Liver International ISSN 1478-3223

REVIEW ARTICLE

Neuropsychological assessment of hepatic encephalopathy: ISHEN

practice guidelines
Christopher Randolph1, Robin Hilsabeck2, Ainobu Kato3, Parampreet Kharbanda4, Yu-Yuan Li5, Daniela Mapelli6,
Lisa D. Ravdin7, Manuel Romero-Gomez8, Andrea Stracciari9 and Karin Weissenborn10
1 Department of Neurology, Loyola University Medical Center, Maywood, IL, USA
2 Department of Psychiatry, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX, USA
3 Department of Internal Medicine, Iwate Medical University, Iwate, Japan
4 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
5 Department of Gastroenterology, First Municipal Peoples Hospital of Guangzhou, Guangzhou, China
6 Department of General Psychology, University of Padova, Padova, Italy
7 Department of Neurology, Weill Cornell Medical Center, New York, NY, USA
8 UGC Enfermedades Digestivas, Hospital Universitario de Valme, Sevilla, Spain
9 Department of Neurology, S. Orsola-Malpighi Hospital, Bologna, Italy
10 Department of Neurology, Medizinische Hochschule Hannover, Hannover, Germany

Keywords
assessment encephalopathy hepatic
neuropsychological outcome
psychometric

Correspondence
Dr Christopher Randolph, 1 East Erie, Suite 355,
Chicago, IL 60611, USA
Tel: 11 708 216 3539
Fax: 11 708 216 4629
e-mail: crandol@lumc.edu
Received 11 December 2008
Accepted 24 January 2009

Abstract
Low-grade or minimal hepatic encephalopathy (MHE) is characterised by relatively
mild neurocognitive impairments, and occurs in a substantial percentage of patients
with liver disease. The presence of MHE is associated with a significant compromise of
quality of life, is predictive of the onset of overt hepatic encephalopathy and is
associated with a poorer prognosis for outcome. Early identification and treatment of
MHE can improve quality of life and may prevent the onset of overt encephalopathy,
but to date, there has been little agreement regarding the optimum method for
detecting MHE. The International Society on Hepatic Encephalopathy and Nitrogen
Metabolism convened a group of experts for the purpose of reviewing available data
and making recommendations for a standardised approach for neuropsychological
assessment of patients with liver disease who are at risk of MHE. Specific recommendations are presented, along with a proposed methodology for further refining these
assessment procedures through prospective research.

DOI:10.1111/j.1478-3231.2009.02009.x

Hepatic encephalopathy (HE) is a condition that is relatively

common in patients with liver disease (1, 2), results in significant compromise of quality of life (3, 4), requires a high burden
of care (2), and is associated with poor prognostic outcomes,
including an elevated risk of death (5). Overt HE involves
clinically obvious compromise of consciousness/arousal, behavior, and motor functions. This is typically classified along a
gradient of severity ranging from mild confusion to coma (6, 7).
Low-grade or minimal hepatic encephalopathy (MHE) is
characterised predominantly by a subtle impairment of neurocognitive status, and is not readily detectible via standard
mental status testing or neurological examination. This has also
been termed subclinical HE in the past, because of the lack of
overt clinical symptomatology, but MHE is now the preferred
nosology (8). There is currently a lack of consensus regarding
how best to detect MHE. Early detection of MHE is perceived to
be clinically important; however, as MHE can impair quality of
life (3, 4, 911), it is predictive of the onset of overt HE (1215),
and may have some prognostic value in the outcome for
patients with end-stage liver disease (16). Treatment of MHE
can improve quality of life (17), and may theoretically avert
more severe HE.
A variety of approaches have been used in efforts to detect
MHE, including neuropsychological testing, EEG/evoked
Liver International (2009)
2009 John Wiley & Sons A/S

