|Year : 2018 | Volume
| Issue : 2 | Page : 53-57
Critical flicker frequency: A useful tool in diagnosis of minimal hepatic encephalopathy
Sukanya Bhrugumalla, Padmavathi R Choudeswari, Nayana Joshi, Ajit Kumar
Department of Gastroenterology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Web Publication||26-Mar-2019|
Professor and Head, Department of Medical Gastroenterology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background: Minimal hepatic encephalopathy (MHE) is viewed as mild neuro-cognitive abnormalities in cirrhotics without overt encephalopathy. Diagnostic strategies for MHE include portosystemic encephalopathy (PSE) syndrome test, critical flicker frequency test (CFF), computerised tests like Inhibitory control test, Scan test etc. We compared critical flicker frequency test with standard PSE syndrome test.
Methods: Fifty patients with cirrhotics of liver without overt encephalopathy were studied. PSE syndrome test was done with the standard charts. PSE score was calculated from the normal distribution tables. CFF was tested with manual CFF tool.
Results: Their mean age (years) was 46 ± 12.8; there were 45 males. Of these 22, 21 and 7 patients belonged to Child's A, B and C categories. PSE score detected MHE in 40%, of which 35% were in Child's A and 65% in Child's B/C. CFF was normal (>39HZ) in 36% patients and abnormal (<39HZ) in 64% patients. Mean ammonia levels were significantly higher in abnormal CFF (70.87 ± 14.38) as compared normal CFF (32.21 ± 7.9) group (P < 0.001). The sensitivity of CFF for detecting MHE was 85%, specificity 52%, positive predictive value 56% and negative predictive value 85%. Thus, CFF appears to be a good test for excluding MHE.
Conclusions: CFF test is highly sensitive (85%) with high negative predictive value (85%). It is a useful test to rule out MHE. The test is simple, quick and in-expensive and can be performed in the outpatient settings.
Keywords: Critical flicker frequency, hepatic encephalopathy, portosystemic encephalopathy syndrome test
|How to cite this article:|
Bhrugumalla S, Choudeswari PR, Joshi N, Kumar A. Critical flicker frequency: A useful tool in diagnosis of minimal hepatic encephalopathy. J Clin Sci Res 2018;7:53-7
|How to cite this URL:|
Bhrugumalla S, Choudeswari PR, Joshi N, Kumar A. Critical flicker frequency: A useful tool in diagnosis of minimal hepatic encephalopathy. J Clin Sci Res [serial online] 2018 [cited 2020 Jun 1];7:53-7. Available from: http://www.jcsr.co.in/text.asp?2018/7/2/53/254977
| Introduction|| |
Minimal hepatic encephalopathy (MHE) is viewed as mild neurocognitive abnormalities in cirrhotics without overt encephalopathy. The prevalence of MHE has been reported to vary between 30% and 84% in patients with cirrhosis of the liver. Detection of MHE by sensitive and specific tests is important in the management of cirrhotics. Timely and effective treatment with lactulose and probiotics has been shown to be effective in reversing MHE and improving performance.
The diagnosis of MHE rests on confirmation of disease, demonstration of cognition abnormality and exclusion of concomitant neurological disorder. Diagnostic strategies for MHE are many but are limited by time and financial constraints. Various tests described are portosystemic encephalopathy (PSE) syndrome test, critical flicker frequency test (CFF), computerised tests such as inhibitory control test and scan test. PSE syndrome (PSES) test includes battery of five psychometric tests that have been recommended by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). The various tests used in PSE syndrome test are number connection test-A (NCT-A), NCT-B, line tracing (trail drawing) test (LTT), serial dotting test (SDT) and digit symbol test (DST). In a recent consensus meeting, the PSES test was recommended as the gold standard in the diagnosis of MHE because (1) it covered the spectrum of cognitive aspects that are affected in hepatic encephalopathy (HE), (2) normative age corrected data are available and (3) it is in-expensive. PSE syndrome test measures psychomotor speed, visual scanning efficiency, sequencing, concentration, attention, visual perception, working memory, graphomotor speed, cognitive processing speed, motor speed and accuracy.
CFF test is a simple test, wherein the frequency of light at which patient perceives it as flickering light is measured. CFF is a well-established neurophysiological technique that measures ability of CNS to detect flickering light. This test applies the theory that the pathogenesis of HE comprises low-grade astrocytes swelling, which disrupts neuronal communication. This same process occurs in the glial cells of the retina. The retinal gliopathy could serve as a marker of cerebral gliopathy occurring in MHE., CFF can detect a broad spectrum of neuropsychological abnormalities ranging from visual signal processing to cognitive functions.
