Critical Flicker Fusion

Number: 0860

Policy

Aetna considers critical flicker fusion experimental and investigational for the following indications (not an all-inclusive list) because the effectiveness of this approach for these indications has not been established:

• Diagnosis of low-grade (minimal) hepatic encephalopathy
• Diagnosis of visual acuity
• Differential diagnosis of demyelinating optic neuritis and ischemic optic neuropathy
• Prediction of executive dysfunction.

Background

Critical flicker fusion (CFF) is the rate of flicker at which one perceives no flicker.  The clinical evidence is insufficient to permit conclusions on the health outcome effects of critical flicker fusion in the diagnosis of visual acuity. 

In continuing to develop a potential vision test based on the CFF phenomenon by using a brighter stimulus and optimizing its size, Shankar and Pesudovs (2007) reported the results of a prospective non-randomized study in which 225 participants were assigned to 1 of 4 groups: normal, media opacity only, retinal/neural disease only, and cataract plus retinal/neural disease.  The CFF thresholds were measured for 3 stimulus sizes: 0.5 degree, 1.0 degree, and 1.5 degrees.  Discrimination between groups was tested by analysis of variance and receiver operating characteristic analysis.  The relationship between visual acuity and CFF in eyes without media opacity was determined by linear regression and used to predict visual outcomes in 23 eyes having cataract surgery.  The mean age of the 225 participants was 71.4 years +/- 13.2 (SD); 134 (59.8 %) were women.  The normal group had 41 participants, and the other 3 groups had 61 participants each.  Critical flicker fusion thresholds were reduced in retinal/neural disease but resistant to image degradation from media opacity.  The 1.5-degree stimulus had 88 % sensitivity and 90 % specificity for discriminating groups.  Visual acuity after cataract surgery was accurately predicted within +/-1 line in 43 % of eyes, +/-2 lines in 83 %, and +/-3 lines in 100 %.  All eyes with poor visual acuity (greater than 0.50 logMAR) or dense cataract (greater than 4.0 Lens Opacities Classification System III) were predicted within +/-2 lines.  The authors concludedthat the CFF phenomenon effectively discriminated between subjects with and without retinal/neural disease and accurately predicted visual outcome after cataract surgery.  The use of a brighter stimulus enhanced performance in cases of dense media opacity. 

Vianya-Estop et al (2004) determined whether CFF thresholds fulfill the criteria for a potential vision test (PVT) by being unaffected by media opacity yet affected by retinal disease.  Critical flicker fusion thresholds for 3 different stimulus sizes (0.5, 1.0, and 1.5 degrees) were measured in 72 patients (mean age of 78.43 +/- 7.07 years) comprising 31 subjects with media opacity, 21 with macular disease, and 20 with pseudophakia.  There were no statistically significant differences between CFF values from the media opacity and the pseudophakia groups for any target size (p > 0.10).  However, CFF values were significantly lower in patients with macular disease for all the target sizes (p < 0.05).  Analysis of a subset of 6 subjects with media opacity and 7 subjects with macular disease and visual acuity of 20/200 or worse showed the media opacity group still had similar CFF values as the pseudophakia group and had significantly higher CFF than the macular disease group.

Del Romo and colleagues (2006) reported the details of the clinical utility of CFF as a PVT (which attempts to predict the visual outcome that might be expected as a result of a cataract operation).  ritical flicker fusion thresholds were determined in 31 subjects with age-related idiopathic cataract and no other eye disease, 19 subjects with macular disease (MD) and clear ocular media, and 24 age-matched control subjects.  In addition, the CFF technique was administered before cataract surgery in 52 patients and compared with the information provided by pre-surgical case history and ocular examination alone (ophthalmological judgment [OJ]) and results from 2 commonly used PVTs (the retroilluminated pinhole and the potential acuity meter).  ritical flicker fusion thresholds obtained in the nonsurgical cataract group were unrelated to cataract severity and were similar to those in the control group.  In contrast, CFF scores were significantly related to visual acuity (VA) in the MD group.  In the pre- and post-surgical studies, OJ predicted postoperative VA very well in patients with moderate cataract and normal fundi and better than all the PVTs.  Ophthalmological judgment performed less well in patients with comorbid eye disease and dense cataracts, when information from the PVTs would probably have been useful.  Critical flicker fusion provided the most accurate predictions of postoperative VA in the small sample of patients with dense cataracts.  The authors concluded, “CFF was unaffected by cataract, yet sensitive to MD, and provided useful information about the postoperative visual outcome beyond that obtained through history and ocular examination in patients with dense cataracts”.