potentials (1822) and critical flicker frequency (2325), which

is a psychophysiological measure. It is not yet clear as to which
approach is superior in terms of sensitivity and/or clinical
validity. Neuropsychological tests have more face validity in
this context, as they directly measure cognitive functions (e.g.
memory, attention and visuospatial skills) that are directly
relevant to activities of daily living. Biological or psychophysiological markers, on the other hand, may be less affected by
variables such as age, education and language, which are known
to impact performance on neuropsychological tests, and may
therefore complicate interpretation/classification.
Although the neuropathophysiology of MHE is not definitively established, elevated levels of ammonia have been implicated, and a variety of structural and functional imaging studies
have suggested that the primary manifestations of MHE may be
mediated by subcortical systems, including the basal ganglia
(2631). This hypothesis is consistent with neuropsychological
investigations that have attempted to profile the patterns of
impairment in MHE. These typically report a pattern of impairment characterised by prominent deficits in the domains of
attention, visuospatial abilities and fine motor skills (32, 33).
Although these domains (attention, visuospatial abilities and
fine motor skill) are most commonly implicated in MHE,
impairments of memory have also been reported (3438).

629

ISHEN MHE NP recommendations

These appear to be primarily characterised by diminished

immediate memory performance as a consequence of slowed
or inefficient cognitive processing (33, 39, 40). This is distinct
from a primary impairment of anterograde memory produced
by damage to limbic memory systems, as in Alzheimers disease.
Language is typically reported to be intact, with the exception of
slowed verbal fluency. The consistent finding of impaired verbal
fluency performance is also likely secondary to overall slowing
of cognitive processing speed, rather than to an intrinsic
disruption of language.
The attentional impairments in MHE are observed on a
variety of measures. These include measures of cognitive
processing speed involving psychomotor responding, such as
the Number Connection Test or Trailmaking Test and the Digit
Symbol subtest from the Wechsler Intelligence Scales or the
Symbol Digit Modalities Test (1, 17, 37, 4146). Impairments
on measures of cognitive processing speed and response inhibition that do not require a motor response have also been
reported (e.g. with verbal fluency tasks and measures such as
the Stroop test) (33, 4749). Impairments have also been
reported on various measures of attention span/working memory, in both verbal and visual domains (33, 49, 50). In addition,
the use of continuous response-type measures of sustained
attention and freedom from distractibility (e.g. inhibitory
control test) have been reported to be sensitive to impairments
in patients with liver disease (51).
Visuospatial impairments have been primarily reported on
block design tasks (17, 37, 42, 43, 52) (which also include a
motor/practic component), but also on more pure measures of
visuospatial perception, such as line orientation or the Hooper
test (48, 53). Fine motor skill impairments have been noted on
measures such as the grooved pegboard task (33, 47, 54), and on
line tracing tasks (55, 56) (the latter also involve visuospatial
abilities).
The International Society for Hepatic Encephalopathy and
Nitrogen Metabolism (ISHEN) formed a commission to review
the available data on the role of neuropsychological testing in
this context, and to make recommendations regarding the
routine neuropsychological assessment of patients with liver
disease. The commission chairs (C. R. and K. W.) recruited a
panel of experts in this field, and drafted a survey designed to
reach some consensus on the nature of a suitable battery for this
purpose. The goal of this process was to identify the characteristics of a gold standard battery via which researchers could
pool results, compare findings across studies, make clinical
decisions regarding their own patients and ultimately compare
with other methodologies for diagnosis and treatment planning
in MHE. This process is similar to consensus batteries that have
been developed for the purpose of evaluating patients with
other diseases where neurocognitive outcome has emerged as a
potential target of treatment, such as neuropsychiatric systemic
lupus erythematosus (57) and schizophrenia (58).

Methodology
Commission members were informed of the overall purpose of
the survey, and each commission member then independently
responded to a series of questions about the features of a
putative gold standard battery for the assessment of MHE.
Responses were recorded on a seven-point Likert-type scale,
with a score range from 1 reflecting not important to 7
reflecting very important. The final question asked was
whether or not each member would recommend an existing
battery for this purpose.

630

Randolph et al.

