Keratoconus and Cross-linking

Seeking consensus on disease progression in keratoconus. Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

Atighter definition of “progressive keratoconus” is needed to allow clinicians to better plan treatment strategies for affected patients and facilitate the metaanalysis of data, Ingemar Gustafsson MD, PhD told delegates at this year’s hybrid conference.

“It is difficult to perform a meta-analysis if we do not know how to define progressive keratoconus. This has also been suggested by the Cochrane Institute in a study in 2015 that stated the efficacy of corneal cross-linking in halting disease progression is very low, in part due to how we diagnose progressive disease. This lack of consensus could reduce the speed at which evidencebased protocols are implemented in clinical practice,” he said.

The current absence of consensus is not purely a theoretical issue and can have a very real impact on everyday clinical practice, Dr Gustafsson explained. For instance, the lack of robust evidence-based results for corneal cross-linking (CXL) appears to have contributed to the late approval of CXL for the treatment of keratoconus in the United States.

“The Food and Drug Administration (FDA) approved corneal cross-linking in 2016, but this decision appears to be based less on hard data and more on a lack of treatment options,” he said.

Keratoconus progression is usually determined by comparing the results of corneal tomographic measurements on different occasions. However, one reason it is difficult to define progression in terms of changes in magnitude—for example, an increase of Kmax of 1.0 D—is the incongruences in results between scientific investigations, Dr Gustafsson pointed out.

“We believe this is due to the association between measurement error and disease severity. We have demonstrated this in a published study last year that showed there is a five-times difference in the repeatability between the mildest and the more advanced keratoconus,” he told EuroTimes.

Another issue is almost all research on repeatability is performed intra-day (within the same day), while progression is defined over time (between clinical visits).

“This is rarely considered,” Dr Gustafsson explained. “We performed an inter-day assessment (i.e., on different days) and concluded it makes quite a difference if we compare one measurement against another single measurement or if we compare a mean of replicates against another mean of replicates. This needs to be accounted for. We also suggest limits at which we can detect progression for patients with stage 1 and 2 keratoconus as defined on the Amsler-Krumeich classification system.”

Dr Gustafsson’s studies also suggest the Belin ABCD keratoconus Progression Display—integrated into the standard Pentacam software—appears to have the same stratification-limit need at which progression is detected for the A (anterior) and C (minimal corneal thickness) parameters.

“With the exception of mild keratoconus, the ABCD Progression Display could overdiagnose keratoconus as progressive, at least according to our data,” he said.

In the future, Dr Gustafsson invited colleagues to carry out their own investigations using the same methodology.

“If our research is reproduced, then perhaps we could at least find limits on which we all can agree. Ultimately, a consensus on which parameters should be used may be less important than understanding the repeatability and the dynamics of the parameters used and designing the investigation accordingly,” he concluded.

Photo credit Tove Smeds

Ingemar Gustafsson MD, PhD, conducts clinical research at Lund University in Sweden. Ingemar.gustafsson@med.lu.se