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Critical flicker frequency: It is time to break down barriers surrounding minimal hepatic encephalopathy
Journal of Hepatology 47 (2007) 10–11 www.elsevier.com/locate/jhep
Editorial
Critical flicker frequency: It is time to break down barriers surrounding minimal hepatic encephalopathy Manuel Romero-Go´mez* Unit for Clinical Management of Digestive Diseases and Ciberehd, Hospital Universitario de Valme, 41014 Seville, Spain
See Article, pages 67–73
From the moment barely 30 years ago when Rikkers et al. [1] first reported the detection and prevalence of subclinical hepatic encephalopathy, this issue has remained controversial. The term latent, or subclinical, was used largely because of a lack of clearly identifiable clinical manifestations of the disease. However, subsequent evaluations showed a clear impact of the disease on the individual’s quality-of-life [2] such as the ability to drive a motorized vehicle [3], together with a higher risk of overt hepatic encephalopathy [4]. Also, when coupled with altered ammonia production, survival was lower [5]. Currently, the name-change to minimal hepatic encephalopathy is preferred [6]. However, the name-change has not improved the management of the disease perhaps because, as a consequence of the terminology, the awareness of the importance of this entity has been reduced. Indeed, in two recent surveys carried out in Spain and the USA, more than a half of all hepatologists consulted were shown not to check for minimal hepatic encephalopathy despite agreeing with its relevance [7,8]. According to the latest consensus, diagnosis of MHE requires a normal mental status examination and impairment in the performance of at least two psychometric tests; the values being corrected for age and education level relative to a healthy control group of individuals [9]. The most frequently used criteria are: (a) psychometric tests including the number connection test (NCT) and two tests (the digit symbol test and block design test) of the Wechsler Adult Intelligence Scale (WAIS); (b) a combination of a psychometric test, mainly NCT, and a neuro-physiological assessment such as electroencephalography or evoked potentials; (c) the PHES battery
*
Tel.: +34 955 01 57 61; fax: +34 955 01 58 99. E-mail address: [email protected]
including NCT-A and NCT-B, serial dotting and line drawing test. Several inconveniences preclude a wide use of these diagnostic tools. Psychometric tests such as the block design test are not handy because of the wooden cubes used. Paper-and-pencil tests such as those included in PHES are time consuming and require large numbers of healthy control subjects in order to define normality with respect to age and education levels. Lastly, neuro-physiological assessments are expensive, difficult to perform, require trained personnel, and standardization. Thus, it would seem that MHE is not studied due to the absence of any easy method for diagnosis together with the lack of any effective treatment. The development of new, easy-to-apply, tools is a prerequisite at improving the management of MHE. However, each new method of identification and management of the condition requires comparison between cirrhotic individuals and a healthy control group, together with a demonstration of an impact on the risk of developing overt HE, or even on survival. In recent years, a diagnostic method termed the ‘‘critical flicker frequency’’ (CFF) has been developed for the diagnosis of MHE [10]. In the current issue of the Journal, Sharma and colleagues [11] demonstrated the usefulness of CFF measurement in the diagnosis of MHE. CFF strongly correlated with P300 auditory evoked potentials, ammonia levels and liver function, and was not influenced by age or education level. The authors demonstrate that it is easy to perform and not time consuming. This makes it strongly recommendable for the diagnosis of MHE. Further, in a recent study, CFF was found to be independently associated with a higher risk for the development of overt hepatic encephalopathy. Indeed, just under two-thirds of the cirrhotic patients in Child–Pugh B or C stage and altered CFF suffered from overt hepatic encephalopathy in the first year of follow-up [12].