CFF analysis has been found to be sensitive and objective in the quantification of low-grade HE. Very few studies are available regarding comparative evaluation of CFF with the PSE syndrome (PSES) tests. The aim of the present prospective study was to compare critical CFF with the standard paper and pencil test that is, PSES test in diagnosis of MHE.
| Material and Methods|| |
After approval of the study by Institutional Ethics Committee of Nizam's Institute of Medical Sciences, 50 patients with cirrhosis of liver who were attending the outpatient department of Gastroenterology were included in the study. Informed written consent was obtained from them. The diagnosis and aetiology of cirrhosis was based on clinical history, examination, evaluation with liver function tests, ultrasound abdomen, Doppler of splenoportal flow and upper GI endoscopy. Routine haematological and biochemical tests were performed. Blood ammonia levels were estimated using Randox kits (Randox Laboratories, UK). Patients were categorised according to Child–Pugh class. All cirrhotic patients between age 19 and 65 years without overt encephalopathy or neurological disease were included in the study. Recent alcohol intake (<3 months), overt encephalopathy, neurological diseases such as cerebrovascular insufficiency, poor vision even after wearing spectacles and unwillingness to perform the test and/or sign the informed consent form were the exclusion criteria. Twenty age- and sex-matched healthy controls were also included in the study to obtain normal CFF value of our population.
PSE syndrome test was done with the standard charts approved by the ISHEN. The various tests performed were (i) NCT-A: evaluates psychomotor speed, visual scanning ability, sequencing, attention and concentration. The patient is instructed to join numbered circles from 1 to 25 in serial order on a piece of paper; (ii) NCT-B: evaluates attention and set shifting ability also. The patient is instructed to join numbered circles and alphabets for example, 1, A, 2, B and so on. Time taken to complete the task is compared with age-related norms; (iii) LTT: evaluates motor speed and accuracy. The patient is asked to trace a path of 5 mm wide as fast as possible without touching the border. The following are documented, (a) completion time in seconds and (b) error score; (4) SDT: evaluates motor speed. The patient is asked to dot the centre of 10 × 10 rows of circles on a piece of paper and (5) DST: This test evaluates associative learning, graphomotor speed, visual perception and processing speed. The patient is given a code in which a digit is represented by a symbol. He has to reproduce the symbol corresponding to the digit in the boxes. The number of completed boxes in a fixed time of 90 s is the score.
Critical flicker frequency
CFF was tested with manual CFF tool designed by Anand Agencies, Pune, India. In a bioscope-like instrument, the patient is presented with a light at 60 Hz frequency whence it is perceived as steady light. The frequency is slowly reduced by intervals of 2 till patient perceives it as flickering light. This usually happens around 42–44 Hz. Then, frequency is increased and the frequency at which light is perceived as steady light is noted. Usually, it corresponds to flicker frequency. Flicker to fusion and fusion to flicker are tested for three times each to reduce test errors and average is taken as the final figure.
The results of psychometric tests were expressed as PSE score after correction for age and education level derived from the normal distribution tables. The Fisher exact test or the Chi-square test was used to assess differences between qualitative variables. The online calculations were done using www.statpages.org.
| Results|| |
The study group included 50 patients with cirrhosis of the liver (45 males). Twenty age- and sex-matched normal healthy controls were also included to obtain normal CFF value. The mean age in patients was 46.02 ± 12.8 years. Alcohol was the predominant a etiological factor amongst our patients (54%). Alcohol + Hepatitis B was seen in 10% while only HBV was observed in 8%. Cryptogenic cirrhosis was noted in 12%, HCV in 6%, Budd-Chiari and NASH were seen in 4% each and autoimmune hepatitis in 2% of our patients. Child's A cirrhosis was observed in majority of the patients 44% (22/50) followed by Child's B in 42% (21/50) and Child's C in 14% (7/50). PSES was done in all patients. Norms provided in manual of PSE syndrome test by the ISHEN were taken as the gold standard for analysis of data.
The scoring of PSE tests is shown in [Table 1].
Converted scores on each subtest are assigned a value ranging from +1 to −3 based on age-related norms. The scores were calculated as depicted in [Table 1].
