1. Aetna considers the ocular blood flow tonometer, which has been used in the screening, diagnosis, and monitoring of glaucoma, experimental and investigational because there is a lack of evidence in the peer-reviewed published medical literature proving that measurement of pulsatile ocular blood flow significantly improves outcomes by enhancing the screening, diagnosis or management of glaucoma.

2. Aetna considers the ocular Blood Flow Analyzer (BFA) experimental and investigational for screening, diagnosis and monitoring of glaucoma and for all other indications because of insufficient evidence of its effectiveness.

3. Aetna considers measurement of corneal hysteresis experimental and investigational for the screening, diagnosis and monitoring of glaucoma and for all other indications because of insufficient evidence of its effectiveness.

4. Aetna considers genotyping for the screening, diagnosis and monitoring of glaucoma experimental and investigational because of insufficient evidence of its effectiveness.

Glaucoma is a leading cause of blindness, affecting over 60 million people worldwide.  Open-angle glaucoma, the most common subtype of the disease, affects over 2.5 million people in the United States.  On behalf of the American Academy of Ophthalmology, Jampel et al (2011) reviewed the published literature to summarize and evaluate the effectiveness of visual function tests in diagnosing glaucoma and in monitoring progression.  Literature searches of the PubMed and Cochrane Library databases were conducted last on May 7, 2010, and were restricted to citations published on or after January 1, 1994.  The search yielded 1,063 unique citations.  The first author reviewed the titles and abstracts of these articles and selected 185 of possible clinical relevance for further review.  The panel members reviewed the full text of these articles and determined that 85 met inclusion criteria.  They conducted data abstraction of the 85 studies, and the panel methodologist assigned a level of evidence to each of the selected articles.  One study was rated as level I evidence.  The remaining articles were classified broadly as providing level II evidence.  Studies deemed to provide level III evidence were not included in the assessment.  Standard white-on-white automated perimetry remains the most commonly performed test for assessing the visual field, with the Swedish interactive threshold algorithm (SITA) largely replacing full-threshold testing strategies.  Frequency-doubling technology and its refinement into Matrix perimetry, as well as short-wavelength automated perimetry, now available with SITA, have been evaluated extensively.  Machine learning classifiers seem to be ready for incorporation into software to help distinguish glaucomatous from non-glaucomatous fields.  Other technologies, such as multi-focal visual-evoked potential and electro-retinography, which were designed as objective measures of visual function, provide testing free of patient input, but issues prevent their adoption for glaucoma management.  The authors concluded that advances in technology and analytic tools over the past decade have provided us with more rapid and varied ways of assessing visual function in glaucoma, but they have yet to produce definitive guidance on the diagnosis of glaucoma or its progression over time.  They stated that further research on an objective measure of visual function is needed. 

An Agency for Healthcare Research and Quality review on "Screening for Glaucoma: Comparative Effectiveness" (Ervin et al, 2012) summarized evidence linking glaucoma screening to health outcomes.  It found insufficient evidence to address whether glaucoma screening is effective in improving vision-related outcomes and concluded that more research is needed to address the association between screening and quality of life outcomes. 

Ocular Blood Flow Tonometer:

The ocular blood flow (OBF) tonometer measures not only intra-ocular pressure (IOP) but also pulsatile OBF.  According to the manufacturer, taking the IOP and OBF test results together increases the detection rate for glaucoma when compared to traditional tonometry, which measures only average IOP.  In addition, the manufacturer claims that the OBF tonometer can be used to provide ongoing analysis of the effectiveness of glaucoma treatment.  The manufacturer explains that the OBF applanation tonometer has a resolution of 0.01 mm Hg, and automatically takes 200 readings per second, continuously analyzing the pulsatile variations in IOP.  These data are analyzed by a computer, which calculates the OBF.  The OBF  tonometer records the complete IOP waveform and prints out of the average, maximum, and minimum values in a group of chosen pulses.

To date, the OBF tonometer has been studied primarily as a research tool.  The evidence published to date on the OBF tonometer provides comparisons of IOP measurements to standard tonometers.  There are no prospective clinical studies, however, demonstrating that measurement of waveforms and calculation of pulsatile OBF improves the management of glaucoma patients or glaucoma suspects, such that clinical outcomes are improved.

Neither the American Academy of Ophthalmology's Preferred Practice Patterns on Glaucoma nor the American Optometric Association's Clinical Practice Guidelines on Glaucoma mention any role for the OBF tonometer in the evaluation and management of patients with glaucoma.

There is no adequate evidence that OBF tonometers offer any clinically significant benefits over conventional applanation or indentation tonometers for screening, diagnosing or monitoring glaucoma.