Results
General features
There were several questions regarding the general nature of a
gold standard battery. Four of these resulted in near-universal
agreement, with the modal response for each being a 7, and the
mean response also being 7 (means were rounded to whole
numbers). The general characteristics of such a battery that
were seen as strongly desirable were as follows:
 A specific battery should be identified for this purpose, and
that it should serve as a benchmark against which to compare
newer, or experimental approaches.
 The battery should measure multiple cognitive domains.
 The battery should be easily translatable and applicable
cross-culturally.
 The battery should have age-based norms.
General features of the battery that received moderately strong
support included applicability for patients who are illiterate
(modal response 7, mean = 6), and that it was not important that
the battery be computerised (modal response = 1, mean = 3).
As far as the length of the battery was concerned, the modal
response was that it needed to be o 60 min. The mean
suggested that the maximum time for completion was 40 min.
Generally, commission members felt that the shorter the
battery, the better, but they also recognised that obtaining a
reliable measurement of neurocognitive status was likely to
require a minimum of 2040 min of testing. Most felt that a
computerised battery would be more cumbersome (i.e. less
portable), require greater expense and might not be as useful
as pencil-and-paper testing in this context. Several members
spontaneously pointed out the need for alternate forms of the
battery, to eliminate or reduce practice effects. The need for
appropriate training in order to correctly administer and score
the battery was also pointed out, as was the desirability of a
global score, to improve reliability, increase power and ease
interpretation.

Specific components
Commission members were also queried regarding the desirability of specific test paradigms as components of a gold
standard battery. The paradigms are listed in Table 1, in the
order of perceived desirability.
In their comments, several members pointed out that
language per se was felt to be unaffected, but that verbal fluency
measures were useful as a processing speed or executive
component. Most did not feel that measures of reaction time
were feasible without the use of a computer, which was
discouraged. It was also noted that, while MHE has not been
reported to produce a true impairment of anterograde memory
(i.e. rapid forgetting), slowed processing impacts upon memory
performance and it was felt that this was a clinically useful
measure that might have ecological significance (i.e. in terms of
affecting daily functioning).
There was some discussion regarding the inclusion of executive or self-regulatory measures, but it was also noted that these
are typically not amenable to the creation of equivalent multiple
forms, that there is limited agreement on what types of
executive tests might be useful in this context (apart from
measures of verbal fluency). The use of motor measures, despite
the demonstrated sensitivity of some of these to MHE, was
discouraged by several members who felt that performance on
these measures could be confounded by other variables not
directly related to MHE. It was noted that motoric dysfunction

Liver International (2009)

2009 John Wiley & Sons A/S

Randolph et al.

ISHEN MHE NP recommendations

Table 1. ISHEN committee ratings

Neurocognitive domain

Modal
response

Mean
response

Processing speed
Working memory
Verbal memory (anterograde)
Visuospatial ability
Visual memory (anterograde)
Language
Reaction time
Motor functions

7
7
7
6
6
5
5
4.5

7
6
5
6
5
4
4
4

Neurocognitive domains were rated on their importance for inclusion in

a battery designed to detect impairments associated with minimal
hepatic encephalopathy (MHE), using a Likert scale ranging from 1 (not
important) to 7 (very important).

could potentially impact upon any neuropsychological measure

that involved a motor response (e.g. drawing, coding and block
design), but that this was to some extent an unavoidable
confound.

Existing candidate batteries

Commission members were also asked to nominate any existing
batteries that could potentially serve as a gold standard for
assessment of MHE. Most of the members did not choose a
specific battery for this purpose. The only two specific batteries
that were recommended were the PSE-Syndrom-Test (59) and
the Repeatable Battery for the Assessment of Neuropsychological StatusTM (RBANS) (60).

PSE-Syndrom-Test
The PSE-Syndrom-Test is a battery consisting of five paperand-pencil tasks, including Number Connection Tests A and B,
a coding test (Digit Symbol Test) similar to the Digit Symbol
subtest of the Wechsler scales, the Serial Dotting Test and the
Line Drawing Test. The Serial Dotting Test consists of 10 rows of
10 circles, and the subject is timed on how quickly he or she can
place a dot in the center of each circle. The Line Drawing Test
requires the subject to draw a continuous line between two
parallel (winding) lines, and scores include completion time
and errors. There are four alternate forms of the PSE-SyndromTest (only the Serial Dotting Test is unchanged across forms),
and the battery requires 1520 min to complete.
Normative data were initially collected in Germany (32, 61).
The analysis of the single test results 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 determined by linear regression analysis and
KolmogorovSmirnov test. The effect of education and occupation were negligible compared with the age effect. Thus, the
regression lines together with parallel lines of  1,  2 and  3
standard deviations were calculated, yielding the known normal
quantiles, including the 95% range around the midpoint for
each single test. The regression lines and the standard deviation
lines were finally transformed into the original scales (32). For
the purpose of scaling an individuals test performance, scores
on each subtest are assigned a value ranging from 11 to 3,
based on age-related norms (11 for scores better than 1 SD
above the normal mean to
3 for scores more than 3 SDs
Liver International (2009)
2009 John Wiley & Sons A/S