Since LTT generates 2 scores, a total of 6 measures which gives a range of +6 to −18 score make up the total PSES score. A total score of −4 or below was considered as abnormal. If the patient could not perform all the tests, at least two abnormal test results (<2 standard deviation from normal) were considered as the presence of MHE.
None of the patients were able to do all the five tests (especially DST and NCT-B). NCT-A and LTT were performed by all patients hence were taken for calculation of score to eliminate test bias.
A combined score of − 4 or below for the two tests (NCT-A and LTT) was diagnostic of MHE [Table 2].
|Table 2: Portosystemic encephalopathy syndrome tests in patients with cirrhosis|
Click here to view
Prevalence of MHE
MHE was diagnosed by PSE was detected in 20/50 (40%) (< – 4 score). 30/50 (60%) had normal PSE score hence diagnosed as no MHE. 7/20 (35%) patients were in Child A status and 13/20 (65%) were in Child B and C status.
Critical frequency test
The cut-off value of 39 Hz for CFF was obtained from control group. CFF was normal (>39 Hz) in 18 (36%) patients and abnormal (<39 Hz) in 32 (64%) patients.
CFF was analysed in relation to PSE score. The results showed normal CFF in 17/30 (57%) patients with no MHE and 3/20 (15%) with MHE, while 17 (85%) out of 20 patients with MHE showed abnormal CFF [Table 3]. P value was statistically significant (P = 0.003). The sensitivity of CFF for detecting MHE was 85% and specificity was 52% with positive predictive value (PPV) of 56% and negative predictive value (NPV) of 85%.
|Table 3: Critical flicker frequency and minimal hepatic encephalopathy in patients with cirrhosis|
Click here to view
The mean CFF was low in patients with MHE (34.96 ± 3.71 Hz) as compared to no MHE (37.77 ± 4.47 Hz) and the difference was statistically significant (P = 0.0258) [Table 3]. The mean CFF in Child's A, B and C was 38.62 ± 3.94, 36.7 ± 3.05 and 30.78 ± 1.71 Hz, respectively. The mean CFF was significantly low in Child's C as compared to Child's A (P < 0.0001) and Child's B (P < 0.0005).
Flicker frequency test in comparison to number connection test-A
When CFF was analysed against NCT-A, CFF was abnormal (<39 Hz) in 87% of abnormal NCT-A patients as compared to 41% in normal NCT-A group. This was statistically significant with P = 0.001 (Chi-square: 11.022), with sensitivity of 85.7%, specificity of 59.1%, PPV of 72.7% and NPV of 76.5% [Table 4].
|Table 4: Number of patients with normal and abnormal critical flicker frequency in relation to number connection test – A score|
Click here to view
The mean of CFF was compared in normal and abnormal NCT-A score. The mean CFF was 41.49 ± 2.48 Hz in normal NCT-A (scores 1, 0, −1, −2), and 34.47 ± 2.74 Hz in abnormal NCT-A group (score-3). The difference was found to be statistically significant (P < 0.0001) [Table 5].
|Table 5: Mean critical flicker frequency in normal and abnormal number connection Test A|
Click here to view
Blood ammonia and critical flicker frequency
The blood ammonia levels in normal and abnormal CFF are shown in [Table 6]. None of the normal CFF patients had raised ammonia levels (>47 μmol/l), while ammonia was raised in 56.5% of abnormal CFF patients (Chi-square 9.182, P < 0.001). The sensitivity of NH3 levels in relation to CFF was found to be 56% and specificity was 100%. The PPV and NPV were 100% and 58%, respectively.
|Table 6: Relationship of critical flicker frequency with blood ammonia levels|
Click here to view
The mean ammonia levels in normal CFF was 32.21 ± 7.9 μmol/l while the levels were 70.87 ± 14.38 μmol/l in abnormal CFF. The difference in mean ammonia level in normal and abnormal CFF was statistically significant (P < 0.001) [Table 7].
|Table 7: Ammonia levels in normal and abnormal critical flicker frequency|
Click here to view
The CFF value correlated with PSE scores (R = 0.32509 P < 0.038) and was statistically significant. Correlation between NCT-A score and CFF value showed R = 0.398 and two-tailed P value was < 0.009 which was highly statistically significant. CFF also correlated with blood ammonia levels (R = 0.5957 and P < 0.00005) with statistical significance.
| Discussion|| |
MHE is characterised by a decrease in psychomotor speed together with deficits in attention and visual constructive abilities. PSE syndrome test is the recommended tool for diagnosis of MHE because it is able to detect a majority of these MHE related psychometric Impairment.