Bhan et al (2003) examined the repeatability of OBF pneumotonometry and its agreement with Goldmann tonometry.  Intra-ocular pressure was measured by 1 experienced ophthalmologist in both eyes of 10 healthy female subjects on 10 different occasions at the same time of day.  The 2 methods were performed by alternate allocation, and laterality was chosen by random order.  The authors concluded that the repeatability of the OBF pneumotonometer was worse than that of the Goldmann tonometer.  This casts doubt on the value of the OBF pneumotonometer as a tool for measuring IOP.  The agreement plots indicate that the OBF pneumotonometer may produce significant numbers of false-positive results in screening programs.

Furthermore, pulsatile OBF assessment is used to measure the choroidal circulation and provides diagnostic value to certain ocular diseases such as glaucoma.  This technique assumes a constant ocular rigidity and is influenced by axial length, diurnal variation, and age.  Lam et al (2003) investigated the effect of age on pulsatile OBF, with consideration of the above factors (n = 118).  Ocular blood supply in the ophthalmic artery was also determined using color Doppler ultrasonography.  These investigators found that the reduction in pulsatile OBF with age was significant.  Although aging affects scleral rigidity and systemic blood pressure, multiple regression analysis indicates that the most influential factor affecting pulsatile OBF is aging.

Also, Gunvant et al (2004) ascertained the effect of central corneal thickness and corneal curvature on IOP measurements using the pulsatile OBF tonograph and the Goldmann applanation tonometer, and assessed the agreement between the pulsatile OBF tonograph and the Goldmann applanation tonometer in IOP measurement (n = 479).  The IOP measurements obtained with both the Goldmann applanation tonometer and the pulsatile OBF tonograph varied with central corneal thickness and mean keratometric reading.  IOP measured using the Goldmann applanation tonometer increased by 0.027 mm Hg per micro m increase in central corneal thickness.  IOP measured using the pulsatile OBF tonograph increased by 0.048 mm Hg per microm increase in central corneal thickness.  For an increase of 1 mm of mean corneal curvature there was rise in IOP of 1.14 mm Hg measured by the Goldmann applanation tonometer and of 2.6 mm Hg measured by the pulsatile OBF.  When compared to the Goldmann applanation tonometer, the pulsatile OBF tonograph under-estimated at low IOP and over-estimated at higher IOP.  The authors concluded that central corneal thickness and corneal curvature affected measurements obtained with the pulsatile OBF tonograph more than they affected measurements obtained with the Goldmann applanation tonometer.

Tonnu et al (2005) compared the inter-method agreement in IOP measurements made with 4 different tonometric methods: (i) the Goldmann applanation tonometer (GAT), (ii) Tono-Pen XL, (iii) OBF tonograph, and (iv) Canon TX-10 non-contact tonometer (NCT) in a randomized order in 1 eye of each of 105 patients with ocular hypertension or glaucoma.  A total of 3 measurements were made with each method, and by each of 2 independent GAT observers.  GAT inter-observer and tonometer inter-method agreement was assessed by the Bland-Altman method.  The outcome measures were 95 % limits of agreement for IOP measurements between GAT observers and between tonometric methods, and 95 % confidence intervals for intra-session repeated measurements.  The authors reported that there was good inter-observer agreement with the GAT and moderate agreement between the NCT and GAT.  The differences between the GAT and OBF tonograph and between the GAT and Tono-Pen probably preclude the OBF tomography and Tono-Pen from routine clinical use as objective methods to measure IOP in normal adult eyes.

The ocular Blood Flow Analyzer (BFA) (Paradigm Medical Industries, Inc., Salt Lake City, UT) is an electronic pneumotonometer that measures IOP 200 times per second over a period of 5 to 15 seconds and automatically measures OBF.  Ocular pressure rises and falls with each heartbeat and a pressure waveform is created when the bolus of blood from each heartbeat passes through the ocular choroid.  The systolic increase and diastolic decrease in IOP caused by the pulsatile OBF is recorded by the BFA.  The data are then analyzed by an on board computer in real time and a resultant OBF is calculated.  Six test parameters are taken per eye with a calculated average mean value in microliters/second.  Measurements for each pulse with a calculated average are given for IOP (tonometry) and pneumoplethysmographic vascular activity including: pressure, pulse amplitude, systole and diastole duration, pulse rate, and OBF rate.  The BFA is fundamentally an OBF tonometer, using a pneumatic mode of operation.