below the normal mean. Because the Line Drawing Test

generates two scores, there are a total of six measures that
contribute to the total score, which can therefore range from
16 to 18.
The PSE-Syndrom-Test was specifically developed to measure the effects of MHE, and has been shown to be sensitive to
impairment in patients with cirrhosis (24, 31, 32, 40, 62). It has
also been shown to correlate with functional neuroimaging
results in these patients (6365). A consensus paper by the
World Congress of Gastroenterology in 1998 recommended the
PSE-Syndrom-Test for the evaluation of patients at risk of MHE
(7). Additional normative data from Italy have been published
(66), and normative data have also been collected in Spain and
Great Britain. While the British data are not yet available, the
Spanish data can be accessed by the interested clinician via the
internet (http://www.redeh.org). Unfortunately, the calculation
of the normative data has been performed differently in
different countries; the Italian and the Spanish groups did not
include line-tracing errors in their scoring (changing the score
range from 16 to 18 to 15 to 15), and there would appear
to be a need to perform a direct comparison of the raw data
from the four European countries, standardise the scoring and
determine the extent to which local norms are required for
these individual countries. On principle, the battery is presumably relatively culture-free, given the components, and the
instructions are easily translatable. This battery is only commercially available in the German form presently.

Repeatable Battery for the Assessment of

Neuropsychological StatusTM
The RBANS was designed with two basic goals: To serve as a
core battery for the assessment of dementia, and to efficiently
screen/track neurocognitive impairment in other disorders. It
contains measures of verbal and visual anterograde memory,
working memory, cognitive processing speed, language (including semantic fluency) and visuospatial function (line orientation and figure copy). There are four alternate forms (A, B, C
and D), and there are no practice effects with repeated testing
using alternate forms. The RBANS underwent a US populationbased standardisation for ages 2089, and generates age-scaled
index scores with a normal mean of 100 and SD = 15 for five
domains (immediate memory, visuospatial/constructional, language, attention and delayed memory), as well as a total scale
score. It is a portable pencil-and-paper test that requires a
folding stimulus booklet and paper record form to administer.
Administration time is approximately 2025 min.
The RBANS has undergone extensive clinical and psychometric validation for a variety of disorders, including various
forms of dementia, traumatic brain injury, schizophrenia,
stroke, multiple sclerosis and bipolar disorder, including studies
completed in North America, Europe and Asia. It is currently
being used in multiple clinical trials for Alzheimers disease and
schizophrenia, and as of August 2008, there were approximately
20 different official translations available for clinical and
research purposes.
The use of the RBANS in evaluating patients with liver
disease has been largely restricted to the USA to date. In a
sample of 300 consecutive outpatients presenting for liver
transplantation, RBANS scores were strongly correlated with
liver disease as measured by the model for end-stage liver
disease staging (38). Scores on the RBANS also predicted
disability independently of liver disease severity in this study.
A similar finding was reported in a separate study of 148 liver

631

ISHEN MHE NP recommendations

Randolph et al.

transplant candidates (36), and in a recent report on 66 patients

with end-stage liver disease (67).

Candidate battery characteristics compared with

commission recommendations
Table 2 lists the parameters of the ideal gold standard battery
for the detection of MHE as recommended by the commission,
together with an indication of the degree to which the PSESyndrom-Test and the RBANS meet these requirements.

Discussion and recommendations

The commission members were remarkably consistent in their
recommendations for a gold standard neuropsychological battery for the detection of MHE. A clear need was seen for a
consistent approach across centers for the purposes of both
diagnosis and measuring the effects of treatment. The commission members were in agreement that a suitable battery should
be a portable, pencil-and-paper battery taking o 40 min to
complete, that it should be easily translated, should have
alternate forms to minimise or eliminate practice effects, have
age-based norms and that it should measure multiple cognitive
domains but generate a single global score with adequate retest
reliability for detecting change. The suggested component
neurocognitive domains to be tested by the battery were also
fairly consistently agreed upon.
The only existing batteries that were recommended for this
purpose (each by a minority of the commission members) were
the PSE-Syndrom-Test and the RBANS. Each of these has at
least a few peer-reviewed publications, suggesting sensitivity to
the effects of MHE. In addition, the PSE-Syndrom-Test has
been shown to correlate with functional brain imaging results in
cirrhotic patients, and the RBANS has been demonstrated to be

