This is a NON-coverage policy for all corneal hysteresis assessments as a
means of risk assessment or monitoring for progression of ophthalmic disease
activity.

Hysteresis is a measure of resistance to deformation to an applied force.
Corneal hysteresis (CH) is a measure of the viscoelastic dampening property of
the cornea and is postulated to be a surrogate for the viscoelastic dampening
properties of the posterior sclera and lamina cribrosa through which the
retinal ganglion cell axons pass as they exit the eye. It has been theorized
that glaucomatous damage to the retinal ganglion cell axons occurs at the
lamina cribrosa and that viscoelastic differences in the lamina cribrosa are
responsible for differential effects of intraocular pressure within these
tissues and contribute to the susceptibility to intraocular pressure
(IOP)-mediated damage. Studies show an association between a lower CH and
glaucoma or glaucoma risk, and it has been proposed as a risk stratification
tool for use in the treatment of glaucoma, glaucoma suspect, and ocular
hypertension. CH is not itself a modifiable risk factor for glaucoma, but
theoretically could signal the need for more aggressive IOP reduction.

The Ocular Response Analyzer (ORA) (Reichert Inc., Buffalo, New York, USA) is
a non-contact tonometer that measures CH. The ORA received FDA 510(k)
clearance in 2004 for the intended use of measurement of intraocular pressure
and biomechanical response of the cornea "for the purpose of aiding in the
diagnosis and monitoring of glaucoma (1)." This device measures CH by
measuring the difference of two applanation event pressures taken during the
inward and outward movement of the cornea following delivery of a metered
pulse of air.

A 2006 retrospective, observational study compared CH and central corneal
thickness (CCT) on various indices of glaucomatous damage in 230 patients
(mean 65 years), 85% diagnosed with primary open angle glaucoma (POAG) or
glaucoma suspect, and 15% with angle-closure glaucoma, suspected angle-closure
glaucoma, or secondary glaucoma (2). Multivariate analysis found CCT, but not
CH to be predictive of higher cup-to-disk ratio (CDR) (P=0.02 vs P=0.36).
Multivariate analysis found lower CH but not CCT to be predictive of visual
field progression (P = 0.30), but not after factoring in axial length (P =
0.09). Neither CH nor CCT were significantly associated with worsening mean
deviation (MD) or pattern standard deviation (PSD). A 2011 prospective
observational study of 162 POAG subjects found no statistical difference in CH
compared with 150 normal subjects (3). A small (57 patients), 2012
retrospective study found both CH and IOP to be independent, statistically
significant predictors of response to topical prostaglandin treatment (4).

A 2012 prospective cohort study of 153 patients (153 eyes) with established
glaucoma evaluated the relationship between CCT and CH and their correlation
with progressive visual field (VF) loss (5). Baseline measurements included
age, race, sex, CH, MD, PSD, CCT, and IOP (calculated by averaging the first 4
measurements following the baseline VF), peak IOP, and corneal compensated IOP
(IOPcc). Progression of glaucoma was determined by an automated pointwise
linear regression analysis of visual field tests. Progression occurred in 25
enrolled eyes (16%) and demonstrated significantly lower CCT and CH compared
with non-progressed eyes (p=0.04 and p<0.01, respectively). There was
significant correlation between CH and CCT (r=0.33, P<0.01). After
multivariate analysis, peak IOP, age, and CH were demonstrated to be
significantly associated with glaucomatous visual field progression. The
authors conclude that "as CH may describe corneal properties more completely
than thickness alone, it may be a parameter that is better associated with
progression." However, of the 25 subjects that demonstrated glaucomatous
progression, 9 had either secondary glaucoma, juvenile glaucoma, or angle
closure glaucoma. No subgroup analysis was performed. Other confounders
include the use of CH measurements obtained during a non-standardized episode
in the care continuum (not at baseline), as well as the non-standardized
treatment and follow-up (provider discretion) protocol.

A 2013 retrospective study of 131 glaucoma patients investigated the
correlation between CH and other structural markers of glaucomatous damage on
spectral domain optical coherence tomography (SDOCT) (6). In a multivariable
analysis including MD, age, average retinal nerve fiber layer (RNFL)
thickness, and glaucoma status, only MD (p = 0.001) and age (p < 0.001)
retained significant associations with CH. The authors conclude that "in
patients under evaluation and treatment for glaucoma, CH was more closely
related to visual field MD than to structural markers of glaucoma damage as
measured by SDOCT."

A 2017 cross sectional study compared single CH measurements among 123
patients (123 eyes) previously diagnosed with either glaucoma (high tension
glaucoma, N=37; pseudoexfoliative glaucoma, N=12; normal tension glaucoma,
N=24), ocular hypertension (OHT) (N=28), or glaucoma-like optic discs (GLD)
(N=22) (7). A One-way Analysis of Covariance (ANCOVA), correcting for
differences in age and IOP, found mean CH to be significantly lower in
patients with glaucoma versus those with OHT and GLD (p < 0.001). The authors
hypothesize there may be greater viscoelasticity in ocular tissues of GLD and
OHT which may have a protective role against glaucomatous nerve damage.