Vianya-Estopa et al (2006) evaluated the usefulness of a battery of PVTs including potential acuity meter (PAM), laser interferometer (LI), CFF, superilluminated pinhole at distance (SPH(d)) and near (SPH(n)), and optimal reading speed (ORS) by their independence of the effects of cataracts and sensitivity to MD in 76 patients with age-related cataract and no other eye disease, 52 patients with MD and clear ocular media, and 28 patients with normal, healthy eyes.  Potential vision tests were independent of the degrading effects of cataract up to a visual acuity (VA) level of 20/200 or worse (CFF), 20/125 (ORS and SPH), and 20/40 (PAM and LI).  A high degree of association was found between PVT scores and distance VA in the MD group for SPH(d) (r2 = 0.93), SPH(n) (r2 = 0.89), and PAM (r2 = 0.71).  A moderate correlation was found for LI (r2 = 0.55), CFF (r2 = 0.50), and ORS (r2 = 0.45).  The authors concluded, “in regard to critical flicker/fusion frequency that while the test showed the greatest ability to bypass cataracts, its ability to predict VA in patients with early MD was limited”.

Trick (2003) noted that the temporal processing capability of the visual system has historically been evaluated by measuring sensitivity to flicker.  The sensation of flicker occurs when light stimulation is intermittent rather than continuous.  In general, as the flicker frequency increases, a point is reached at which the perception of flicker is lost and the light appears continuous or fused.  This point is known as the CFF frequency.  Trick wrote that CFF is one of many techniques and tools available to measure aspects of visual function that extend beyond visual acuity.

Goldbecker et al (2013) stated that hepatic encephalopathy (HE) is a common complication of liver insufficiency.  While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE.  These investigators compared the 4 most favored methods for the diagnosis of HE.  A total of 170 patients who were on the waiting list for liver transplantation as well as 86 healthy controls were included in the study.  All patients and controls underwent the porto-systemic encephalopathy syndrome test yielding the psychometric hepatic encephalopathy score (PHES), the repeatable battery for the assessment of neuropsychological status (RBANS), the inhibitory control test (ICT) and CFF measurement.  Psychometric hepatic encephalopathy score and ICT targets had the best sensitivity (85.7 % versus 85.7%) and specificity (96.5 % versus 97.6 %) for the diagnosis of overt HE.  Critical flicker fusion showed inferior sensitivity (40.9 %) for the diagnosis of HE and dependency from previous alcohol abuse (p = 0.015).  Multiple regression analysis showed that all test results apart from PHES were influenced by secondary diagnoses such as diabetes mellitus and renal insufficiency.  The authors concluded that in the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.

Kircheis et al (2014) stated that CFF and PHES analyses are widely used to diagnose HE, but little is known about their value in the diagnosis of low-grade HE.  The diagnostic values of CFF and PHES were compared using a computerized test battery and West Haven criteria as reference.  These investigators performed CFF analysis on 559 patients with cirrhosis and 261 without (controls).  Of these 820 patients, 448 were evaluated using a modified PHES system and 148 were also evaluated using the conventional PHES system.  Critical flicker fusion distinguished between patients with overt HE and without minimal or overt HE in the entire study population with 98 % sensitivity and 94 % specificity and in the subgroup of patients who were evaluated by conventional PHES with 97 % sensitivity and 100 % specificity.  Conventional PHES identified patients with overt HE with 73 % sensitivity and 89 % specificity.  Critical flicker fusion distinguished between patients with and without minimal HE with only 37 % sensitivity but 94 % specificity (entire study population).  In the subgroup of patients evaluated by conventional PHES, CFF distinguished between patients with and without minimal HE with 22 % sensitivity and 100 % specificity; these values were similar to those for conventional PHES (30 % sensitivity and 89 % specificity).  The modified PHES distinguished between patients with and without minimal HE with 49 % sensitivity and 74 % specificity.  The diagnostic agreement values between CFF and conventional or modified PHES in patients with minimal HE were only 54 % or 47 %, respectively.  The authors concluded that in an analysis of patients with cirrhosis and controls, CFF distinguished between patients with overt HE and without minimal or overt HE.  Psychometric hepatic encephalopathy score testing produced a statistically significant difference among groups, but there was considerable overlap between controls and patients with overt HE.  Moreover, these researchers stated that PHES, CFF, and a combination of PHES and CFF could not reliably distinguish patients with minimal HE from controls or those with overt HE.