predictive of disability in these patients. These initial findings

are encouraging, but there has been no direct comparison of the
two tests to date.
The RBANS has the advantage of having a large body of
clinical validity data in other disorders, demonstrating both the
sensitivity of the test to various forms of cerebral dysfunction
and the predictive value of the total scale score with respect to
various measures of functional independence in disorders such
as stroke (68), schizophrenia (61, 69) and Alzheimers disease
(70). It is somewhat closer in nature to the battery recommended by the commission, as it includes measures of verbal
and visual memory, visuospatial perception and construction,
and verbal fluency that are not contained in the PSE-SyndromeTest. The RBANS also underwent a rigorous population-based
standardisation and norming in the USA, and the broad clinical
utility of this test (in conjunction with its use in ongoing
multinational clinical trials in other diseases) is likely to
stimulate local norming projects, many of which are already
underway. Therefore, the application of the RBANS in the
context of liver disease may benefit from the more widespread
use of this scale.
On the other hand, the PSE-Syndrome-Test was developed
specifically for the purpose of detecting MHE, utilising measures extracted from a much larger battery for their sensitivity
to this syndrome. It requires somewhat less time to administer
than the RBANS, and all of the tasks are essentially non-verbal,
requiring translation of only the instructions for administration. It has been utilised in the measurement of MHE over a
longer period of time than the RBANS, and cross-cultural
sensitivity in that context has been demonstrated. Substantial
normative data have been collected in Germany, Spain, Italy
and Great Britain, and the basic psychometrics of the test
appear to be satisfactory.
The commission recommends that, until one of these
batteries is demonstrated to have superior clinical validity in

Table 2. Existing tests compared with commission recommendations

Commission recommendations

PSE-Syndrom-Test

RBANS

Measurement of multiple cognitive

domains

Cognitive processing speed (psychomotor) and

visuospatial demands (psychomotor)

Portable, penciland-paper
Ease of translation/cross-cultural
application
Use with illiterate patients
Availability of age-based norms

Yes

Verbal memory, visual memory, working

memory, visuospatial perception, visuospatial
construction, language (including fluency),
and cognitive processing speed
(psychomotor).
Yes

Demonstrated

Demonstrated

Yes
German
Spanish
Italian and British (yet unpublished)
Four forms
Yes sum of six categorical scores based on
normal SDs range 16 to 18
1520
Retest reliability for total score 0.81 in
normals, no practice effects
2/7

Yes
US population-based
Italian

Alternate forms
Global score generated
Time for administration (min)
Retest reliability, minimal practice
effects
Number of cognitive domains
measured with a modal ranking of 5
or higher in importance by the
commission

Four forms
Yes, index score (mean of 100, SD = 15)
normally distributed
25
Retest reliability for total score 0.86 in
normals, no practice effects
6/7

RBANS, Repeatable Battery for the Assessment of Neuropsychological StatusTM.

632

Liver International (2009)

2009 John Wiley & Sons A/S

Randolph et al.