The following four studies by the same principal investigator included
subjects who were part of the larger Diagnostic Innovations in Glaucoma Study
(DIGS) (8-11). DIGS is a single-center, prospective, longitudinal cohort study
of the relationships between optic nerve structure and glaucomatous vision
loss, and to assessment of new diagnostic and monitoring modalities that could
be used to mitigate functional vision loss by identifying at-risk patients
through earlier detection and intervention.

A 2012 observational cross-sectional study of the association between CH and
severity of glaucoma, as defined by automated visual field deficits and RNFL
thickness, among 299 eyes in 191 glaucoma or glaucoma suspect patients (8). In
multivariable regression models, after adjusting for central corneal
thickness, age, and axial length, the relationship of CH to RNFL thickness was
not statistically significant. The authors conclude they found only "a weak
relationship between corneal biomechanical parameters and measures of
structural and functional damage in glaucoma."

A 2013 prospective, observational study looked at the relationship between
baseline CH and visual field progression in 68 patients (114 eyes) with
confirmed diagnosis of open angle glaucoma (9). CH measurements were obtained
at the baseline study visit. Subjects underwent baseline and every 6 month
follow-up examinations which included examination and assessment of Goldmann
applanation tonometer (GAT) IOP, CCT, Humphrey visual field, stereoscopic disc
photos, and axial length measurements. Treatment was uncontrolled and at the
discretion of the treating physician. Subjects were followed for an average of
4 years (range, 2.0-6.6 years), during which visual fields were assessed for
evidence of progression using the visual field index (VFI) method. Univariable
analysis found that each 1 mmHg lower baseline CH was significantly associated
with a 0.25%/year faster rate of visual field progression (p<0.001). The
multivariable model showed an interaction between IOP and CH; eyes with high
IOP and low CH were at increased risk for having fast rates of disease
progression. CH explained a larger proportion of the variation in VFI change
than CCT (17.4% vs. 5.2%, respectively). The authors conclude: "The
prospective longitudinal design of this study supports the role of CH as an
important factor to be considered in the assessment of the risk of progression
in glaucoma patients."

In a 2016 prospective, observational cohort study, the relationship between CH
and progressive loss of the retinal nerve fiber layer (RNFL) was analyzed in
133 patients (186 eyes) with confirmed diagnosis of open angle glaucoma (10).
CH measurements were obtained at the baseline study visit. Subjects underwent
baseline and every 6 month follow-up examinations which included examination
and assessment of GAT IOP, CCT, Humphrey visual field, stereoscopic disc
photos, and circumpapillary retinal nerve fiber layer thickness measurements
with the spectral domain optical coherence tomography (SD-OCT). Treatment was
uncontrolled and at the discretion of the treating physician. Subjects were
followed for an average of 3.8 years (range, 2.0-5.2 years) during which time
average circumpapillary RNFL thickness measurements and stereodisc photos were
assessed for evidence of glaucomatous progression. Univariable analysis found
that each 1 mmHg lower baseline CH was significantly associated with a 0.13
um/year faster loss of RNFL (p = 0.011). In multivariable analysis adjusting
for age, race, average GAT IOP and CTT, CH was still associated with a faster
rate of RNFL loss (p=0.015). The authors conclude that "the prospective
longitudinal design of this study supports a role for CH as a risk factor for
progression in glaucoma." Both the Medeiros and Zhang studies were small and
confounded by the fact that treatment was not controlled. Though findings were
suggestive, the use of a complex regression model that was not clearly
developed from a-priori hypothesized relationships and not validated following
development do not allow firm conclusions about the generalizability of the
results.

A 2018 prospective, observational study investigated the predictive role of CH
as a risk factor for the development of glaucoma in a cohort of glaucoma
suspect patients (11). The study included 199 patients (287 eyes) recruited
from a single site. Treatment for glaucoma suspect was uncontrolled and
subject to discretion of the treating physician. Baseline measurements
included CH, GAT IOP, CCT, Humphrey visual field, and stereoscopic disc
examination. Subjects were examined every six months for an average follow-up
period of 3.9 years during which time glaucoma developed in 19% of enrolled
eyes (54 eyes in 48 patients). Baseline CH and age was significantly lower in
those who developed glaucoma vs those who did not (9.5 1.5 mm Hg vs. 10.2
2.0 mm Hg; p = 0.012). Baseline MD and PSD were significantly different
between the two groups. CH was found to be predictive of glaucoma development
in a multivariable model (hazard ratio = 1.20; 95% CI: 1.01-1.42; p = 0.04),
while baseline IOP, CCT, and treatment were not. Each 1 mmHg lower CH was
associated with a 21% increase in risk of glaucoma development (95% CI
1.04-1.41; p = 0.013). The authors acknowledged that "because the impact of
CCT on risk of glaucoma development is now widely known, it is likely that
physicians may have treated more aggressively eyes of glaucoma suspects who
had thin corneas, also artificially reducing the impact of CCT as a predictive
factor," and that, "the higher predictive value of CH compared to CCT in our
study should be seen with caution." Additionally, the multivariable analysis
included only some of the known risk factors of glaucoma development,
specifically, age, IOP, CCT, PSD, and treatment, but excluded others such as
race, family history, and optic disc morphology (CDR). The authors conclude
that "future studies including randomization protocols controlling for
treatment should be performed to clarify the relative importance of these
predictive factors."

