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Neurotrophic Keratitis and Limbal Stem Cell Deficiency; Diagnostic Error Rates and Frequency of Disease Coexistence

Presenter:

John Affeldt

Authors:

John Affeldt 1, Tomi Luan 4, Susan Orr 4, Michael Straiko 2, Jennifer Nottage 3

1. Loma Linda University

2. Legacy Devers Eye Institute -Legacy Good Samaritan Medical Center

3. Midwest Eye Institute

4. Claris Biotherapeutics

Affiliation:

Purpose: To report diagnostic disagreement/error rates for neurotrophic keratitis (NK) and limbal stem cell deficiency (LSCD) between investigators and robust verification processes, and for the first time, their coexistence frequency.

Methods: Subjects (131) were enrolled in a prospective, randomized, masked, multi-center, vehicle-controlled US trial evaluating the safety and efficacy of topical ocular oremepermin-α (hepatocyte growth factor) for treatment for stage 2 and 3 NK. Enrollment was based on the Principal Investigator (PI)’s clinical diagnosis. NK diagnostic verification entailed a masked corneal central reading center (CRC)’s assessment of slit lamp white light and blue light (fluorescein stained and Wratten filter) images captured by study centers. PIs LSCD diagnosis was obtained from the Medical History Case Report Form. Verification of LSCD was performed by a three-member cornea specialist diagnostic verification panel (DVP) using the same images. NK and LSCD diagnoses by PIs was compared to the verification diagnoses.

Results: The CRC confirmed presence of stage 2 or 3 NK in 80% of enrolled subjects (n=105/131). Only 2% of subjects (3/131) were noted by PIs to have LSCD, while the DVP confirmed its presence in 38% (50/131). Combined CRC and DVP analysis verified coexistence of LSCD in 40% (42/105) of the verified stage 2 or 3 NK subjects compared to a PIs coexistence rate of 2% (3/131).

Conclusions: A significant NK diagnostic disagreement/error rate between PIs and CRC was identified in this study and a meaningful difference in LSCD diagnosis disagreement/error rate between PIs and the DVP was shown. A higher LSCD prevalence than previously appreciated was observed based on the DVP, as was an unexpected NK/LSCD coexistence frequency of 40%. The possibility of this disease inter-relationship was recently suggested in the literature but until now was not quantified by any large NK or LSCD study. These observations may reflect the relatively recent sense of community interest granted these two disorders and their admittedly confusing clinical presentation overlap. This data suggests a national gap in clinician diagnostic skills for these two rare diseases. Improved physician NK/LSCD diagnostic training has the potential to improve the accuracy of clinical trial data and real world patient outcomes.

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