Anterior-segment spectral domain optical coherence tomography in epidermolysis bullosa
Introduction
Epidermolysis bullosa (EB) is a devastating connective tissue disorder that can lead to disfigurement, immobility, and blindness [1,2]. It is caused by genetic mutations affecting adhesion proteins that are critical for anchoring stratified squamous epithelium to underlying tissue [[3], [4], [5]]. Phenotypic expression involves blistering and poor wound healing, typically of the skin, ocular surface—including the cornea, conjunctiva, and lids— and the gastrointestinal and genitourinary tracts [6]. EB is classified as an orphan disease affecting an estimated 19.6 people per million in the United States [7].
Ophthalmic manifestations are most common in two EB subtypes known as recessive dystrophic EB (RDEB), caused by impaired type VII collagen function, and junctional EB (JEB), caused by absence of laminin 5 [8]. The precise incidences of complications in EB are not well established. Previous studies have reported a wide range: in RDEB, corneal blisters and erosions are estimated to occur in 35–74% of patients, scarring in 24–41%, and vision loss in 3–64% [[9], [10], [11], [12], [13], [14]]. In JEB, estimated incidences range from 24 to 80%, 14–80% and 0–33%, respectively. The third subtype, known as simplex (EBS), causes abrasions in fewer patients (up to 6%), yet vision loss still occurs in approximately 15% [1]. Standard management is lubrication and light avoidance [6]. Advanced therapies for those severely affected include bandage contact lenses to stabilize the corneal surface and autologous limbal epithelial cell transplant to promote epithelialization [15].
At present, numerous phase 1–2 clinical trials of disease-specific therapies are in progress. Standard endpoints for skin trials include changes in the surface area of discrete and active EB lesions, and biopsy-proven increases in anchoring fibrils [16,17]. To our knowledge, no non-surgical therapies are being developed for ophthalmic use. One critical hurdle for drug development is the inability to objectively show clinically meaningful disease modification. Without the ability to non-invasively “biopsy” the cornea, especially in children, subjective assessments such as visual acuity testing, interpretation of photographs, and slit-lamp examination remain the primary tool for assessment. Thus, there is a need for objective and reliable methods of quantifying and monitoring ocular surface pathology.
In the last three decades, optical coherence tomography (OCT) has revolutionized the practice of ophthalmology. Although OCT is most routinely used to image the posterior segment, anterior segment (AS) protocols allow high-resolution, depth-resolved imaging of the cornea [18,28,29,40]. As such, AS-OCT is a valuable tool for non-invasive assessment of corneal pathology[33,[37], [38], [39]]. To our knowledge, large studies of AS-OCT in EB patients have not been published.
Prior studies using animal models have shown that 89% (17/19) of EB-affected murine corneas are histologically different than wild-types [19]. Specifically, EB-affected mice show epithelial hyperplasia and stromal fibrosis. Thus, we hypothesized that EB patients would show thickening of both epithelium and stroma on AS-OCT when compared with age-matched controls. Furthermore, such increases in epithelial and stromal thickness would correlate with vision loss.
Herein, we describe the first use of AS-OCT to visualize EB-related corneal lesions. We generated a novel pathology grading system for EB lesions, based upon grading systems commonly used for retinal disease [20,21]. We also tested best corrected visual acuity (BCVA) and applied a short questionnaire tool to query corneal abrasion frequency, duration, pain severity, and onset and etiology of scarring and vision loss. Finally, we explored associations between AS-OCT findings and clinical metrics, including ocular symptoms and vision.
Section snippets
Methods
This study was approved by the Tufts Health Science Institutional Review Board (IRB) and adhered to the tenets of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act of 1996. Written informed consent was obtained for all subjects.
Results
We enrolled 63 EB patients and 28 controls at the conference (July 2018), and 35 age-matched controls at Tufts Medical Center (TMC) between April and July 2019. No patients were unable to be scanned due to physical limitations. After analysis of scan quality, we excluded one patient and three control subjects for excessive movement artifact and included 62 patients and 60 controls for final analysis. For analysis with both eyes (OU), one additional scan of the right eye from one patient was
Novel AS-OCT findings in EB
Our results demonstrate the ability of AS-OCT to visualize a range of EB-related corneal pathology, including quantitative assessment of anatomy and lesion dimensions. AS-OCT may be a valuable tool in monitoring corneal pathology in EB patients, including in longitudinal studies and future clinical trials. Our results confirmed the hypothesis that EB patients have thicker epithelium and stroma compared with controls. This difference is greatest in the inferior sectors where the cornea is often
Conclusions
Our findings support the hypothesis that ultrastructural changes occur in the corneas of patients with EB, like those seen in the hypomorphic mouse model. AS-OCT offers a non-contact method of corneal assessment that mirrors histology in animals (Fig. 4). This study demonstrates the utility of AS-OCT for imaging the cornea of EB patients and supports further development of this tool. As we work toward gene and protein therapies in mice, products that normalize histologic tissue in mice have the
Financial Support
This work was supported by the Children's Glaucoma Foundation (Boston, MA, USA), Research to Prevent Blindness (New York, NY, USA), the Macula Vision Research Foundation (West Conshohocken, PA, USA), the Massachusetts Lions Clubs (Belmont, MA, USA), the National Institutes of Health (grant number 5-R01-EY011289-31), the Air Force Office of Scientific Research (grant number FA9550-15-1-0473), the Champalimaud Vision Award (Lisbon, Portugal), the Beckman-Argyros Award in Vision Research (Irvine,
Declaration of competing interest
Dr. Chen reports grants from Children's Glaucoma Foundation, the Epidermolysis Bullosa Research Partnership, the Epidermolysis Bullosa Medical Research Foundation, and Research to Prevent Blindness, during the conduct of the study. Dr. Chen is a consultant for Phoenix Tissue Repair.
Dr. Duker reports grants from Carl Zeiss Meditech, grants from Optovue, is a consultant for Allegro, is a consultant for Allergan, is a consultant for Aura Biosciences, is a consultant for Beyeonics, is a consultant
Acknowledgements
We gratefully acknowledge William Binotti, PhD, post-doctoral fellow in the lab of Pedram Hamrah, MD, for his excellent idea of testing ETM in patients with EB. We also acknowledge Hong Chang, PhD, biostatistics, for his thoughtful analysis and clear explanations.
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