A 2017 meta-analysis included 19 studies that assessed CH in 1213 eyes with
glaucoma and 1055 healthy eyes (12). Mean CH was 1.5 mm Hg lower, and mean CCT
8.5 micrometer less thick, in eyes with glaucoma (P < 0.0001 and P < 0.001,
respectively). The authors conclude that there are differences in corneal
properties such as CH and CCT between patients with glaucoma and healthy
controls "and support further studies on the influence of CH and CCT in
glaucoma screening and diagnosis." In a 2018 prospective cross-sectional study
of CH as a potential glaucoma screening tool in 46 patients (76 eyes) on
routine eye exam, the 21 eyes (27.6%) found to have normal tension glaucoma
(NTG) did not differ statistically in CH (P = 0.19) (13).

A limited body of evidence suggests there may be a role in the application of
CH in the identification of corneal pathology or in preoperative assessment
prior to refractive surgery. A 2007 study first described a statistically
significant difference in the mean CH of 207 normal and 93 keratoconic eyes
(10.7 + 2.0 mmHg vs. 9.6 + 2.2 mmHg; p<0.0001) (14). The study also revealed
that CH values in the keratoconic eyes decreased with increasing severity of
disease, though could not differentiate between eyes with mild keratoconus and
normal controls. A subsequent study similarly found poor overall predictive
accuracy for CH to detect mild keratoconus from age- and gender-matched
controls (15). A 2011 study investigated the ability of the ORA parameters to
aid in diagnosis of keratoconus in preoperative laser in situ keratomileusis
(LASIK) patients (16). Biomechanical measurements were acquired from 103 eyes
with mild keratoconus and 97 control eyes and 12 parameters were analyzed.
Though sensitivity and specificity of the parameters was low (66% and 67%,
respectively, for CH), the authors concluded that some parameters offered high
negative likelihood ratios and should be studied in a larger sample size.



Neither the current (2015) nor most recent updates (2017) to the American
Academy of Ophthalmology (AAO) Preferred Practice Pattern (PPP) guidelines for
glaucoma recommend measurement of CH in the management or risk assessment of
glaucoma, glaucoma suspect, or ocular hypertension (17-19). Similarly, the
Canadian Association of Optometrists (CAO), notes that "despite the
association between CH and glaucoma onset and progression, there is still a
paucity of clinical evidence to support adding CH measurement to the standard
glaucoma workup (20). The AAO PPP 2018 guidelines for corneal ectasia concede
that while measures of corneal biomechanics, including CH, are likely altered
in corneal ectasia, the parameters for use in the detection at the subclinical
stage is currently being evaluated (21).

A 2018 Hayes review of 16 qualifying studies found that CH testing has some
capacity to detect presence of glaucoma, to predict risk for glaucoma
progression, and to predict response of glaucoma to certain types of treatment
(22). However, "the evidence is mainly comprised of very poor quality
correlation studies, which lack the rigor to determine diagnostic or
prognostic accuracy. Most of these studies did not use reliable methods to
determine the accuracy of diagnosis or prognosis. No studies were identified
that directly assessed the clinical utility of CH measurement for selecting
treatment for glaucoma or for impacting long-term health outcomes." This
perspective was also reflected in the one recent meta-analysis; although CH
was correlated with glaucoma, there were no findings related to the use of CH
for the prognosis, diagnosis, or management of glaucoma (12).

In summary, CH is promising as a risk assessment tool in the diagnosis and
management of glaucoma or corneal pathology. However, while the body of
evidence is large, the overall quality is low. The studies are relatively
small, observational, often confounded by lack of treatment control, uniformly
citing simple correlations, precluding cause-and-effect conclusions. Not only
are there no Level I studies, none of the reviewed studies demonstrate that CH
measurement alters clinical management and improves clinical outcomes. A wide
array of tests are accepted for detection and monitoring of glaucoma
(tonometry for IOP, perimetry to assess visual field, ophthalmoscopy to detect
a glaucomatous optic nerve head (ONH) and RNFL changes, and pachymetry for
CCT). It is still unclear whether CH provides useful additional information,
much less its optimal role in any diagnostic, prognostic, and treatment
algorithm. Randomized controlled trials (RCTs) that compare outcomes in
patients whose treatment is selected based on CH are needed to determine
definitive patient selection criteria and clinical utility. The lack of level
I evidence, absence of proven clinical utility, no clinical practice guideline
endorsement (18-20, 23), as well neither Medicare (24-27) nor commercial
(28-30) coverage, argue strongly against current CH coverage as reasonable and
necessary for treatment of Medicare patients.