0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.04.005
M. Romero-Go´mez / Journal of Hepatology 47 (2007) 10–11
CFF has been widely used over the past 40 years to investigate the effects of psychoactive drugs and it has been shown to correlate with brain damage. CFF is a well-established neuro-physiological technique that measures the ability of the central nervous system to detect flickering light, and which is directly influenced by cortical activity [13]. CFF appears to detect a broad spectrum of neuro-psychological abnormalities ranging from visual signal processing (retinal gliopathy) to cognitive functions, and it has been applied to the study of several neurological disorders such as multiple sclerosis and Alzheimer’s disease. CFF is particularly apt for the study of alterations in visual signal processing, and is also suitable for the detection of arousal or attention abnormalities. However, CFF cannot be used to study motor function. Indeed, in cirrhotic patients with MHE and hyper-intensity signal T1 in magnetic resonance images of the brain, the alteration of CFF does not indicate altered motor function, but more an altered state of the attention system. Hence, CFF could make a contribution in the detection of some features of MHE that may be misdiagnosed by psychometric tests and, in part, pre-empt the disadvantages associated with the use of neuro-physiological tools. Indeed, Kircheis et al. [10] reported 55% sensitivity and 100% specificity in the diagnosis of MHE compared to several computerized psychometric tests plus NCT. Sharma et al. [11] using a neuro-physiological test (auditory evoked potential P300) plus NCT-A and NCT-B (shifting to the figure symbol test in cases of illiteracy) reported a diagnostic accuracy of 83%. Our group, using PHES as the diagnostic method for MHE, found an area under receiver operating characteristics (AUROC) curve of 79% for CFF. Thus, in all three available studies CFF reached a good level of diagnostic accuracy. In spite of this good scenario we are not completely confident this method could be incorporated into standard clinical practice for the management of cirrhotic patients. An interesting approach involves using a simple questionnaire such as the SHE probability score. This questionnaire consists of five questions from the sickness impact profile combined with Child–Pugh score and the size of the esophageal varices. It may be useful for identifying patients with a high risk of MHE and, in which, CFF measurement can confirm the diagnosis [14]. The majority of hepatologists accept that MHE is a major complication of liver cirrhosis, with clinical and social relevance. Thus, together with the development of easy-to-apply methods for the diagnosis of MHE, an efficacious treatment must be designed to improve the individual’s quality-of-life and to modify the natural history of the complication. The effects of future drugs need to be tested in short- or long-term clinical trials. Short-term aims include improvement in the performance of psychometric tests or neuro-physiological methods and CFF would be very useful in monitoring these goals. Long-term goals would include the effects on quality-of-life, the risk of development of overt hepatic encephalopathy or, even, overall survival.
11
In summary, CFF is not influenced by age, gender, cultural or educational factors. It is economical, can be administered easily by staff with relatively little training, and does not show a learning effect. Further, CFF predicts the risk of development of overt hepatic encephalopathy. Consequently, CFF satisfies many of the requirements of an ideal assessment tool for the diagnosis of MHE. We cannot ignore MHE any longer and CFF has the ability to break down traditional barriers against the diagnosis and management of this entity. Acknowledgements My thanks are due to Dr. Juan Carlos Quero for critically reading the manuscript and Dr. Peter R. Turner for editorial assistance. References [1] Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978;75:462–469. [2] Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998;28:45–49. [3] Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004;39:739–745. [4] Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96:2718–2723. [5] Romero-Gomez M, Grande L, Camacho I. Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 2004;39:939–943. [6] Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005;42:S45–S53. [7] Vergara-Gomez M, Flavia-Olivella M, Gil-Prades M, DalmauObrador B, Cordoba-Cardona J. Diagnosis and treatment of hepatic encephalopathy in Spain: results of a survey of hepatologists. Gastroenterol Hepatol 2006;29:1–6. [8] Bajaj JS, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: an AASLD survey. Hepatology 2007;45:833–834. [9] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna 1998. Hepatology 2002;35:716–721. [10] Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357–366. [11] Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: Diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007;47:67–73. [12] Romero-Gomez M, Cordoba J, Jover R, Del Olmo JA, Ramirez M, Rey R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007;45:879–885. [13] Curran S, Wattis J. Critical flicker fusion threshold: a potentially useful measure for the early detection of Alzheimer’s disease. Hum Psychopharmacol 2000;15:103–112. [14] Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol 2000;32:748–753.