Resch and colleagues (2011) stated that little information is available regarding the relationship between glaucomatous visual field defects, morphological changes of the optic disc and OBF.  In this study, OBF parameters were correlated with parameters of optic nerve head (ONH) morphology and visual field performance in a cross-sectional study.  A total of 103 patients with primary open angle glaucoma were included.  Choroidal and ONH blood flow was assessed using laser Doppler flowmetry.  Retinal blood velocities and retinal vessel diameters were measured with laser Doppler velocimetry and a Retinal Vessel Analyzer, respectively.  To evaluate the ONH morphology, fundus photographs were taken and confocal laser scanning tomography was performed.  Among all measured ocular hemodynamic parameters, the ONH blood flow was most strongly correlated to structural parameters of ONH damage and visual field loss.  Reduced retinal vessel diameters were only slightly correlated with the degree of glaucomatous damage.  The authors concluded that reduced blood flow in the ONH was associated with increasing amount of visual field defect and morphological changes of the ONH.  Retinal vessel diameters were only marginally associated with glaucomatous optic nerve damage.  Based on retinal vessel diameter determination alone, it is not possible to evaluate if reduced retinal blood flow is causative or secondary in glaucoma.

In a case-control study, Hwang et al (2012) examined the relationship among visual field, neural structural, and blood flow measurements in glaucoma.  A total of 47 eyes of 42 patients with perimetric glaucoma were age-matched with 27 normal eyes of 27 patients.  All patients underwent Doppler Fourier-domain optical coherence tomography to measure retinal blood flow and standard glaucoma evaluation with visual field testing and quantitative structural imaging.  Linear regression analysis was performed to analyze the relationship among visual field, blood flow, and structure, after all variables were converted to logarithmic decibel scale.  Retinal blood flow was reduced in glaucoma eyes compared to normal eyes (p < 0.001).  Visual field loss was correlated with both reduced retinal blood flow and structural loss of rim area and retinal nerve fiber layer (RNFL).  There was no correlation or paradoxical correlation between blood flow and structure.  Multi-variate regression analysis revealed that reduced blood flow and structural loss are independent predictors of visual field loss.  Each dB decrease in blood flow was associated with at least 1.62 dB loss in mean deviation (p ≤ 0.001), whereas each dB decrease in rim area and RNFL was associated with 1.15 dB and 2.56 dB loss in mean deviation, respectively (p ≤ 0.03).  The authors concluded that there is a close link between reduced retinal blood flow and visual field loss in glaucoma that is largely independent of structural loss.  They stated that further studies are needed to elucidate the causes of the vascular dysfunction and potential avenues for therapeutic intervention.  Blood flow measurement may be useful as an independent assessment of glaucoma severity.

Ocular Reponse Analyzer for Corneal Hysteresis:

Central corneal thickness has become an important biometric factor and is an essential part of the evaluation of glaucoma.  Goldmann applanation tonometry is the most widely used method of measuring IOP, but it is well known that corneal parameters affect the accuracy of this instrument (Herndon, 2006).  Corneal pachymetry is used to measure central corneal thickness, and is an adjunct to applanation tonometry for screening and diagnosis of glaucoma.  In addition to central corneal thickness, there are probably further biomechanical properties that play a role in IOP measurement (Hager et al, 2007).

A new measure of corneal biomechanics, called corneal hysteresis, assesses corneal resistance to deformation.  The Ocular Response Analyzer (ORA, Reichert Ophthalmic Instruments, Depew, NY) is a new instrument that measures corneal hysteresis, the corneal biomechanical response to rapid indentation by an air jet (Kotecha et al, 2006).  Corneal hysteresis is the difference in applanation pressures between the rising and falling phases of the air jet.

Current evidence for measurement of corneal hysteresis has focused on its potential use in glaucoma, and has focused on correlations between corneal hysteresis and IOP, corneal thickness, and other ocular measurements.  There are no studies demonstrating that measurement of corneal hysteresis alters clinical management such that clinical outcomes are improved.

Kotecha (2007) stated that current evidence suggests that the importance of corneal biomechanics to the glaucoma clinician rests primarily with its effects on IOP measurement.  However, the possibility that corneal biomechanics may give an indication of the structural integrity of the optic nerve head can not be completely excluded.  The author noted that further population and longitudinal studies are needed to clarify whether current in vivo measures of corneal biomechanical properties, including corneal hysteresis, prove to be independent predictors of glaucoma susceptibility.

