive centripetal chorioretinal degeneration. Although the main alterations can be detected at the level of of the outer retina and the retinal pigment epithelium (RPE), an intriguing pathogenic hypothesis suggested Müller cells might also provide a primary site of pathogenesis. Müller cells represent a transretinal cytotype included between the internal limiting membrane (ILM) and the external limiting membrane (ELM), which are direct extensions of the Müller cell’s structure. ILM can be poorly visualized on structural optical coherence tomography (OCT), whereas ELM is easily detected. The main goal of the present study is to quantitatively investigate ELM and outer retinal features in order to assess if ELM could be considered a useful biomarker to monitor the evolution of CHM.
Clinical setting; Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, via Olgettina 60, Milan (Italy).
The study was designed as prospective, observational, case series, with at least two years of follow-up. Patients affected by CHM, confirmed by the genetic assessment of CHM gene mutation, were recruited. For the quantitative comparisons, we included also a cohort of healthy age- and refractive-matched male subjects. All the eyes underwent complete ophthalmologic examinations including best-corrected visual acuity (BCVA) measurement and multimodal imaging assessment. The main outcome of the study was the measurement of thickness and reflectivity of ELM changes over the follow-up. Secondary outcome included the relationship with atrophy progression as assessed on enface OCT and fundus autofluorescence (FAF). Additional investigations regarded the relationship between ELM features and OCT angiography (OCTA) findings. We separately considered the modifications detected in the following three regions: 1) partially preserved islet (PPI); 2) region of the partially preserved islet evolving to atrophy over the last follow-up; 3) region surrounding the borders of the partially preserved islet. The statistical analysis was performed comparing baseline vs last follow-up data.
We included 16 CHM eyes (mean age 39±14 years; LogMAR BCVA 0.0±0.0) and 20 controls (mean age 40±10 years; LogMAR BCVA 0.0±0.0). The mean follow-up was of 3.5±1.4 years. ELM thickness always resulted lower than controls (p<0.01), whereas ELM reflectivity was not statistically different compared to controls (p>0.05). Interestingly, ELM thickness and ELM reflectivity of the borders evolving towards atrophy resulted significantly worse than PPI (p<0.01). OCTA showed preserved superficial capillary plexus and significantly impaired deep capillary plexus in CHM. Regarding the choriocapillaris (CC), we found three different regions. The first region corresponded to the PPI, with CC vessel density (VD) resulting preserved (p>0.05). The second region corresponded to the CC surrounding and extending beyond the borders of the PPI, showing significantly lower VD at baseline (p<0.01) but resulting stable at the last follow-up (p>0.05). The third region was represented by the CC of the PPI undergoing atrophic changes at the last follow-up. This region showed significantly reduced CC VD at baseline, compared to the rest of the PPI (p<0.01) and did not show significant changes over the follow-up (p>0.05). The correlation analyses showed a significant negative association between retinal atrophy progression and both ELM reflectivity and ELM thickness (p<0.01).
The ELM is formed by the apical processes of Müller cells attached to the inner segments of the photoreceptor cells. Both Müller cells and photoreceptors have been implicated in the complex pathogenesis of CHM. In the present study, we showed ELM as a useful quantitative biomarker of CHM evolution. Our results reported significant ELM thinning and reflectivity reduction in CHM eyes compared to healthy controls. ELM changes were more pronounced in those retinal regions undergoing atrophic expansion, and well correlated with the progression of atrophy. Furthermore, the detailed quantitative evaluation of outer retinal changes allowed to detect three significantly different CC regions. Although limited by the relatively low number of eyes, our findings might have useful implications both for disease monitoring and for the optimization of gene therapy administration.