An UpToDate review on “Hepatic encephalopathy in adults: Clinical manifestations and diagnosis” (Ferenci, 2014) states that “Electrophysiologic tests to detect minimal hepatic encephalopathy include EEG monitoring, evoked potentials, and critical flicker frequency testing.  However, none of these tests is widely used …. Retinal glial cells are involved in ammonia detoxification by glutamine synthesis.  In patients with liver failure, they exhibit morphological changes similar to those observed in brain astrocytes, suggesting that retinal gliopathy could serve as a marker of cerebral gliopathy in patients with hepatic encephalopathy.  These observations provided the rationale for the development of a visual test (the critical flicker/fusion frequency) for determining whether hepatic encephalopathy is present.  Advantages of the test are that it is objective and it is not affected by the patient's age or education/literacy level.  However, a meta-analysis suggests that it is only moderately sensitive for detecting minimal hepatic encephalopathy.  The meta-analysis included 9 studies with 622 patients and found that critical flicker frequency had a sensitivity for detecting minimal hepatic encephalopathy of 61 % and a specificity of 79 %”.

Prediction of Executive Dysfunction

Mewborn et al (2015) stated that CFF, a measure of visual processing speed, has often been regarded as a basic metric underlying a number of higher cognitive functions. To test this, these researchers measured CFF, global cognition, and several cognitive subdomains. Because age is a strong co-variate for most of these variables, both younger (n = 72) and older (n = 57) subjects were measured. Consistent with expectations, age was inversely related to CFF and performance on all of the cognitive measures except for visual memory. In contrast, age-adjusted CFF thresholds were only positively related to executive function. Results showed that CFF predicted executive function across both age groups and accounted for unique variance in performance above and beyond age and global cognitive status. The authors concluded that the current findings suggested that CFF may be a unique predictor of executive dysfunction; further study in a more heterogeneous sample is needed to define any specific relation between CFF and brain function. They noted that because CFF thresholds are quick and inexpensive to obtain, they may serve as a good biomarker of higher cognitive function, especially in clinical situations.  These preliminary findings need to be validated by well-designed studies. 

Reached for comment, Dr. Hendrik Scholl, head of visual neurophysiology at the Wilmer Eye Institute in Baltimore, stated that “The findings are "potentially interesting”, but he urged caution in their interpretation. The [probability] that this is a chance finding is not low, and the meaning of the finding is questionable because there is most likely no causality between critical fusion frequency and brain functions.  You don't know, if your critical flicker frequency is high, if this is the reason that you do better on executive function.  It's also not very plausible that the visual system and a specific dimension of the visual system should have any impact on executive function" (Brooks, 2015)

Also, an UpToDate review on “The mental status examination in adults” (Lu, 2016) does not mention critical flicker fusion as a diagnostic/management tool for executive functioning.

Differential Diagnosis of Demyelinating Optic Neuritis and Ischemic Optic Neuropathy

In a retrospective review, Young and colleagues (2018) compared CFF in optic neuritis (ON) and non-arteritic anterior ischemic optic neuropathy (NAION).  These researchers compared multiple variables for eyes with ON or NAION using 2-sided t-test and Chi-square tests.  A multi-variate linear regression was performed for the dependent variable CFF.  A receiver operating characteristic (ROC) curve was used to define a CFF threshold for distinguishing these entities.  Unaffected eyes had an average CFF value of 31.5 Hz.  CFF values for ON (20.7 Hz ± 7.36) and NAION (24.3 Hz ± 9.03) were not significantly different from each other (p = 0.06).  However, the CFF for ON, 18.27 Hz ± 9.29, was significantly lower than for NAION, 23.92 Hz ± 7.02, p = 0.02 when limiting the comparison to moderate and severe disease.  An ROC curve demonstrated that a CFF value of less than or equal to 24 Hz was 71 % sensitive for ON and that a value greater than 24 Hz was 74 % specific for excluding ON.  A multi-variate linear regression model demonstrated that ON contributed to approximately an 8 Hz decrease in CFF compared to NAION.  Patients with a CFF of less than or equal to 24 Hz had a 2.89 odds ratio (95 % confidence interval [CI]: 1.76 to 4.01) of having ON.  The authors concluded that CFF values in eyes with ON were significantly lower compared to eyes with NAION when evaluating moderate and severe disease; 24-Hz may be a useful CFF threshold value when trying to distinguish between these 2 entities.  These findings need to be validated in well-designed studies.

The above policy is based on the following references: