Journal of Hepatology
Volume 34, Issue 5 , Pages 768-773, May 2001

Neuropsychological characterization of hepatic encephalopathy

  • Karin Weissenborn

      Affiliations

    • Department of Neurology, Medizinische Hochschule Hannover, 30623 Hannover, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49-511-532-2391; fax: +49-511-532-3115
    • ,
  • Jochen C Ennen

      Affiliations

    • Department of Neurology, Medizinische Hochschule Hannover, 30623 Hannover, Germany
    • ,
  • Hans Schomerus

      Affiliations

    • Department of Gastroenterology and Hepatology, Diakonie-Krankenhaus Rotenburg/Wümme, 27342 Rotenburg/Wümme, Germany
    • ,
  • Norbert Rückert

      Affiliations

    • Department of Psychology, Evangelische Fachhochschule Hannover, 30625 Hannover, Germany
    • ,
  • Hartmut Hecker

      Affiliations

    • Department of Biometrics, Medizinische Hochschule Hannover, 30623 Hannover, Germany

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1. Introduction 

The neuropsychological features of hepatic encephalopathy (HE) were described centuries ago. Hippocrates stated that “those who are mad on account of phlegm are quiet, but those on account of bile are vociferous, vicious, and do not keep quiet” [1]. It can be assumed that Hippocrates was describing a patient with acute liver injury. Patients with fulminant hepatic failure often present with agitation and restlessness. The behaviour of cirrhotics with HE, however, is dominated by significant psychomotor slowing. The first comprehensive study of the neuropsychiatric manifestations of HE was performed by Sherlock et al. in 1954 [2]. The authors described the clinical presentation of 18 patients with liver disease and neurological signs. In all subjects, clouding of consciousness was accompanied with a loss of facial expression and speech disturbances together with a disorder of the motor system represented by asterixis, tremor, increased tendon reflexes, increased muscle tone and ataxic gait. In a subsequent paper the same group [1] vividly described the disturbances of visual perception in patients with HE. They observed visual agnosia, macropsia, distortion and prolongation of the images, spatial disorientation and a predominance of visual hallucinations. Auditory, tactile, olfactory and gustatory hallucinations were noted in rare cases. The patients' moods fluctuated, while varying degrees of personality change could be observed in all patients even in the early stage of the disease.

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2. ‘Subclinical’ vs. ‘minimal’ encephalopathy 

Since the 1970s, several groups have shown that many patients with cirrhosis who present without clinical signs of encephalopathy do significantly worse in psychometric tests when compared to healthy controls [3], [4], [5], [6], [7], [8], [9], [10]. They were regarded as suffering from ‘latent’ or ‘subclinical’ HE, a term that has been recently replaced by the term ‘minimal HE’ [11], [12]. A common finding of all studies was a worse performance of cirrhotic subjects in tests of psychomotor speed, visual perception and attention, while their verbal ability was unimpaired. Schomerus et al. [8] concluded that the cerebral dysfunction in minimal HE had a major impact on the patients' daily living. In their study [8], 40 cirrhotic patients without clinical signs of HE and a control group of 12 patients with alcoholic pancreatitis underwent a comprehensive psychometric examination used for expert evaluation of the capacity to drive a vehicle. Of the cirrhotic patients, 60% were considered unfit to drive, in 25% driving capacity was questionable, and only 15% – all of them non-alcoholic cirrhotics – were considered fit to drive. In contrast, 75% of the patients with alcoholic pancreatitis were considered fit to drive. This finding was confirmed, in principle, by Watanabe et al. [13] in 1995, while Srivastava et al. [14] after a praxis test in 15 patients were not convinced that patients with minimal HE are in fact unfit to drive a car.

An analysis of the patients' earning capacity was also performed [15]. This study showed that 73% of the cirrhotics who were blue collar workers had an impaired earning capacity in the presence of minimal HE; 50% of the white collar workers were fit for work even in the presence of minimal HE due to the preservation of verbal abilities in this condition. While 80% of the white collar workers suffering from cirrhosis were considered fit for work, only 40% of the blue collar workers met such criteria [15]. These data underscore the importance of a significant impairment of motor performance in minimal HE where verbal abilities appear unaffected.