In the busy outpatient clinics, because of time constraints, it may not be feasible to perform time-consuming psychometric tests. Therefore, development and standardisation of simple and rapid tests is essential. Different batteries of tests have been evaluated in various studies. CFF is a well -established neurophysiological technique that measures the ability of the central nervous system to detect flickering light and which is directly influenced by cortical activity. In our study using PSE syndrome test, MHE was diagnosed in 40% of cirrhotics. MHE was observed in 65% Child C and B and 35% in Child A. It varies from 30%–52% in other studies.,
The CFF was abnormal in 85% cases with MHE as compared to 15% of cases without MHE, which was statistically significant [Table 3]. The results are similar to the study by Sharma et al. The mean CFF was significantly low in MHE compared to no MHE [Table 3] and was also low in Child C (30.78 ± 1.71 Hz) compared to Child A (38.62 ± 3.94 Hz) and Child B (36.7 ± 3.05 Hz).
There was statistically significant difference in levels of ammonia in patients with normal CFF vis-a-vis abnormal CFF.
In our study, the sensitivity of CFF for detecting MHE was 85% and specificity was 52% with PPV of 56% and NPV of 85%. Although the sensitivity was high, the low specificity makes it difficult to recommend CFF as a standalone modality in the diagnosis of MHE. However, a normal CFF can rule out MHE with 86% certainty.
CFF has been compared with computerised tests in a study by Kircheis et al. They have shown 55% sensitivity and 100% specificity. In a study done by Sharma and Sharma, 200 cirrhotic patients were evaluated using NCT-A and B and CFF. CFF cut-off <39 Hz showed 72% sensitivity and 86.6% specificity for MHE. They had used computerised CFF testing, while we used manual instrument designed by Anand agencies, Pune, India.
CFF showed significant correlation with PSE score, NCT-A score and blood ammonia levels. CFF is simple to perform. However, larger studies are needed to evaluate factors which may adversely affect the performance of patient. In addition, CFF being a subjective test, as the patient has to indicate the frequency at which he is able to perceive light as fused or flickering, there can be perception bias, communication delay, etc., during testing which can impact the accuracy of the test.
PSE syndrome test although accepted as the gold standard is time-consuming in the busy outpatient clinics. In our study, we found CFF as a useful alternative tool in the diagnosis of MHE. CFF test is highly sensitive (85%) with high NPV (85%) making it a useful test to rule out MHE. The test is simple, quick and in-expensive and can be performed in the outpatient settings. However, it requires further studies with larger sample size.
We wish to sincerely acknowledge the technical assistance given in conducting CFF tests by Dr T. Ramesh Kumar Rao, Professor and Head (Retired) and Dr P. Ravinder, Research Scholar, Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dhiman RK, Chawla YK. Minimal hepatic encephalopathy. Indian J Gastroenterol 2009;28:5-16.
Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM, et al.
Synbiotic modulation of gut flora: Effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441-9.
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT, et al.
Hepatic encephalopathy – Definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th
World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716-21.
Eckstein AK, Reichenbach A, Jacobi P, Weber P, Gregor M, Zrenner E, et al.
Hepatic retinopathia. Changes in retinal function. Vision Res 1997;37:1699-706.
Reichenbach A, Fuchs U, Kasper M, el-Hifnawi E, Eckstein AK. Hepatic retinopathy: Morphological features of retinal glial (Müller) cells accompanying hepatic failure. Acta Neuropathol 1995;90:273-81.
Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: Diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007;47:67-73.
Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The Liver and Portal Hypertension. Philadelphia: Saunders; 1964. p. 50-8.
Randolph C, Hilsabeck R, Kato A, Kharbanda P, Li YY, Mapelli D, et al.
Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009;29:629-35.
Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34:768-73.
Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey R, et al.
Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007;45:879-85.
Sharma P, Sharma BC. Predictors of minimal hepatic encephalopathy in patients with cirrhosis. Saudi J Gastroenterol 2010;16:181-7.
] [Full text]
Sharma P, Kumar A, Singh S, Tyagi P, Kumar A. Inhibitory control test, critical flicker frequency, and psychometric tests in the diagnosis of minimal hepatic encephalopathy in cirrhosis. Saudi J Gastroenterol 2013;19:40-4.
] [Full text]
Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357-66.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]