Genotyping for Glaucoma:

Gibson et al (2012) stated that primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss.  Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved.  These researchers analyzed carefully characterized POAG cases in a genome-wide association study (GWAS).  They performed a GWAS in 387 POAG cases using public control data (WTCCC2).  They also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP).  Promising single nucleotide polymorphisms (SNPs), based on various prioritization criteria, were genotyped in a cohort of 294 further POAG cases and controls.  These investigators found 2 GWAS significant results in the discovery stage for association, one of which had multiple evidence in the gene neural precursor cell expressed, developmentally down-regulated 9' (NEDD9; rs11961171, p = 8.55E-13) and the second on chromosome 16 with no supporting evidence.  Taking into account all the evidence from risk and quantitative trait ocular phenotypes these researchers chose 86 SNPs for replication in an independent sample.  Their most significant SNP was not replicated (p = 0.59).  They found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing.  Two of these, for phenotypes CDR (rs4385494, discovery p = 4.51x10-5, replication p = 0.029) and CCT (rs17128941, discovery p = 5.52x10-6, replication = 0.027), show the consistent direction of effects between the discovery and replication data.  These investigators also assessed evidence for previously associated known genes and found evidence for the genes 'transmembrane and coiled-coil domains 1' (TMCO1) and 'cyclin-dependent kinase inhibitor 2B' (CDKN2B).  The authors concluded that although they were unable to replicate any novel results for POAG risk, they did replicate 2 SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing.  There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits.  The authors found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study.  Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing (also known as targeted exome capture) may hold the key to unraveling the remaining contribution of genetics to complex diseases such as POAG.

Ulmer et al (2012) noted that central corneal thickness (CCT) is associated with POAG.  Using SNP data from the GLAUGEN and NEIGHBOR consortia, these researchers investigated the effects of CCT-associated variants on POAG risk.  They performed a replication analysis of previously reported CCT SNPs in their CCT dataset (n = 1,117) and tested these SNPs for association with POAG using the full dataset (n = 6,470).  They performed a CCT GWAS, selected top SNPs from this analysis, and tested these for association with POAG.  They generated cDNA libraries from fetal and adult brain and ocular tissue samples for candidate gene expression analysis.  They replicated association with 1 of 20 previously published CCT SNPs: rs12447690, near the ZNF469 gene (p = 0.001; beta = -5.08 microns/allele).  None of these SNPs was significantly associated with POAG.  In the CCT GWAS, no SNPs reached genome-wide significance.  After testing 50 candidate SNPs for association with POAG these investigators identified rs7481514 within the NTM gene that was significantly associated with POAG in a low tension subset (p = 0.00099; OR = 1.28).  Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; p = 0.018; OR = 0.84).  They found evidence of NTM and CNTNAP4 gene expression in ocular tissues.  The authors concluded that these findings suggested that previously reported CCT loci are not significantly associated with POAG susceptibility.  By performing a quantitative analysis of CCT and a subsequent analysis of POAG, they identified SNPs in 2 cell adhesion molecules, NTM and CNTNAP4, which may increase POAG susceptibility in a subset of cases.

Gemenetzi et al (2012) noted that most of the molecular mechanisms leading to POAG development are still unknown.  Gene mutations in various populations have been identified by genetic studies and a genetic basis for glaucoma pathogenesis has been established.  Linkage analysis and association studies are genetic approaches in the investigation of the genetic basis of POAG.  Genome-wide association studies are more powerful compared with linkage analysis in discovering genes of small effect that might contribute to the development of the disease.  POAG links to at least 20 genetic loci, but only 2 genes identified in these loci, myocilin and optineurin, are considered as well-established glaucoma-causing genes, whereas the role of other loci, genes, and variants implicated in the development of POAG remains controversial.  Gene mutations associated with POAG result in retinal ganglion cell death, which is the common outcome of pathogenetic mechanisms in glaucoma.  The authors stated that if the sensitivity and specificity of genotyping increases, it may be possible to screen individuals routinely for disease susceptibility. 

Guidelines from the Australian National Health and Medical Research Council (2010) state that mutations in transcription factor genes have been found to be responsible for developmental disorders associated with childhood glaucoma. The guidelines list the following genetic syndromes associated with childhood glaucoma: Nail Patella Syndrome with the LMX1B gene, Axenfeld Rieger Syndrome/Anterior segment dysgenesis with the PITX2 and FOXC1 genes and Aniridia with the PAX6 gene. Patients with these syndromes or mutations are usually followed closely for glaucoma. The guidelines note that there is some evidence that adult-onset POAG is linked to mutations in the same genes. The guidelines state that the situation is complex and it is likely that multiple mutations in more than one gene may be involved, given that POAG is likely to be inherited as a complex trait. The guidelines note that current research has identified more than 30 mutations of the myocilin gene alone, with connections to POAG in different ethnic groups. The guidelines conclude that there is "evolving evidence" for genetic screening for glaucoma.