Groeneweg et al. [16] analyzed the impact of minimal HE on daily functioning by applying the ‘sickness impact profile’ (SIP) – a questionnaire consisting of 136 statements considering ambulation, mobility, body care, social interactions, alertness, emotional behaviour, communication, sleep and rest, home management, recreation and pastime or work – to 179 cirrhotic outpatients. Forty-eight patients suffered from minimal HE, while the remaining 131 patients were normal with regard to the clinical examination, psychometric test results and EEG. The authors found a diminished level of daily functioning in the patients with minimal HE reflected by significantly more impairments in all categories of the SIP. The sum of these studies indicates an important influence of minimal HE on the patients' daily functioning and quality of life. Minimal HE is clinically significant. Experts in the field discourage the use of the term ‘subclinical HE’ as such a connotation runs the risk of considering this mildest degree of HE void of clinical significance. A consensus has emerged that patients with minimal HE should be treated [12].

Unfortunately, the diagnostic approach to the assessment of minimal HE is not uniform. Various combinations of psychometric tests with or without neurophysiologic measures like EEG and evoked potentials have been assessed for their use in the diagnosis of minimal encephalopathy [17], [18], [19], [20], [21], [22]. Table 1 lists some of these studies. Although the studies are not comparable, most of them recommend the application of the number connection test (NCT), the digit symbol test and/or the block design test for the diagnosis of minimal HE. However, Table 1 also illustrates the shortcomings of most of the studies. In only a few studies was a comprehensive battery of psychometric tests applied [18], [19], [20] and in only a few studies were the patients' data compared to an appropriate number of healthy matched controls (especially for age) [20], [21] or to normal data given in the literature [22]. Therefore, a ‘gold standard’ to diagnose minimal HE has not been defined.

Table 1. Trials for evaluation of neurophysiological and/or neuropsychological measures for the diagnosis of minimal HE
Loguercio et al. [17]Koch et al. [20]Sood et al. [19]Gitlin et al. [18]Weissenborn et al. [21]Quero et al. [22]
SubjectsCi: 45, Co: 35, not matchedCi: 146, Co: 146Ci: 20, Co: 18Ci: 37, Co: 19 (med. disorders)Ci: 66, Co: 56Ci: 137, Co: literature
NCT AXXXXXX
NCT B XX
Hand testX
Simple RTXX
Multiple choice RT X
Mini mental state X
Digit span X
Line drawing X
Digit symbol XXX X
Block design XXX
Picture completion XXX
Picture arrangement XXX
Object assembly XXX
WAIS verbal IQ XX
Memory tests X
EEG XXX
VEP X X
P300 X
RecommendationNCT AMultiple choice RT, digit symbol, block designNCT A, block designNCT A, block design, digit symbolNCT B, P300NCT A, digit symbol, EEG

One of the most comprehensive attempts to understand the neuropsychological characteristics of minimal HE was performed by Hamster [11], [15]. On a whole, he applied more than 30 psychometric tests, including measures of premorbid intelligence levels, verbal abilities, mnestic function, attention, psychomotor function, visual perception and visuo-constructive abilities, to 96 cirrhotics compared to 163 age-matched healthy controls, 20 patients with alcoholic pancreatitis and 19 patients with alcoholic polyneuropathy and cerebral atrophy but no cirrhosis. To determine the specificity of the neuropsychological deficit in minimal HE, a multiple group stepwise discriminant analysis of the test results was performed. The following tests were found to discriminate best between cirrhotics and non-cirrhotics: line tracing, peg board, aiming and steadiness of the motor performance scale and the digit symbol test [11]. The NCT was not considered for this discriminant analysis as it was thought to be represented by and to resemble the attention diagnostic method, a test that requests the subject to point to subsequent numbers of different size which are randomly distributed on a digit table.

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3. A standardized battery to diagnose minimal HE 

We decided to standardize and evaluate a ‘paper and pencil’ test battery for the assessment of minimal HE – the psychometric hepatic encephalopathy score (PHES) – that in accordance with the data of Hamster [11], [15] included seven tests: the line tracing test, the serial dotting test, the digit symbol test, NCTs A and B, the digit span test and the cancelling d-test [23]. The NCTs were included considering their widespread use as psychometric tests in cirrhotic patients. The digit span and the cancelling d-test were studied because they are appropriate to measure deficits of attention – a cognitive domain significantly altered in these patients [10], [12]. We performed a two step standardization procedure of the test battery mentioned above in healthy controls [25]. In the first step, those tests which had not yet been standardized were presented to healthy volunteers – that is, NCTs A and B, the line drawing test, the serial dotting test and a digit symbol test. NCTs A and B were performed by 249 healthy volunteers (99 male) aged 18–76 years (mean 40.2 years, SD 14.7) [26], while 131 healthy subjects (60 male) aged 16–76 years (mean 40.1 years, SD 14.1) were examined with the line drawing test, the serial dotting test and the digit symbol test. The analysis of the test results with the Kolmogorov–Smirnov test showed that they were normally distributed only after logarithmic transformation. After such a transformation, all data showed a linear dependence on age with normally distributed residuals of homogenous variance as proven by linear regression analysis and the Kolmogorov–Smirnov test. Thus, the regression lines together with parallel lines of ±1, ±2 and ±3 standard deviations were calculated, yielding the known normal quantiles, especially the 95% range between x−2s and x+2s for each single test [23], [27]. Fig. 1 shows the results that exemplify the serial dotting test.

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  • Fig. 1. 

    (A) Linear age-dependence of the serial dotting test results after logarithmic transformation. (B) Transformation of the regression line and the standard deviation lines of the serial dotting test into the original scale.

In the second step, the results of the whole test battery in a group of 120 healthy volunteers (53 male) aged 16–76 years (mean 40.5 years, SD 14.3) were compared to the results of a control group of 24 in-patients with inflammatory bowel disease (ten male, aged 34.9±14.7 years), 63 cirrhotics with grade 0 HE (38 male, aged 42.8±15.1 years; child grade: A, n=20; B, n=27; C, n=16) and 25 cirrhotics with grade 1 HE (14 male, aged 50.2±10.8 years; child grade: A, n=10; B, n=9; C, n=6). The grading of HE was done according to the criteria given by Adams and Foley [28]. Patients with alcoholic cirrhosis were excluded. In addition to alcoholism, exclusion criteria for all groups were concomitant neurological and psychiatric disorders or internal diseases like atherosclerosis, diabetes, renal failure or the use of drugs acting at the central nervous system. The test results of all subjects were evaluated according to the age-related standard values elaborated before. For the digit span and the cancelling d-test, normal ranges given in the literature were used [29], [30].

Test results within the ±1 SD range were scored with 0 points, those between 1 and 2 SD beyond the mean were scored with −1 point, those between 2 and 3 SD were scored with −2 points and those worse than the mean plus 3 SD were scored with −3 points. Results better than the mean plus 1 SD were scored with 1 point. Since on a whole, not seven but nine single test results were evaluated (the line drawing test and the cancelling d-test each submit two results – time needed and number of errors in the line drawing test and number of correctly identified ds and the percentage of errors in the cancelling d-test) the subjects could achieve between +9 and −27 points for the whole battery. The healthy controls scored between +6 and −5 points (mean 0.95, SD ±2.35). The 95% range between x−2s and x+2s was −3.75 to +5.65 points. Therefore, the cut-off between normal and pathological results in the test battery was set at −4 points. With respect to this cut-off no subject in the group with inflammatory bowel disease achieved a pathological test result (range +5 to −3, mean 0.96, SD ±2.03). The cirrhotics with grade 1 HE scored between −5 and −27 points (mean −15.44, SD ±5.91), and those with grade 0 HE scored between +4 and −20 points (mean −2.94, SD ±4.36). Twenty-five percent of the grade 0 HE patients were rated with less than −4 points, and could be regarded as suffering from minimal HE.

The results of the single tests were regarded to be pathological if they were beyond the 2 SD range of the normal data to the pathologic direction. Thus, the specificity of each test is expected to be approximately 97.5%. The same conclusion holds for the total score. When examining sensitivity, a comparison of the single tests showed that the patients with grade 1 HE mainly accrued pathological results with the serial dotting and the digit symbol test (Table 2). However, the sensitivity of the test battery clearly surpassed that of the single tests used. Each test of the battery was checked for its contribution to the battery's sensitivity. It became obvious that an exclusion of the digit span and the cancelling d-test had only a minor impact on the subjects' classification as ‘normal’ or ‘encephalopathic’ (Fig. 2). Therefore a re-analysis of the results was done excluding both tests. Now, a total score of +6 to −18 points could be achieved. The cut-off between normal and pathological results was again set at −4 points with regard to the mean total score of the healthy controls (mean 0.50, SD 1.83). The specificity and sensitivity of the PHES changed only slightly. The sensitivity was now 96%, and the specificity was 100% (Table 2). An additional exclusion of the line drawing test would have reduced the sensitivity to 84% while the specificity remained at 99%.