Editorial
Critical flicker frequency: It is time to break down barriers surrounding minimal hepatic encephalopathy Manuel Romero-Go´mez* Unit for Clinical Management of Digestive Diseases and Ciberehd, Hospital Universitario de Valme, 41014 Seville, Spain
See Article, pages 67–73
From the moment barely 30 years ago when Rikkers et al. [1] first reported the detection and prevalence of subclinical hepatic encephalopathy, this issue has remained controversial. The term latent, or subclinical, was used largely because of a lack of clearly identifiable clinical manifestations of the disease. However, subsequent evaluations showed a clear impact of the disease on the individual’s quality-of-life [2] such as the ability to drive a motorized vehicle [3], together with a higher risk of overt hepatic encephalopathy [4]. Also, when coupled with altered ammonia production, survival was lower [5]. Currently, the name-change to minimal hepatic encephalopathy is preferred [6]. However, the name-change has not improved the management of the disease perhaps because, as a consequence of the terminology, the awareness of the importance of this entity has been reduced. Indeed, in two recent surveys carried out in Spain and the USA, more than a half of all hepatologists consulted were shown not to check for minimal hepatic encephalopathy despite agreeing with its relevance [7,8]. According to the latest consensus, diagnosis of MHE requires a normal mental status examination and impairment in the performance of at least two psychometric tests; the values being corrected for age and education level relative to a healthy control group of individuals [9]. The most frequently used criteria are: (a) psychometric tests including the number connection test (NCT) and two tests (the digit symbol test and block design test) of the Wechsler Adult Intelligence Scale (WAIS); (b) a combination of a psychometric test, mainly NCT, and a neuro-physiological assessment such as electroencephalography or evoked potentials; (c) the PHES battery
*
Tel.: +34 955 01 57 61; fax: +34 955 01 58 99. E-mail address: [email protected]
including NCT-A and NCT-B, serial dotting and line drawing test. Several inconveniences preclude a wide use of these diagnostic tools. Psychometric tests such as the block design test are not handy because of the wooden cubes used. Paper-and-pencil tests such as those included in PHES are time consuming and require large numbers of healthy control subjects in order to define normality with respect to age and education levels. Lastly, neuro-physiological assessments are expensive, difficult to perform, require trained personnel, and standardization. Thus, it would seem that MHE is not studied due to the absence of any easy method for diagnosis together with the lack of any effective treatment. The development of new, easy-to-apply, tools is a prerequisite at improving the management of MHE. However, each new method of identification and management of the condition requires comparison between cirrhotic individuals and a healthy control group, together with a demonstration of an impact on the risk of developing overt HE, or even on survival. In recent years, a diagnostic method termed the ‘‘critical flicker frequency’’ (CFF) has been developed for the diagnosis of MHE [10]. In the current issue of the Journal, Sharma and colleagues [11] demonstrated the usefulness of CFF measurement in the diagnosis of MHE. CFF strongly correlated with P300 auditory evoked potentials, ammonia levels and liver function, and was not influenced by age or education level. The authors demonstrate that it is easy to perform and not time consuming. This makes it strongly recommendable for the diagnosis of MHE. Further, in a recent study, CFF was found to be independently associated with a higher risk for the development of overt hepatic encephalopathy. Indeed, just under two-thirds of the cirrhotic patients in Child–Pugh B or C stage and altered CFF suffered from overt hepatic encephalopathy in the first year of follow-up [12].
