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C 2004) Metabolic Brain Disease, Vol. 19, Nos. 3/4, December 2004 (

Methods for Diagnosing Hepatic Encephalopathy in Patients With Cirrhosis: A Multidimensional Approach Sara Montagnese,1 Piero Amodio,2 and Marsha Y. Morgan1,3 Received November 14, 2003; accepted November 25, 2003

There is no “gold standard” for diagnosing hepatic encephalopathy in patients with cirrhosis. In consequence, the presence of this condition, unless floridly overt, is often missed. As a result, the majority of patients are denied the benefits of treatment. There are a number of individual techniques, which access different aspects of cerebral function that can be used, singly or in combination, to provide diagnostic information in this condition, including mental state assessment, psychometric testing, electroencephalography, sensory and cognitive evoked potentials, and neuroimaging. These have been variously applied to the study of hepatic encephalopathy but fundamental differences in the essential aims of the studies, as well as differences in the patient populations and the acquisition and analysis of the data, have made comparisons difficult. Thus, there is no clear consensus as to the sensitivity, specificity, or validity of these tests when used alone or in combination. There are, however, a number of additional methods that could be used to analyze the electrophysiological data, and a number of alternative evoked potentials that could be measured to provide better diagnostic information. In addition, there are a number of techniques, such as critical flicker frequency and smooth pursuit eye movements, which have not yet been applied systematically in this condition and which may provide useful diagnostic information. Clearly the methods for assessing hepatic encephalopathy need to be reviewed, newer methods for analyzing the electrophysiological data and newer techniques for assessing alternative aspects of cerebral function need to be explored for their diagnostic utility. This process should aim at developing a multidimensional diagnostic tool. Key words: Cognitive evoked potentials; electroencephalogram; hepatic cirrhosis; hepatic encephalopathy; mental state; movement evoked potentials; neural imaging; psychometric tests; sensory evoked potentials.

INTRODUCTION The presence of hepatic encephalopathy has a detrimental effect on the overall quality of life in patients with cirrhosis (Groeneweg et al., 1998) and a significant negative effect on survival (Bustamante et al., 1999). Nevertheless, there is still no “gold standard” method for diagnosing this syndrome. Some centers rely solely on clinical assessment, which will preclude identification of the subtle changes in cognition present in up to 50% of seemingly unimpaired individuals (Quero et al., 1996). Where more objective diagnostic techniques, 1 Centre

of Hepatology, Royal Free Campus, Royal Free and University College Medical School, Rowland Hill Street, Hampstead, London, United Kingdom. 2 Clinica Medica 5, CIRMANMEC, University of Padova, Italy. 3 To whom correspondence should be addressed at Centre for Hepatology, Royal Free Campus, Royal Free and University College Medical School, University College London, Rowland Hill Street, Hampstead, London NW3 2PF, United Kingdom. E-mail: [email protected] 281 C 2004 Plenum Publishing Corporation 0885-7490/04/1200-0281/0 

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such as psychometric and electrophysiological measures are used, they tend to be those most easily accessible within a given department/institution, irrespective of whether or not they have been validated or standardized. However, even these tests are not routinely or consistently applied, primarily because there is little or no consensus as to their value. In consequence, the diagnosis of this syndrome, unless floridly manifest, is often missed. As a result, the majority of patients, unless treated empirically, are suboptimally managed. In addition, as there is little or no consensus on the optimal way to diagnose and classify these patients, significant difficulties arise in replicating or validating the findings of others and in undertaking collaborative studies. In 2002, an International Working Party on Hepatic Encephalopathy published a report in which they acknowledged the difficulties associated with the diagnosis of this condition (Ferenci et al., 2002). They called for a redefinition of the whole spectrum of neuropsychiatric abnormalities that arise in relation to the presence of chronic liver disease and recommended that a multidimensional definition of the syndrome be obtained. In the interim they suggested that the syndrome is best diagnosed by use of a combination of clinical grading of the mental state using the West Haven Criteria (Conn et al., 1977), assessment of psychometric performance, using a standardized test battery (Weissenborn et al., 2001), and, where possible, a quantitative neurophysiological measure such as the electroencephalogram (EEG) mean dominant frequency (Amodio et al., 1999) or the P300 auditory evoked potential (Kullmann et al., 1995). This situation is obviously unsatisfactory. There is a clear need for a sensitive, specific, well-validated, and universally applicable tool for assessing neuropsychiatric status in this patient population to ensure that patients are diagnosed and monitored effectively, and that research efforts are consolidated. In this review, the published literature on the variables used to diagnose hepatic encephalopathy will be reviewed, the key findings enumerated, and attempts made to assess diagnostic validity, sensitivity, and specificity. Information will be provided on alternative methods for acquiring and analyzing certain electrophysiological variables and on alternative techniques, which may prove to have diagnostic utility in this condition. Finally, a plan for devising a multidimensional diagnostic scoring system will be delineated.

ASSESSMENT OF THE CANDIDATE DIAGNOSTIC TOOLS Neurological Examination Including Mental State Assessment A detailed discussion of the methodology for assessing neuropsychiatric status is not required as the International Working Party on Hepatic Encephalopathy was fairly explicit in their recommendations on this point (Ferenci et al., 2002). They recommended that, in patients with cirrhosis, the diagnosis or exclusion of overt, or clinically apparent, hepatic encephalopathy should be based upon: i) A careful and detailed neuropsychiatric examination and anamnestic enquiry, with particular attention being paid to cognitive and motor function, the ability to perform the activities of daily living and sleep-wake cycle abnormalities;

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ii) Use of two-grading systems to assess mental status: the West Haven criteria (Conn et al., 1977), based on changes in consciousness, intellectual function, and behavior, and the Glasgow Coma Scale (Teasdale and Jennett, 1974); iii) The exclusion of other potential causes of neuropsychiatric abnormalities, for example, concomitant neurological disorders such as subdural haematoma and Wernicke’s syndrome, other metabolic abnormalities such as electrolyte imbalance, and intoxication with alcohol or drugs. These recommendations do not preclude use of additional instruments such as the Hodkinson Mental State Test (Hodkinson, 1972) or the Mini Mental Score Test (Folstein et al., 1975), which tend to be considered as clinical rather than psychometric tools, and have been widely applied in this patient population.

Psychometric Performance The majority of patients with cirrhosis show disturbances of attention, executive function, concentration, and psychomotor speed whether or not they have features of overt hepatic encephalopathy (Tarter et al., 1984; Weissenborn et al., 2001). A number of tests or test systems have been used to identify these abnormalities. The earliest used, and most widely applied are the Trail-Making Tests A and B, later renamed Number Connection Tests (NCT) A and B (Reitan, 1955), although equally popular are the digit-symbol and block design subtests of the Wechsler Adult Intelligence Scale Revised (WAIS-R) (Wechsler, 1981). These tests, particularly NCT A, have been used as reference measures for the introduction of alternative diagnostic and monitoring tools. However, the results of these, and other psychometric tests, are highly dependent on age, educational attainment, and probably cultural and ethnic origin. As a result, use of simple raw thresholds for abnormality can produce misleading results if applied to all age groups and in all cultural contexts. In addition, use of different commercially available versions of the tests can result in analogue confounding (Quero et al., 1996). Thus, all tests must be appropriately validated and standardized within the populations in which they are to be applied. To date there has, with some notable exceptions (Amodio et al., 2002; Weissenborn et al., 2001), been little attempt to produce, or use, norm-based test scoring schemes. There have been several attempts to produce psychometric tests batteries for use in the detection and monitoring of hepatic encephalopathy (Gitlin et al., 1986; Sood et al., 1989). The test battery most recently proposed includes NCT A and B, digit-symbol, line tracing, and serial dotting (Weissenborn et al., 2001). This battery, which has been called the Psychometric Hepatic Encephalopathy Score (PHES), is easily applied and has been shown to have a high specificity for the diagnosis of hepatic encephalopathy. However, the reference test scores were normalized for a German population and thus need to be validated, and, if necessary, adjusted for use in other patient populations. Computer-based psychometric tests have also been used in this patient population. They allow for a more precise quantification of reaction times and for more refined testing. Instruments such as the Posner test or the Scan test based on the Sternberg paradigm tend to explore better defined cognitive functions and to isolate subtle attention or memory defects

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such as divided attention and working memory, but to date they have only been applied and standardized in a single center (Amodio et al., 1998a,b). The presence of psychometric abnormalities defines minimal hepatic encephalopathy in patients with cirrhosis who appear clinically unimpaired, and provides an objective measure of severity in those with clinical apparent impairment. However, at present, there is no consensus as to the best test/test system to use to detect these abnormalities, although the PHES test battery is worthy of further study. In addition, the more refined computerbased test systems should be further explored, particularly if they can be made more widely accessible. Electrophysiology A number of electrophysiological techniques have been used in the assessment of hepatic encephalopathy, either in isolation or combined with other techniques. Electroencephalography Electroencephalography (EEG) is the electrophysiological technique most frequently used to diagnose, assess, and monitor neuropsychiatric status in patients with cirrhosis (Table 1). However, the studies undertaken to date are difficult to compare because of interstudy differences in the patient and control populations and in the methods used to acquire and analyze the EEG recordings. More importantly these studies often differ in their fundamental aims. Thus, approximately 50% of the studies aimed simply to provide descriptive data on the changes observed in the EEG in patients with overt hepatic encephalopathy, while in the remainder the EEG was variously used: i) As a diagnostic tool in severely impaired or even comatose patients with cirrhosis; ii) To monitor the effects of treatment, dietary and pharmacological manipulations, portal-systemic shunt surgery, TIPS insertion, or orthotopic liver transplantation; iii) To detect abnormalities in clinically unimpaired patients with cirrhosis and hence to define minimal hepatic encephalopathy. Few, if any, studies provide data on the incidence of EEG abnormalities in consecutive patients with cirrhosis irrespective of their neuropsychiatric status. In approximately 30% of the studies reviewed there was no information on how the diagnosis of cirrhosis was made; in 30% it was based on clinical signs, laboratory data, ultrasound, and endoscopic findings and confirmed histologically where needed; in 40% of the studies it was histologically confirmed in all or in the majority of patients. The aetiology of the cirrhosis was typically mixed; very few studies excluded patients with alcohol-related cirrhosis and the period of abstinence required for inclusion varied from 2 weeks to 6 months. In the majority of studies the diagnosis of hepatic encephalopathy was based on historical and clinical criteria although this varied depending on the aim of the study (Table 1). Thus, in the studies designed to simply document the changes in the EEG in patients with overt hepatic encephalopathy, the patients selected all displayed features of neuropsychiatric disturbance, whereas in the studies designed to assess the utility of the

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Table 1. Summary Details of the Studies on the Utility of EEG in the Diagnosis and Monitoring of Hepatic Encephalopathy in Patients with Cirrhosis Articles reviewed: (n) Total –Experimental studies –Commentaries/reviews Publication dates: Patients: (n) Total Mean patients/study Range of patients/study EEG recordings: (n) Total Mean EEG recordings/study Healthy controls: (n) Other controls: (n) Diagnosis/exclusion of HE: (number of studies) Unspecified Clinical (± anamnestic enquiry) Clinical + EEG Clinical + psychometry Diagnosis of minimal HE: (number of studies) Psychometry Psychometry + EEG Details of EEG acquisition: (number of studies) Unspecified Specified number electrodes/derivations Specified recording conditions (positioning, eye-opening etc) Specified length of the recording Specified filters, impedance, sampling frequency Details of EEG analysis: (number of studies) Search for triphasic waves only Visual descriptive report, unspecified Parsons-Smitha original or modified classification Semi-quantitative methods for base frequency Spectral analysis Any visual analysis plus additional spectral analysis Spectral analysis and brain mapping a Parsons-Smith

78 66 12 1950–2002 3659 55 1–615 5140 78 472 225 9 43 4 5 3 2 15 32 17 10 19 3 12 15 19 20 8 4

et al., 1957.

EEG for diagnosing minimal hepatic encephalopathy the patients selected had no clinical evidence of neuropsychiatric impairment. There were notable and significant differences in the ways in which the EEG data were acquired and analyzed (Table 1). Virtually no information was provided on the quality of the tracings and the ease with which they are analyzed in any of the studies. The visual methods applied were poorly described, they are subject to inter- and intraoperator variability and this was not quantified; classifications of the EEG features were often arbitrarily defined within individual studies. The studies utilizing spectral analysis were heterogeneous in terms of equipment, bandwidth, filters, epoching, and choice of derivations; the ratios between spectral parameters were applied in too few studies for their value to be assessed

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and information on the variation of spectral indices in the form of standard deviations was only available in four studies. A number of abnormalities have been documented in patients with cirrhosis but these findings must be viewed bearing the caveats on study heterogeneity in mind. The findings include: • Initial replacement of the α rhythm with faster rhythms; this was first described by Parsons-Smith et al. (1957), but only seldom considered in later studies; • Background slowing; this is variously described and quantified; it is generally observed in the temporal areas but may also be observed in the frontal areas/more anteriorly or diffusely on the scalp; • Desynchronization/disorganization of the dominant activity; • Bursts of slow activity in the θ and/or δ range; these occur mainly in the temporal regions, are superimposed on a normal rhythm and are sometimes described as high voltage; • Triphasic waves: these are synchronous, have anterior dominance, appear in groups or runs, have a fronto-occipital lag time and are superimposed on a slowed rhythm; • Arrhythmic δ activity; • A general decrease in amplitude. The presence of triphasic waves or arrhythmic δ activity have prognostic value in relation to the evolution of coma, but they are not specific for hepatic encephalopathy and their diagnostic use is limited in that they reflect a condition of unquestionable clinical severity. In contrast, the presence of generalized slowing of the background EEG activity appears to be a constant, progressive, and more objectively quantifiable finding, although it is also observed in other metabolic and drug-induced encephalopathies (Niedermeyer, 1999; Bauer and Bauer, 1999). A number of semiquantitative classifications of the background frequency of the EEG, based on visual analysis, were initially devised (Conn et al., 1977; Laidlaw, 1959). Later spectral analysis, which provides an automated estimation of the dominant EEG frequency, was introduced (Van der Rijt et al., 1984). This technique is less inter- and intraoperatordependent (Amodio et al., 1999) and also allows the relative contribution of the different rhythms to the overall background frequency to be estimated. In more recent years, major efforts have been made to optimize spectral analysis and to evaluate its role in improving the diagnostic and prognostic value of the EEG in hepatic encephalopathy (Amodio et al., 2001; Van der Rijt and Schalm, 1985). In a few studies brain mapping of the spectral parameters has been used (Sagal´es et al., 1990), but in general, the spatial distribution of the slowing has not received much attention. The absence of a “gold standard” for the diagnosis of hepatic encephalopathy makes it difficult to draw conclusions about the sensitivity of the EEG in this condition. In the studies reviewed, the reported diagnostic sensitivity varies from 83 to 100% for overt hepatic encephalopathy, depending on the technique used and the patients studied. EEG abnormalities are also detected in 8 to 40% of clinically unimpaired patients, but this again depends on the technique used. The studies reviewed clearly demonstrate that, regardless of their role or sensitivity in diagnosing hepatic encephalopathy, EEG alterations in cirrhotic patients:

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• Generally reflect the patients’ neuropsychiatric status, the effects of treatment, dietary manipulation, and surgical/nonsurgical shunt creation; • Tend to be more common in patients with a history of hepatic encephalopathy; • Tend to parallel the severity of hepatic dysfunction; • Have a weak relationship with laboratory parameters such as the plasma ammonia concentrations; • Predict the occurrence of overt encephalopathy and death, at least in the patients with decompensated liver disease; • Correlate with health-related quality of life. Thus, the EEG provides information, which is useful for detecting, assessing, and monitoring hepatic encephalopathy of varying degrees of severity. The sensitivity and specificity of the technique are critically dependent on the quality of the recording and the analysis performed. There are a number of alternative techniques for analyzing EEG data, which could be utilized in the study of patients with hepatic encephalopathy, including coherence analysis, nonlinear analysis (Lopes Da Silva, 1999), and spatiotemporal (S-T) decomposition (Jackson and Sherratt, 2004). Application of these techniques might provide better quantifiable and more informative data.

Evoked Potentials Evoked potentials are small phasic potentials that are elicited in conjunction with sensory, motor, and cognitive events. They are grouped as follows: • Sensory or exogenous evoked potentials; these are elicited by direct stimulation of visual, auditory, or somatosensory systems. • Movement-related evoked potentials; these relate to the preparation for movement and its execution. • Cognitive or endogenous evoked potentials; these relate to cognitive activity.

Sensory Evoked Potentials Visual evoked potentials (VEPs). A visual evoked potential is the low-voltage electrical response evoked, in the cerebral cortex, by visual stimulation in the form of a flash, a pattern-reversal stimulus, or the onset of motion in the visual field. The potential consists of multiple peaks of 1–40 µV amplitude, labelled either as N1, P1, N2, P2, N3, with N indicating a negative and P a positive deflection, or as N80 (≡N2), P100 (≡P2), N145 (≡N3), where the number indicates the approximate time location after the stimulus, in milliseconds. N1 and P1 are not always detected; the peak that possesses the smallest intra- and interindividual variability and is most widely used for diagnostic purposes is the P2/P100 evoked by pattern-reversal stimuli (Kullmann et al., 1995). Abnormalities in the VEP waveform are observed in pure optic nerve diseases, demyelinating processes, changes within both subcortical and cortical neurons in response to metabolic abnormalities, or the consumption of psychotropic medications (Davies et al., 1991; Kullmann et al., 1995).

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A number of studies have been undertaken in which VEP variables have been assessed in patients with cirrhosis (Table 2). The results are difficult to compare because of interstudy differences in the patient and control populations and in the methods used to acquire and analyze the VEP data. In addition, the studies often differ in their fundamental aims. Thus, approximately 30% of the studies aimed simply to provide descriptive data on the VEP changes in patients with overt hepatic encephalopathy, while in a further 30% the aim was to determine the prevalence of VEP abnormalities in patients with no clinical evidence of hepatic encephalopathy and thus to provide an operative definition of minimal hepatic encephalopathy. In the remaining studies VEPs were variously used: i) To monitor the effects of treatment, pharmacological manipulations, TIPS insertion, or orthotopic liver transplantation; ii) As a reference measurement to test the utility of different electrophysiological tools, typically other evoked potentials, in the diagnosis of overt or minimal hepatic encephalopathy. In 9 of the 21 studies reviewed there was no information on how the diagnosis of cirrhosis was made; in 7 studies it was histologically confirmed in all but a minority of patients, while in the remaining 5 it was based on clinical signs, laboratory data, hepatic imaging, and endoscopic findings. The aetiology of the cirrhosis was typically mixed; patients with alcohol-related cirrhosis were excluded in 5 studies while in one study all 25 of the included patients had alcohol-related disease; little information was available on the length of abstinence from alcohol required for inclusion, if any. One study included 19 patients with acute paracetamol-related hepatic failure. The fact that controls were exercised for visual impairment was referred to in most of the studies, but adequately detailed in only 7; electroretinography was performed in 4 studies. The diagnosis of hepatic encephalopathy was made on clinical grounds although the criteria applied were not specified in the majority of papers. Where studies included or centered on patients with minimal hepatic encephalopathy the diagnosis was based on the absence of clinical evidence of hepatic encephalopathy ± abnormal psychometric test results, slowing of the EEG, or changes in other evoked potentials (Table 2). There were notable and significant differences in the way in which the VEP data were acquired and analyzed (Table 2): • Very little, if any, information was provided on the quality of the recordings obtained or the ease with which they were analyzed; • In 50% of the studies the visual stimulus was evoked by a flash. The potentials evoked using this technique are known to be highly variable and poorly reproducible; this technique is not recommended for use in adults; • There was little if any standardization, or even comparability between studies of important acquisition parameters such as stimulus frequency and intensity, eye distance from the lamp, size of pupils, checkerboard size, and contrast or electrode positioning; • The methods used for wave analysis rarely complied with the recommendations of the various Neurophysiological Societies; there was no consistency between studies with regard to the VEP component selected for analysis;

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Table 2. Summary Details of the Studies on the Utility of Visual Evoked Potentials (VEPs) in the Diagnosis and Monitoring of Hepatic Encephalopathy in Patients with Cirrhosis Articles reviewed: (n) Total –Experimental studies Flash VEPs Pattern-reversal VEPs Motion-onset VEPs –Commentaries/reviews Publication dates: Patients: (n) Total Mean patients/study Range of patients/study VEPs recordings: (n) Total Mean VEPs recordings/study Healthy controls: (n) Other controls: (n) Diagnosis/exclusion of HE: (number of studies) Clinical Parsons-Smith’s criteriaa Zieve’s criteriab Adams and Foleyc Glasgow Coma Scaled Unspecified Conn’s PSE Indexe Diagnosis of minimal HE: No clinical abnormalities but psychometric, EEG or EP alterations Details of VEPs acquisition: Generally complete and precise with regard to stimulation equipment, delivering modality, reference and positioning of the electrodes, recording conditions, number of stimuli delivered, luminance, or checkerboard features but variables were not standardized between studies. Details of VEPs analysis: (number of studies) Quality of the recordings Ease of wave analysis Wave analysis Comparison of raw data (patients/controls) Defined thresholds for abnormal latency/amplitude: 2 SD > mean of a reference population 3 SD > mean of a reference population a Parsons-Smith

et al., 1957.

b Zieve, 1982. c Adams and Foley, 1953. d Teasdale and Jennett, 1974. e Conn et al., 1977.

25 21 10 11 1 4 1984–2001 756 36 5–116 784 37 369 51 16 7 1 1 1 6 1 5

1 2 16 5 3 2

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• Reference values and thresholds for abnormality were often arbitrarily defined and derived from small reference populations (Table 2). The findings of these various studies are inconsistent and vary in relation to the type of stimulus applied, but include Flash Stimulation • Reversible prolongation in N3 latency in parallel with increasing severity of hepatic encephalopathy. N3 prolongation > 2SD over the mean of the reference group was observed in –50% of patients with overt hepatic encephalopathy (sensitivity 50%; specificity 92%; accuracy 72%; negative predictive value 80%); –40% of clinically unimpaired patients with normal psychometric and EEG results (sensitivity 29%; specificity 92%; accuracy 64%; negative predictive value 61%). • Reversible loss of N1 followed by loss of P1 in patients with Grades III and IV hepatic encephalopathy; • Prolongation of P1, N2, and P2.

Pattern-Reversal Stimulation • Prolonged latency of P100 was observed in 31–38% of patients with Grade I hepatic encephalopathy and in 10–15% of patients with no clinical evidence of hepatic encephalopathy; • A correlation between hepatic encephalopathy grade and P100 amplitude was observed in one study; • No significant differences were observed in pattern-reversal VEP before and after TIPS insertion, whereas significant changes were observed after the procedure in the EEG and in the cognitive evoked potential, P300.

Motion-Onset Stimulation • The latency of motion-onset VEPs was prolonged both pre- and post-TIPS insertion and was not significantly affected by the procedure; in the same study patternreversal VEPs were normal both before and after the procedure whereas a significant slowing of the EEG was observed postprocedure. There is limited information on the changes in VEPs in relation to changes in the severity of hepatic encephalopathy or in relation to treatment. However, the diagnostic yield of this test modality, at least in the studies undertaken to date, is too poor for it to be considered as a useful tool for the assessment and monitoring of hepatic encephalopathy. Brainstem auditory evoked potentials (BAEPs). A BAEP is the electrical response evoked in the cerebral cortex, by brainstem structures, in response to auditory click stimuli. It consists of five wavelets, designated I–V, which have amplitudes of 5–15 µV and latencies of 50–400 ms. The wavelets are conventionally quantified in terms of the latency of the

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individual waves, the latency differences between the waves (interpeak latency), and the amplitude ratio between waves I and V. Because wave V can be recorded reliably in a wide variety of experimental situations, its latency has proven to be the most useful measure, at least in clinical practice. BAEP alterations are detected in lesions of the acoustic nerve and the brainstem, multiple sclerosis, and other conditions associated with demyelination such as diabetes and alcohol misuse (Kullmann et al., 1995; Regan, 1989). BAEPs have also proven useful in the assessment and follow-up of patients with Wilson’s disease (Grimm et al., 1990). A number of studies have been undertaken in which BAEP patterns have been assessed in patients with cirrhosis (Table 3). The results are difficult to compare because of interstudy differences in the patient and control populations and in the methods used to acquire and analyze the BAEP data. In addition the studies often differ in their fundamental aims. Thus, approximately 20% of studies aimed simply to provide descriptive data on the BAEP changes observed in patients with overt hepatic encephalopathy, while in the remainder the BAEP was variously used: i) To detect abnormalities in clinically unimpaired patients with cirrhosis and hence to define minimal hepatic encephalopathy; in most of these studies the diagnostic utility of BAEPs was compared with that of other sensory evoked potentials; ii) To evaluate the predictive value of BAEPs for the development of overt hepatic encephalopathy and death; iii) To monitor the effect of dietary manipulation and orthotopic liver transplantation. In 5 of the 14 studies reviewed there was no information on how the diagnosis of cirrhosis was made; in 3 studies it was histologically confirmed in all patients and in the remaining 6 it was based on clinical signs, laboratory data, hepatic imaging, endoscopic findings, and/or on liver biopsy. The aetiology of the cirrhosis was typically mixed; patients with alcohol-related cirrhosis were not included in 9 of the 14 studies; in the remaining studies few details were provided on current drinking behavior. None of the studies included patients with Wilson’s disease. Two studies excluded patients with diabetes. Patients with noncirrhotic, alcohol-related liver injury, noncirrhotic chronic active hepatitis, and acute hepatic failure were included in 5 of the studies. Thus, the patient populations included in at least 7 of these studies were heterogeneous, including patients with alcohol-related chronic liver disease, individuals with noncirrhotic, alcohol-related and non-alcohol-related liver injury, and a number with ill-defined liver disease. Adequate audiometric details were provided in only one study and details on other physiological factors possibly affecting BAEPs, such as gender and body temperature were infrequently detailed. The diagnosis of hepatic encephalopathy was made on clinical grounds, although the criteria applied were not specified in the majority of papers. A percentage of the patients included in these studies had fulminant hepatic failure and hence acute hepatic encephalopathy. In the studies that included or centered on patients with minimal hepatic encephalopathy the diagnosis was based on the absence of clinical evidence of hepatic encephalopathy ± abnormal psychometric test results, slowing of the EEG, or alterations of other evoked potentials (Table 3).

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Table 3. Summary Details of the Studies on the Utility of Brainstem Auditory Evoked Potentials (BAEPs) in the Diagnosis and Monitoring of Hepatic Encephalopathy in Patients with Cirrhosis Articles reviewed: (n) Total –Experimental studies –Commentaries/reviews Publication dates: Patients: (n) Total Mean patients/study Range of patients/study BAEP recordings: (n) Total Mean BAEP recordings/study Healthy controls: (n) Other controls: (n) Diagnosis/exclusion of HE: (number of studies) Clinical Parsons-Smith’s criteriaa Zieve’s criteriab Unspecified Conn’s PSE Indexc Diagnosis of minimal HE: No clinical abnormalities but psychometric, EEG or EP alterations Details on BAEP acquisition: Generally precise Details on BAEP analysis: Quality of the recordings obtained Ease of wave analysis Wave analysis Comparison of raw data (patients/controls) Threshold for abnormal latency/amplitude defined: 2 SD > mean of a reference population 2.5 SD > mean of a reference population 3 SD > mean of a reference population a Parsons-Smith b Zieve, 1982. c Conn

18 14 4 1983–2001 465 33 1–116 510 36 302 — 12 3 1 8 2 6

0 4 9 5 1 1 3

et al., 1957.

et al., 1977.

There appears to be reasonable interstudy consistency in the methods for BAEP acquisition (Table 3). The technique(s) utilized for analysis of the BAEP data are consistent and well detailed, although very little, if any, information was provided on the quality of the recordings obtained or the ease with which they were analyzed. There is considerable variation in the findings of the BAEP studies, more so than for any of the other sensory evoked potentials: • The most commonly reported alterations were prolongation of I, III, IV, and V peak latencies and I–III and I–V interpeak latencies; a positive relationship between latency prolongation and the degree of hepatic encephalopathy has been reported;

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• In comatose patients, the disappearance of wave III was useful in predicting the outcome of coma; • A reduction in wave amplitudes has also been reported, but not consistently; • Prolongation of one or more peak or interpeak latencies was observed in 0–70% of patients with non-alcohol-related cirrhosis with overt hepatic encephalopathy; • Prolongation of one or more peak or interpeak latencies was observed in between 10 and 41% of patients with non-alcohol-related cirrhosis with no clinical evidence of hepatic encephalopathy; varying percentages of such patients showed EEG slowing and/or alterations in other sensory evoked potentials and/or psychometric performance. There is very limited information on the changes in BAEPs in relation to changes in the severity of hepatic encephalopathy or in relation to treatment. The findings, to date, indicate that even when patients are reasonably well-selected and potential confounding variables, such as the aetiology of liver disease, alcohol misuse, and diabetes, are taken into account, BAEP data are too inconsistent to be of diagnostic value in this patient population. Somatosensory evoked potentials (SEPs). A SEP is the electric response, which is evoked in the cerebral cortex by the stimulation of afferent pathways from peripheral nerves to the brain. SEPs comprise i) ii) iii) iv) v)

Early components corresponding to peripheral nerve action potentials; Early components generated in the brainstem; Short- and medium-latency cortical components; The vertex potential; An after discharge.

SEP responses are usually measured following brief electric shocks, administered via skin electrodes, to large, mixed peripheral nerves, such as the median and ulnar nerves at the wrist, the peroneal nerve at the knee, or the tibial nerve at the ankle. Alterations in the various components of SEPs are observed in disorders of the peripheral nervous system, the spinal cord, and the brain and brainstem (Davies et al., 1991; Regan, 1989). A number of studies have been undertaken in which SEP patterns have been assessed in patients with cirrhosis (Table 4). The results are difficult to compare because of interstudy differences in the patient and control populations and in the methods used to acquire and analyze the SEP data. In addition the studies often differ in their fundamental aims. Thus, approximately 40% of the studies aimed simply to provide descriptive data on the changes in SEPs observed in patients with overt hepatic encephalopathy, while in the remainder SEPs were variously used: i) To detect abnormalities in clinically unimpaired patients with cirrhosis and hence to define minimal hepatic encephalopathy; in most of these studies SEP responses were compared with other sensory evoked potentials; ii) To monitor the effects of treatment and orthotopic liver transplantation; iii) To obtain pathophysiological information on the cortical vs. subcortical nature of hepatic encephalopathy.

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Table 4. Summary Details of the Studies on the Utility of Somatosensory Evoked Potentials (SEPs) in the Diagnosis and Monitoring of Hepatic Encephalopathy in Patients with Cirrhosis Articles reviewed: (n) Total –Experimental studies Median nerve Median and peroneal nerves –Commentaries/reviews Publication dates: Patients: (n) Total Mean patients/study Range of patients/study SEP recordings: (n) Total Mean SEP recordings/study Healthy controls: (n) Numbers not provided in four studies Other controls: (n) Diagnosis of HE: (number of studies) Unavailable Clinical Parsons-Smith’s criteriaa Zieve’s criteriab Others Conn’s PSE Indexc Diagnosis of minimal HE: No clinical abnormalities but psychometric, EEG or EP alterations Details on SEP acquisition: (number of studies) Generally complete and precise with regard to stimulation equipment, delivering modality, electrode reference and positioning, recording conditions, number of stimuli delivered, intensity. Cortical SEPs only Cortical and cervical SEPs only Cortical, cervical, and brachial plexus SEPs Details on SEP analysis: (number of studies) Quality of the recordings obtained Ease of waves analysis Wave analysis Comparison of raw data (patients/controls) Threshold for abnormal latency/amplitude defined: 2 SD > mean of a reference population 3 SD > mean of a reference population a Parsons-Smith et al., b Zieve, 1982. c Conn et al., 1977.

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23 18 17 1 5 1983–2002 847 47 5–886 909 50 308 — 1 7 2 1 4 7 8

11 6 1 6 6 9 9 6 3

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In 7 of 18 studies there was no information on how the diagnosis of cirrhosis was made; in 5 studies it was histologically confirmed in all of the patients while in the remaining 6 studies it was based on clinical signs, laboratory data, radiological and endoscopic findings, and/or on liver biopsy. The aetiology of the cirrhosis was typically mixed; patients with alcohol-related cirrhosis were not included in 7 of the studies; details on current drinking behavior were provided in half of the studies in which these patients were included. Patients with other potential causes of peripheral neuropathy, such as diabetes or renal impairment were excluded in a further 7 studies. Patient with noncirrhotic alcohol-related liver injury, noncirrhotic chronic active hepatitis, and acute hepatic failure were included in 9 of the studies. Thus, the patient populations included in at least 11 of these studies were heterogeneous including not only patients with alcohol-related cirrhosis but individuals with noncirrhotic alcohol-related and non-alcohol-related liver injury and a number with ill-defined liver disease. Nerve conduction studies were only undertaken in one study; in the remainder the presence/absence of peripheral neuropathy was determined by anamnestic enquiry and clinical examination, which is clearly inadequate, particularly in patients with a history of alcohol misuse. There appears to be reasonable interstudy consistency in the methods utilized for SEP acquisition (Table 4). Likewise the techniques utilized for analysis of the SEP data are consistent and well detailed, although very little, if any, information is provided on the quality of the recordings obtained or the ease with which they were analyzed. There is considerable greater cohesion in the findings of the SEP studies, in this patient population, than for any of the other sensory evoked potentials. The findings include: • A clear prolongation in the peak and interpeak latencies of the cortical components of the potential, which correlate with the severity of hepatic encephalopathy, mirror clinical improvement/worsening and the beneficial effect of therapeutic manoeuvres, including liver transplantation; • Prolongation of peak and interpeak latencies of one or more of the cortical SEP components was observed in up to 50% of cirrhotic patients with no clinical evidence of hepatic encephalopathy; the majority of these individuals developed overt hepatic encephalopathy during the follow-up period; • Prolongation of peak and interpeak latencies of one or more of the cortical SEP components was observed in up to 100% of cirrhotic patients with overt hepatic encephalopathy; • Late SEP components were significantly distorted or even absent in hepatic coma/ Grade IV hepatic encephalopathy; • A small, not as consistently observed delay in the central conduction time, which is the time required for a stimulus entering the oblongata to reach the primary sensory cortex; • No changes were observed in the latency of the medium-latency cortical component N70 after TIPS insertion, whereas significant parallel increases were observed in the latency of the cognitive evoked P300 latency. The findings to date seem to indicate that, provided peripheral nerve conduction is unimpaired, SEPs provide a promising tool for the diagnosis and the follow-up of hepatic encephalopathy of varying degrees of severity.

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Movement-Related Evoked Potentials Bereitschaftspotential. The Bereitschaftspotential or Readiness Potential is a symmetrical, early potential belonging to the “premonition” subgroup of the movement-related potentials, immediately preceding self-paced movement. It consists of a slow-rising, negativegoing shift arising about 800 ms before a movement, for instance the extension of a finger, most prominent at the vertex. The Bereitschaftspotential characteristics depend on motor force and also on psychological aspects, for instance, the association of the motor response with risk (Regan, 1989). It has been utilized in studies in patients with Parkinsonian syndromes and with chronic fatigue syndrome (Deecke, 2001; Gordon et al., 1999). Bereitschaftspotentials and consensual electromyograms were recorded in a single study in a group of 15 patients with alcohol-related, postnecrotic, or primary biliary cirrhosis and in an age-matched population of healthy individuals. All subjects were righthanded; none of the patients was currently drinking alcohol or had overt signs of hepatic encephalopathy; two patients had Grade A electroencephalographic abnormalities according to Parsons-Smith et al. (1957). The amplitude of the early component and the peak negativity of the Bereitschaftspotential before the electromyogram onset were significantly reduced in the patient group. There were no relationships between the Bereitschaftspotential amplitudes and the pallidal signal in T1-weighted MRI images or with plasma ammonia concentrations. These findings indicate a defect in the activity of the cortical areas involved in movement preparation (Kulisevsky et al., 1995). Subtle motor abnormalities, particularly mild extrapyramidal symptoms, resembling those observed in Parkinson disease and cerebellar dysfunction, are frequently encountered in patients with even minimal hepatic encephalopathy. It has recently been demonstrated, using computer-assisted movement analysis, that the bradykinesia observed in patients with minimal encephalopathy reflects a disturbance in movement initiation (Joebges et al., 2003). Thus, further studies utilizing the Bereitschaftspotential and other movement-related evoked potentials are warranted in order to quantify the motor dysfunction in hepatic encephalopathy.

Cognitive Evoked Potentials P300. P300 is a cognitive evoked potential elicited when the subject receives an infrequent stimulus embedded in a series of otherwise irrelevant frequent stimuli (“oddball” paradigm); the subject is asked to identify the rare stimuli (“oddballs”) by pressing a button or else to keep a mental count of their occurrence. The potential is elicited independently of the sensory modality used to deliver the stimulus—visual, auditory, or olfactory—and occurs about 300 ms (range 250–1000) after exposure to the rare stimulus, hence its name. The P300 complex can be resolved into its subcomponent waves P3a and P3b (Squires et al., 1975). P3a occurs earlier in the complex, is more prominent frontally and probably relates to the involuntary identification of the infrequent stimulus; P3b is more prominent parietally, has a latency of about 50 ms longer than that of P3a and probably relates to the voluntary identification of the infrequent stimulus. Sometimes the denomination P3a is given to the wave which arises in response to infrequent stimuli in subjects who have not been instructed to note them, that is to say in a “passive” oddball paradigm (Jeon and Polich, 2001).

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A variety of factors can influence the amplitude, latency, and distribution of P300; the rare stimulus probability is the most important determinant of amplitude, to which it is inversely related, while age and task difficulty tend to be directly related to latency. P300 has been applied in clinical conditions such as cortical and subcortical dementias, head injuries, epilepsy, alcohol misuse, and various psychiatric disorders. The most common effect of dementing illnesses on P300 is prolongation of latency (Barrett, 1993); alcoholic patients and their at-risk relatives consistently show a reduction in the wave amplitude, while the effects of alcohol on the latency of the potential vary depending on the recency of consumption (Nacher, 2000). A number of studies have been undertaken in which P300 patterns have been assessed in patients with cirrhosis (Table 5). In contrast to the other neurophysiological tools, the recording of P300 requires patient cooperation. Thus, this technique has only been utilized in patients with cirrhosis who have little or no clinical evidence of hepatic encephalopathy. The results of the studies undertaken to date are difficult to compare because of interstudy differences in the patient and control populations and in the methods used to acquire and analyze the P300 data. In addition the studies often differ in their fundamental aims. Thus, approximately 50% of the studies aimed simply to provide descriptive data on the P300 changes observed in patients with cirrhosis with no evidence of overt encephalopathy and/or to compare the prevalence of P300 abnormalities observed in these patients with the prevalence of other electrophysiological or psychometric abnormalities. In the remainder P300 was variously used: i) To evaluate its predictive value for the development of overt hepatic encephalopathy; ii) To compare its features in patients with hepatic and uraemic encephalopathy; iii) To monitor the effects of dietary manipulation and TIPS insertion. In 12 of the 15 P300 studies the diagnosis of cirrhosis was based on liver biopsy findings in all but a minority of patients. In the remaining 3 studies the diagnosis was based on a variety of clinical signs, laboratory data, ultrasound, and endoscopic findings. The aetiology of the cirrhosis was typically mixed; patients with alcohol-related cirrhosis were included in the majority of studies: the period of abstinence required for inclusion varied from 1 to 6 months. In 4 studies the aetiology of the liver injury was taken into account when analyzing the results. In 3 studies age was taken into account when analyzing the results, but in most of the others an age-matched group of healthy subjects was used for reference. The diagnosis of hepatic encephalopathy was made, or more often excluded, on clinical grounds although the criteria applied were not specified in the majority of papers. Where studies included or centered on patients with minimal hepatic encephalopathy the diagnosis was based on the absence of clinical evidence of hepatic encephalopathy ± abnormal psychometric test results, slowing of the EEG, or alterations in other evoked potentials (Table 5). There were notable and significant differences in the ways in which the P300 data were acquired and analyzed (Table 5): • Nine studies used the auditory and six the visual modality; • The probability of the rare stimulus ranged from 8 to 20%;

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Table 5. Summary Details of the Studies on the Utility of Auditory and Visual P300 Wave Analysis in the Diagnosis and Monitoring of Hepatic Encephalopathy in Patients with Cirrhosis Articles reviewed: (n) Total –Experimental studies Auditory P300 Visual P300 Publication dates: Patients: (n) Total Mean patients/study Range patients/study P300 recordings: (n) Total Mean P300 recordings/study Healthy controls: (n) Other controls: (n) Diagnosis of HE: (number of studies) Clinical Parsons-Smith’s criteriaa Others Conn’s PSE Indexb Diagnosis of minimal HE: No clinical abnormalities but psychometric, EEG or EP alterations Details of P300 acquisition: Stimulus probability (range) Stimulus probability 20% (number of studies) Subject’s task (number of studies) Run a mental count of the rare stimuli Push a button in response to the rare stimuli EEG site at which P300 was measured: (number of studies) Fz Cz Pz Fz, Cz and Pz Unspecified Determination of most appropriate operating conditions by variation of electrode number/placement Details of P300 analysis: (number of studies) Quality of the recordings obtained Baseline length prior to stimulus delivery specified Wave analysis Comparison of raw data (patients/controls) Threshold for abnormal latency defined: 2 SD > mean of a reference population Determination of P3a and P3b Topographical analysis a Parsons-Smith et al., b Conn et al., 1977.

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15 15 9 6 1990–2002 710 47 6–104 810 54 461 49 12 2 10 3 11 12–20% 8 15 11 4 4 5 1 3 2 1

5 5 5 10 10 3 2

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• The accuracy of the subject in responding to the rare stimuli or reporting their count was considered in only a few studies; use of this measure would allow noncompliant patients to be excluded; • In the majority of studies subjects were asked to keep a mental count of the number of rare stimuli rather than marking their occurrence by pushing a button. The latter technique is preferable, for a number of reasons, including – The subject’s ability to distinguishing between the rare and frequent stimuli can be gauged immediately; – Accuracy is measured unequivocally on single responses; – The motor response provides additional information as the reaction time is simultaneously recorded. The only possible draw-back of this technique is the superimposition of a movementrelated potential. • The recording sites varied, but all were reasonable for the detection of the overall P300 complex. There is reasonable cohesion in the findings of the P300 studies in this patient population. The findings include: • A systematic, significant prolongation of the P300 latency and, more rarely, a reduction in amplitude; • Between 90 to 100% of patients with mild encephalopathy and 20 to 60% of those with Grade 0 encephalopathy showed significant prolongation of P300 latency. No significant difference was observed in P300 latency between patients with alcohol and non-alcohol-related liver disease; • P300 latency prolongation correlated with the severity of the hepatic encephalopathy; • The abnormal P300 latency prolongation in patients with minimal hepatic encephalopathy predicted the subsequent development of overt hepatic encephalopathy; • The prolongation of the P300 latency evoked by a visual oddball paradigm has been claimed to have higher sensitivity than the latency prolongation evoked by an auditory oddball paradigm. P300 is modality-independent and therefore comparisons between the results of visual and auditory paradigms are allowed in theory. Nonetheless, the differences found might relate to the fact that P300 is task-difficultydependent and even if the stimulus probability were the same, it would be virtually impossible to match cross-modality tasks for exact task demand; • The diagnostic efficacy of changes in visual P300 latency in the passive condition was found to be lower than in the active condition, but a comparison between active and passive paradigms was performed in only one study and needs to be confirmed; • The prevalence of abnormal P300 latency in patients with cirrhosis with no clinical evidence of hepatic encephalopathy was typically higher than the prevalence of abnormal NCT-A test results and EEG slowing; • The latencies of both P3a and P3b were prolonged in patients with cirrhosis with no clinical evidence of hepatic encephalopathy; • Changes in P300 amplitude showed less consistent changes than those reported for latency, which may reflect:

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– Variability of the length of the baseline prior to stimulus used as a reference for the measurement; – Inclusion of patients with alcohol-related cirrhosis, as alcohol itself causes a reduction in P300 amplitude. • P300 amplitude tended to be reduced in patients with both overt and minimal hepatic encephalopathy; • P300 amplitude decreased following TIPS insertion, although the prolongation in P300 latency was more notable; • Two studies attempted to assessment the stability of P300 measurements over time, with the following results: – The coefficient of variation for P300 latency and amplitude measurements, in clinically stable patients with chronic liver disease, over a 3-month period, were 4.9 and 24% respectively. – Measurements of P3a and P3b latencies, repeated at 8-min intervals, over a 1-h period, yielded mean standard deviations of 12 and 13 msec, respectively. Assessment of P300 latency appears to have diagnostic potential for detecting the presence of minimal hepatic encephalopathy and for monitoring the status of patients with mild to moderate hepatic encephalopathy over time. The techniques currently employed are not suitable for use in patients with more severe encephalopathy because of the need for patient cooperation. The potential of P300 has not been entirely explored in this patient population as: • More information is needed on the relative roles and importance of P3a and P3b as this might provide insights into the cognitive correlates of hepatic encephalopathy; • More extensive use of the passive paradigm may allow assessment of its diagnostic potential in patients with more severe degrees of hepatic encephalopathy; • The potential mismatch negativity, which can be obtained from an oddball paradigm simply by wave subtraction, has never been tested in this patient population. Mismatch negativity directly reflects vigilance and the process of shifting attention (Gen´e-Cos et al., 1999) and it can be identified and recorded in unconscious or otherwise incapacitated individuals (Fischer et al., 2002); • Variations of the oddball paradigm, such as the introduction of random sounds in the sequence of frequent and infrequent tones, in order to evoke the so-called “P3a novel,” have never been applied to this patient population (Squires et al., 1975). Contingent negative variation (CNV). In the mid-1960s a slow negative shift in potential was described, occurring between a warning stimulus (S1) and an imperative stimulus (S2); this potential reached maximum amplitude just before S2 and was named Contingent Negative Variation (CNV). In the original experiment S1 was a click and S2 was a series of light flashes which had to be extinguished by the subject as rapidly as possible by pressing a response button; it was subsequently demonstrated that the potential was independent of the nature of the stimuli used at S1 and S2 (Walter, 1964). In a single study undertaken in a group of 26 patients with ill-defined hepatic impairment, no difference was observed in this potential between those with and without overt hepatic encephalopathy (Jones et al., 1976).

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The application of CNV in a wider and better defined population of cirrhotic patients with different degrees of hepatic encephalopathy is probably warranted. Critical Flicker Frequency (CFF) An individual’s Critical Flicker Frequency (CFF) is the highest frequency in cycles per second at which the flicker of a flickering light source can be detected; at frequencies above the cutoff the light source appears to be continuous even though it is still flickering. CFF is thought to reflect not only the efficiency of the visual pathways, but also of the cerebral cortex. Alterations in CFF have been detected in patients with multiple sclerosis and Alzheimer’s disease, and in individuals consuming psychoactive drugs. CFF has also been used as an attention indicator (Kraemer et al., 2000). In a single, well designed and executed study, undertaken in a carefully characterized population, CFF thresholds were shown to be proportionately lower in patients with minimal and overt hepatic encephalopathy than in healthy controls and in cirrhotic patients who were neuropsychiatrically unimpaired. The reduction in CFF threshold showed a significant reverse correlation with the severity of the hepatic encephalopathy and a threshold value was defined which separated the unimpaired and impaired patients. A reduction in the CFF threshold was observed following the development of hepatic encephalopathy in relation to TIPS insertion while an increase in the CFF threshold was observed in response to treatment. The authors hypothesized that the changes observed in CFF threshold reflect the presence of an hepatic retinopathy, the presence and severity of which exactly mirrors the cerebral changes observed in these patients (Kircheis et al., 2002). This interesting work needs to be replicated and the relationship between CFF, attention deficits and retinal changes explored. Smooth Pursuit Eye Movements (SPEM) Smooth Pursuit Eye Movements (SPEM) are the conjugate movements that track the smooth, predictable trajectories of small targets. Unilateral or bilateral abnormalities of pursuit movements are observed in a variety of clinical situations (Yee, 1983) including: i) The presence of lesions of the anterior or posterior cerebral cortex, the pons, and the cerebellum; ii) Degenerative cerebral disorders such as Alzheimer’s disease, Parkinsonism, and Huntington’s chorea; iii) In patients with schizophrenia and their first degree relatives; iv) In patients taking certain neuroactive drugs. In a single well-designed, carefully executed study undertaken in a well-characterized population, impairment of SPEM was observed in relation to both the presence and severity of hepatic encephalopathy and mirrored the changes observed in clinical status and psychometric performance over time and following treatment (Smith et al., 1997). This work needs to be replicated and the relationship between SPEM abnormalities, attention deficits, retinal changes, and motor impairment explored. The recording of SPEM at different target frequencies and the assessment of the effect of distractive (Kathmann et al.,

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2003) and attention-enhancing (Rosenberg et al., 1997) tasks on SPEM in cirrhotic patients are worthy of further study. Neuroimaging Techniques In the last 10 to 15 years there have been major advances in neuroscience as a result of the development of computed X-ray tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), single photon emission tomography (SPET) and positron emission tomography (PET), and their functional imaging counterparts. These techniques allow relatively rapid and noninvasive assessment of cerebral structure, neurophysiology, and neurobiology. In clinical practice neuroimaging, generally cerebral CT or MRI, has been used simply to exclude other causes of cerebral dysfunction in patients with cirrhosis. However, in the research setting these techniques have provided significant insights into the pathophysiology of hepatic encephalopathy (C´ordoba et al., 2001; Lockwood et al., 1993; Taylor-Robinson et al., 1994; Weissenborn et al., 1995). These techniques are expensive and not readily accessible and this limits their diagnostic potential in the clinical setting, at least at present. Electrical impedance tomography, a new, fast neuroimaging technique, which produces images of the electrical impedance of the head using scalp electrodes, might represent a cheap alternative for use in the clinical setting (Tidswell et al., 2001). A MULTIDIMENSIONAL DIAGNOSTIC APPROACH There are considerable problems with the way in which the proposed candidate tools for assessing hepatic encephalopathy have been evaluated. Although this reflects, to a large extent, the fact that there is no validated “gold standard”or reference diagnostic technique, it also reflects some fundamental misconceptions and problems with study aims and designs, viz: • In the majority of studies patients have been characterized as having hepatic encephalopathy on the basis of clinical findings and as having minimal hepatic encephalopathy on the basis of a normal clinical examination but the presence of impaired psychometric performance and/or neurophysiological performance. It is highly likely, however, that the examination of these patients was not as broad or as comprehensive as the recent recommendations require (Ferenci et al., 2002). Any evaluation of potential diagnostic techniques, which relies on an imperfect or inaccurate classification of patients’ clinical neuropsychiatric state, must be suspect; • The concept that the diagnostic utility of a method for assessing one aspect of cerebral function can be judged against a method that assesses a fundamentally different aspect of cerebral function is flawed; • Judging “diagnostic sensitivity” on the basis that the test producing the highest number of abnormal results must be the most sensitive and hence the reference method for assessing other tests, cannot be justified. Clearly, therefore, a new approach to the problem of diagnosing hepatic encephalopathy is needed on the basis of the concept that hepatic encephalopathy is a continuum ranging from minor clinically indiscernible abnormalities to Grade IV coma. This would mean

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that the neuropsychiatric abnormalities in patients with cirrhosis would need to be redefined using a multidimensional approach, which encompassed motor, affective, behavioral, cognitive, and bioregulatory domains. Each domain should be separately scored and the scores combined to provide an overall final index. Cutoff scores could be determined or else patients could be allocated a raw score, which could then be used to gauge the effects of treatment or to monitor progress over time. There are some obvious candidate tools for assessment of categorical variables but initially it would be important to try to include as many potential tools as possible. In addition there are a number of alternative methods for processing and analyzing electrophysiological data and a number of newer techniques, which, if validated, could be included. It is clearly important that the new tool is relatively simple and quick to use in the clinical setting but robust enough to be used in the research setting. In consequence it is likely that more than one version of the assessment tool will be needed with the level of complexity increasing with the degree of precision required. Collecting these data and devising the multidimensional assessment tool will be a major undertaking. The tool would need to be extensively validated across language and culture. It is unlikely that any one center could undertake this work in its entirety. However, the potential candidate tools could be validated in a small number of centers and the final instrument then assessed under the auspices of a multicenter study. Considerable effort and expertise has been expended, to date, to find the elusive diagnostic “gold standard” for hepatic encephalopathy. The multidimensional approach outlined above represents a much more rational approach. REFERENCES Adams, R.D., and Foley, J.M. (1953). The neurological disorder associated with liver disease. Res. Publ. Assn. Res. Nerv. Ment. Dis. 32:198–237. Amodio, P., Del Piccolo, F., Petten´o, E., Mapelli, D., Angeli, P., Iemmolo, R., Muraca, M., Musto, C., Gerunda, G., Rizzo, C., Merkel, C., and Gatta, A. (2001). Prevalence and prognostic value of quantified electroencephalogram (EEG). Alterations in cirrhotic patients. J. Hepatol. 35:37–45. Amodio, P., Marchetti, P., Del Piccolo, F., Campo, G., Rizzo, C., Iemmolo, R.M., Gerunda, G., Caregaro, L., Merkel, C., and Gatta, A. (1998a). Visual attention in cirrhotic patients: A study on covert visual attention orienting. Hepatology 27:1517–1523. Amodio, P., Marchetti, P., Del Piccolo, F., de Tourtchaninoff, M., Varghese, P., Zuliani, C., Campo, G., Gatta, A., and Gu´erit, J.M. (1999). Spectral versus visual EEG analysis in mild hepatic encephalopathy. Clin. Neurophysiol. 110:1334-1344. Amodio, P., Marchetti, P., Del Piccolo, F., Rizzo, C., Iemmolo, R.M., Caregaro, L., Gerunda, G., and Gatta, A. (1998b). Study on the Sternberg paradigm in cirrhotic patients without overt hepatic encephalopathy. Metab. Brain Dis. 13:159–172. Amodio, P., Wenin, H., Del Piccolo, F., Mapelli, D., Montagnese, S., Pellegrini, A., Musto, C., Gatta, A., and Umilt`a,C. (2002). Variability of trail making test, symbol digit test and line trait test in normal people. A normative study taking into account age-dependent decline and sociobiological variables. Ageing: Clin. Exp. Res. 14:117-131. Barrett, G. (1993). Clinical applications of event-related potentials. In (A.M. Halliday, ed.), Evoked Potentials in Clinical Testing, Churchill Livingstone, London, pp. 589–633. Bauer, G., and Bauer, R. (1999). EEG, drug effects and central nervous system poisoning. In (E. Niedermeyer and F. Lopes Da Silva, eds). Electroencephalography, Basic Principles, Clinical Applications, and Related Fields, 4th edn., Williams & Wilkins, Baltimore, pp. 671–691. Bustamante, J., Rimola, A., Ventura, P.J., Navasa, M., Cirera, I., Reggiardo, V., and Rod´es, J. (1999). Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J. Hepatol. 30:890–895. Conn, H.O., Leevy, C.M., Vlahcevic, Z.R., Rodgers, J.B., Maddrey, W.C., Seeff, L., and Levy, L.L. (1977). Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 72:573–583.

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