Table 2. Number of pathological results in the different neuropsychological tests and sensitivity and specificity of the single tests and the test battery (portosystemic encephalopathy (PSE) test score) (a) before and (b) after exclusion of the cancelling d-test and digit span test results
Healthy volunteers (n=120)Inflammatory bowel disease (n=24)HE 0 (n=63)HE 1 (n=25)Sensitivity % with regard to HE 1Specificity (expected 97.5%)
NCT A0061456100
NCT B117176899.2
Serial dotting test2014218498.3
Digit symbol test5011208095.8
Line drawing time3010124897.5
Line drawing errors316104097.5
Cancelling dprocessed items104176899.2
Cancelling d errors102114499.2
Digit span001416100
PSE test score (a)10172510099.2
PSE test score (b)00142496100
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  • Fig. 2. 

    Comparison of the portosystemic encephalopathy test score of healthy controls, patients with inflammatory bowel disease, and patients with HE grade 0 and HE grade 1 after exclusion of the digit span and the cancelling d-test results.

We also performed a discriminant analysis to discriminate between patients with grade 1 HE and controls before this simple calculation of the score was chosen to be the adequate means to represent cerebral dysfunction in HE. The discriminant analysis gave comparable results with respect to sensitivity and specificity. However, a discriminant analysis yields different, real valued coefficients for each of the tests that have to be considered in the calculation of the total score. Since this is more complicated in clinical practice than merely to sum up the results of the single integer classification points we decided to do without these coefficients.

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4. Conclusion 

The results of this study have led us to recommend a test battery including NCTs A and B, the line drawing test, the serial dotting test and the digit symbol test for the assessment of minimal HE [24]. This battery examines motor speed and accuracy, visual perception, visuo-spatial orientation, visual construction, concentration, attention and to a lesser extent memory. None of the tests is a true classical test of attention. However, a successful performance of all tests requires an unimpaired attention ability, arguing against the inclusion of additional attention tests like the digit span test and the cancelling d-test in the battery. The low sensitivity of the latter tests and the time required to perform them supported this decision.

We have started to apply the PHES to a large number of cirrhotic patients in different studies. It proved to be a short, objective, valid and reliable test that could be easily applied even at the bedside. It has enabled us to differentiate clearly between patients with and without minimal HE. This assumption is supported by patient groups differentiated according to their PHES results, who also differed significantly in the characteristics of diadochokinetic movements [31], attention and memory test results [32] and cerebral ammonia metabolism [33]. In a recent study of resting-state cerebral glucose metabolism in cirrhotics by fluoro-desoxyglucose positron emission tomography a correlation between regional glucose metabolism and the PHES results showed a significant positive correlation between the test results and the glucose utilization of the anterior cingulate, and bifrontal and biparietal regions of the cerebral cortex, while a negative correlation was found for the glucose utilization of the putamen and the hippocampus for example [34]. Thus, it could be shown that the PHES is able to adequately represent the extent of cerebral dysfunction present in minimal HE.

Groeneweg et al. [35] have recently estimated the probability of minimal HE in a patient by calculating an ‘SHE probability’ score that considers the patient's sex, child Pugh score, presence of oesophageal varices and five statements of the SIP before doing further “costly psychometric or neurophysiological tests”. Since it takes 10–20 min to carry out and to evaluate the PHES, we believe it is reasonable to perform the test rather than to estimate the presence of minimal HE. Even if the test result is normal, it can be used as a basis for follow-up examinations, since four parallel versions of the test have been elaborated [27]. Further studies have to clarify whether neurophysiological tests like the EEG can add valuable information in the assessment of minimal HE compared to the test battery. In a former study of our group [21] the diagnostic sensitivity of the EEG was clearly inferior to NCTs A and B. We believe we can omit an EEG in the diagnosis of minimal HE. Future studies need to validate the results of the PHES achieved in a German sample of healthy controls in relation to other populations before the employment of the test battery can be broadly recommended for the diagnosis of minimal HE.

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Acknowledgements 

This paper is dedicated to Hans Schomerus, who died on 25 December 2000, a few days after we had finished this manuscript. All those who met him knew him as an exemplary human being, physician and scientist. We lost a friend and an outstanding personality. We will never forget him.

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PII: S0168-8278(01)00026-5

Journal of Hepatology
Volume 34, Issue 5 , Pages 768-773, May 2001

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