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Subspecialties Cornea / Ocular Surface, Imaging & Diagnostics, Business and Innovation

CFS: It’s a Numbers Game

First popularized in the mid-1990s, ocular image grading scales have long been established as valuable tools for judging the severity of ocular disease. But how do they work? The most commonly-used grading scales contain images (photographs or illustrations) that practitioners use to compare against their patient’s eye. The practitioner then determines the severity based upon the defined scale with higher numbers typically representing more serious disease. Although an initial study (2) suggested that using grading scales with finer increments (for example, 0.1 units) would improve the sensitivity of a scale, a later study found that investigators had a tendency to grade in whole and half unit increments, even when given the opportunity to use smaller units (3).

Corneal fluorescein staining (CFS) is a key clinical sign of corneal surface integrity and clinical trial endpoint for patients with conditions such as dry eye disease (DED). Although numerous CFS grading scales exist, the NEI corneal grading scale provides additional grading detail, evaluating five regions of the cornea as opposed to just one. And that has cemented the NEI corneal grading scale as the most frequently used CFS scale in DED clinical trials (7).

The NEI corneal staining scale was introduced in 1995 as a product of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye (4). This workshop included a group of international experts who wrote a consensus report on the topic to help standardize the first definition of DED and the metrics used to evaluate it. The original NEI corneal grading scale uses a 0 to 3 integer grading scale for each eye across five corneal regions (central, inferior, superior, temporal, nasal); the width of each of these regions is about one third of the corneal diameter. A total NEI corneal staining scale score is obtained by adding the five regions together, resulting in a 0 to 15 scale – with 15 being the worst possible grade (4). Clinical trials frequently use a score of ≥2 units in any corneal region as a trial inclusion criteria (5). When performing this evaluation, sodium fluorescein should not be applied in excess because dye quenching may occur (reduction in fluorescent efficiency/brightness) (6), and grading should happen at a defined time point (for example, two-minute post-application) to decrease test-to-test variability (7). Although the original NEI corneal staining grading scale was an advancement for the field, it was graded based upon gestalt, which is challenging for multicenter clinical trials that include numerous investigators.

With this known issue, investigators have since developed more descriptive grading options, which include the Dot Count NEI staining scale and the Lexitas modified NEI staining scale (8). The Dot Count NEI staining scale still uses a 0 to 3 grading scale, though scores of 0, 1, 2, and 3 correspond to 0, 1-15, 16-30, and ≥31 dots while the Lexitas modified NEI staining scale breaks the Dot Count NEI staining scale system into half step increments and expands this scale to a 0 to 4 scale (see Table 1). The Lexitas modified NEI staining scale furthermore provides additional grading details. The Lexitas modified NEI staining scale subsequently allows greater grade granularity while also likely making it easier for multiple investigators to arrive at consistent grades across sites and over the life of a clinical trial.

A recent study validated the repeatability of the Lexitas modified NEI staining scale in conjunction with the other two noted versions of the NEI staining scale (8). The researchers determined that there was a high degree of inter- and intra-examiner repeatability for all three of the NEI staining scales evaluated. The same result was established when the investigators were asked to grade illustrations or clinic sourced images. Despite these findings, one caveat of this study was that it only used trained expert practitioners for grading. As highlighted in previous studies, trained eye care practitioners provide more reliable grades than non-eye care practitioners (9).

Though there exists a plethora of ocular surface grading scales, the NEI staining scale is one of the most accepted options available for evaluating the cornea. Although the most used versions of the NEI staining scale are all highly repeatable, the Lexitas modified NEI staining scale is arguably the best option currently available because of its highly descriptive grading instructions and because of its expanded grading scale. We would suggest it should be seriously considered for use in future studies.

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  1. N Efront et al., “Validation of grading scales for contact lens complications,” Ophthalmic Physiol Opt, 21, 17 (2001). PMID: 11220037.
  2. I L Bailey et al., “Clinical grading and the effects of scaling,” Investig Ophthalmol Vis Sci, 32, 422 (1991). PMID: 1993595.
  3. J S Wolffsohn et al., “TFOS DEWS II Diagnostic Methodology report,” Ocul Surf, 15, 539 (2017). PMID: 28736342.
  4. M A Lemp, “Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes,” CLAO J, 21, 221 (1995). PMID: 8565190.
  5. K K Nichols et al., “A Comprehensive Review of the Clinical Trials Conducted for Dry Eye Disease and the Impact of the Vehicle Comparators in These Trials,” Curr Eye Res, 46, 609 (2021). PMID: 33238774.
  6. J J Nichols et al., “The use of fluorescent quenching in studying the contribution of evaporation to tear thinning,” Investig Ophthalmol Vis Sci, 53, 5426 (2012). PMID: 22789918.
  7. C G Begley et al., “The effect of time on grading corneal fluorescein and conjunctival lissamine green staining,” Ocul Surf, 25, 65 (2022). PMID: 35568371.
  8. K Sall et al., “Validation of a Modified National Eye Institute Grading Scale for Corneal Fluorescein Staining,” Clin Ophthalmol, 17, 757 (2023). PMID: 36915716.
  9. N Efron et al., “The combined influence of knowledge, training and experience when grading contact lens complications,” Ophthalmic Physiol Opt, 23, 79 (2003). PMID: 12535060.
About the Authors
Andrew D. Pucker

Andrew D. Pucker, OD, PhD, FAAO is the Sr. Director of Clinical and Medical Sciences at Lexitas Pharma Services. He earned his OD, MS, and PhD degrees from The Ohio State University, and he is the former director of the UAB Eye Care Myopia Control Clinic. He has received research or consulting support from Alcon Research, LLC, Art Optical, Haymarket Media, Inc, and Hanall Biopharma in the past year.

George Magrath

George Magrath, MD, is Chief Executive Officer of Lexitas Pharma Services. He is a trained ocular oncologist, balancing his role as CEO with treating patients with rare eye conditions at the Medical University of South Carolina. He has both an extensive medical and business background. While learning his craft with an internship in general surgery, a residency in ophthalmology at the Medical University of South Carolina, and a fellowship in ocular oncology at Wills Eye Hospital in Philadelphia, he also branched out into the business world with an MBA from The Citadel and Masters in Applied Economics from Johns Hopkins University. His dual role gives him a unique, 360-degree insight into the opportunities and challenges for ophthalmic drug development and the clinical trials industry.

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