0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.04.005
M. Romero-Go´mez / Journal of Hepatology 47 (2007) 10–11
CFF has been widely used over the past 40 years to investigate the effects of psychoactive drugs and it has been shown to correlate with brain damage. CFF is a well-established neuro-physiological technique that measures the ability of the central nervous system to detect flickering light, and which is directly influenced by cortical activity [13]. CFF appears to detect a broad spectrum of neuro-psychological abnormalities ranging from visual signal processing (retinal gliopathy) to cognitive functions, and it has been applied to the study of several neurological disorders such as multiple sclerosis and Alzheimer’s disease. CFF is particularly apt for the study of alterations in visual signal processing, and is also suitable for the detection of arousal or attention abnormalities. However, CFF cannot be used to study motor function. Indeed, in cirrhotic patients with MHE and hyper-intensity signal T1 in magnetic resonance images of the brain, the alteration of CFF does not indicate altered motor function, but more an altered state of the attention system. Hence, CFF could make a contribution in the detection of some features of MHE that may be misdiagnosed by psychometric tests and, in part, pre-empt the disadvantages associated with the use of neuro-physiological tools. Indeed, Kircheis et al. [10] reported 55% sensitivity and 100% specificity in the diagnosis of MHE compared to several computerized psychometric tests plus NCT. Sharma et al. [11] using a neuro-physiological test (auditory evoked potential P300) plus NCT-A and NCT-B (shifting to the figure symbol test in cases of illiteracy) reported a diagnostic accuracy of 83%. Our group, using PHES as the diagnostic method for MHE, found an area under receiver operating characteristics (AUROC) curve of 79% for CFF. Thus, in all three available studies CFF reached a good level of diagnostic accuracy. In spite of this good scenario we are not completely confident this method could be incorporated into standard clinical practice for the management of cirrhotic patients. An interesting approach involves using a simple questionnaire such as the SHE probability score. This questionnaire consists of five questions from the sickness impact profile combined with Child–Pugh score and the size of the esophageal varices. It may be useful for identifying patients with a high risk of MHE and, in which, CFF measurement can confirm the diagnosis [14]. The majority of hepatologists accept that MHE is a major complication of liver cirrhosis, with clinical and social relevance. Thus, together with the development of easy-to-apply methods for the diagnosis of MHE, an efficacious treatment must be designed to improve the individual’s quality-of-life and to modify the natural history of the complication. The effects of future drugs need to be tested in short- or long-term clinical trials. Short-term aims include improvement in the performance of psychometric tests or neuro-physiological methods and CFF would be very useful in monitoring these goals. Long-term goals would include the effects on quality-of-life, the risk of development of overt hepatic encephalopathy or, even, overall survival.
11
In summary, CFF is not influenced by age, gender, cultural or educational factors. It is economical, can be administered easily by staff with relatively little training, and does not show a learning effect. Further, CFF predicts the risk of development of overt hepatic encephalopathy. Consequently, CFF satisfies many of the requirements of an ideal assessment tool for the diagnosis of MHE. We cannot ignore MHE any longer and CFF has the ability to break down traditional barriers against the diagnosis and management of this entity. Acknowledgements My thanks are due to Dr. Juan Carlos Quero for critically reading the manuscript and Dr. Peter R. Turner for editorial assistance. References [1] Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978;75:462–469. [2] Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998;28:45–49. [3] Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004;39:739–745. [4] Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96:2718–2723. [5] Romero-Gomez M, Grande L, Camacho I. Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 2004;39:939–943. [6] Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005;42:S45–S53. [7] Vergara-Gomez M, Flavia-Olivella M, Gil-Prades M, DalmauObrador B, Cordoba-Cardona J. Diagnosis and treatment of hepatic encephalopathy in Spain: results of a survey of hepatologists. Gastroenterol Hepatol 2006;29:1–6. [8] Bajaj JS, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: an AASLD survey. Hepatology 2007;45:833–834. [9] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna 1998. Hepatology 2002;35:716–721. [10] Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357–366. [11] Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: Diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007;47:67–73. [12] Romero-Gomez M, Cordoba J, Jover R, Del Olmo JA, Ramirez M, Rey R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007;45:879–885. [13] Curran S, Wattis J. Critical flicker fusion threshold: a potentially useful measure for the early detection of Alzheimer’s disease. Hum Psychopharmacol 2000;15:103–112. [14] Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol 2000;32:748–753.