the detection and monitoring of MHE, researchers choose one

or the other for the routine assessment of patients at risk for
MHE. This choice should be driven on the basis of available
local test translations and normative reference data. If a local
translation of the RBANS is not available, the use of the PSESyndrom-Test is recommended, as only the instructions for this
test require translation, and this is a much simpler process than
translation of the RBANS. In the absence of local norms for the
test being used, the commission recommends relying upon
existing US or German norms while pursuing the collection of
local norms. Local norms can be calibrated to existing test
norms on the basis of relatively small sample sizes, if the
samples are appropriately stratified. Diagnostic cut-offs can
then be set with known false-positive rates for the population of
interest.
The commission also recommends the following general
approach for the future: comparison of the RBANS and PSESyndrom-Test, as well as the comparison of any candidate
replacement batteries. We recognise that there may be a more
efficient or sensitive approach to the detection of MHE in
patients with liver disease than either the RBANS or the PSESyndrom-Test. Any candidate battery or other (e.g. biological)
measure should, however, have an established scoring methodology that provides a single global score for classification
purposes, in order to directly compare sensitivity/specificity
and reliability to the RBANS or the PSE-Syndrom-Test. Candidate measures should be compared with index measures using
appropriate sample sizes as follows:
(1) A common normative reference group, matching a local
cirrhotic sample on demographic variables (age, gender and
education), should be administered both batteries (in counterbalanced sequence) on two occasions at least 1 week apart (the
retest intervals should be the same for both batteries). The first
administration of each test will be used for analyses of sensitivity/clinical validity. The second will be used to establish
testretest reliability. The latter measure is important to establish the capacity of the test to identify group and individual
changes in response to treatment. Normal subject retest reliability is preferred to facilitate comparison with various existing
standardised tests, as patient groups may vary in terms of the
stability of their neurocognitive status as a function of disease
severity.
(2) Both tests should also be given (in counterbalanced sequence) on a single occasion to a sample of cirrhotic patients,
along with the collection of as much additional clinical data
(disease variables, measurements of quality of life, independent
activities of daily living, performance on driving simulators,
measurements of outcome, etc.) as possible.
(3) Using the common normative reference sample, the global
scores from each scale can be used to determine optimal cut-off
points via ROC analyses, and sensitivity/specificity of the scales
can be directly compared. The relative predictive value of each
scale with respect to other clinical data of interest can also be
directly compared.
(4) The statistical properties of each scale can be weighed
against the practical parameters of the scale (time to administer,
cost, effort, available norms, etc.) to determine as to which scale
will be of greater utility in this context.
The commission believes that sufficient data exist to recommend the use of the RBANS or the PSE-Syndrom-Test as
standard assessments for patients at risk of MHE at this point.
This will allow a more systematic approach to the clinical
management of these patients, and facilitate communication
and comparison of results across studies. The commission

Liver International (2009)

2009 John Wiley & Sons A/S

ISHEN MHE NP recommendations

further recommends ongoing research to establish local norms

for these tests, preferably using a stratified sampling approach
to calibrate local norms to published norms in a consistent
fashion. Finally, the commission recommends a systematic
approach for future studies to compare approaches to diagnosing and monitoring MHE.

Statements
 Neuropsychological testing is an established methodology for
quantifying cognitive impairment due to various forms of
encephalopathy, including low-grade or minimal hepatic encephalopathy.
A
 Neuropsychological test batteries that measure multiple
domains of cognitive function are generally more reliable than
single tests, and tend to be more strongly correlated with
functional status.
A
 Both the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and PSE-Syndrom-Test have met
psychometric and clinical validity criteria for use in assessment
of patients at risk for minimal hepatic encephalopathy. B

Recommendations
 Use of either the RBANS or the PSE-Syndrom-Test is recommended for diagnosing and monitoring minimal hepatic encephalopathy. The choice of which battery to use should be based
upon the availability of local translations and normative data
(Table 3).
2

Table 3. Grading of evidence and recommendations

Notes
Grading of Evidence
High-quality
evidence

Further research is very unlikely to

change our confidence in the
estimate of effect
Moderate-quality Further research is likely to have an
evidence
important impact on our
confidence in the estimate of effect
and may change the estimate
Low- or very low- Further research is very likely to
quality evidence
have an important impact on our
confidence in the estimate of effect
and is likely to change the estimate.
Any estimate of effect is uncertain
Grading of Recommendation
Strong
Factors influencing the strength of
recommendation the recommendation included the
warranted
quality of the evidence, presumed
patient-important outcomes, and
cost
Weaker
Variability in preferences and
recommendation values, or more uncertainty: more
likely a weak recommendation is
warranted.
Recommendation is made with less
certainty; higher cost or resource
consumption

Symbol
A

European Association for the Study of the Liver. EASL Clinical Practice

Guidelines: Management of chronic hepatitis B. J Hepatol 50 (2009), doi:

10.1016/j.jhep.2008.10.001.

633

ISHEN MHE NP recommendations

Randolph et al.

Acknowledgements
These guidelines have been prepared by the Commission on
Neuropsychological Assessment of Hepatic Encephalopathy
appointed by the ISHEN. The content was discussed and
approved in the 13th ISHEN Symptosium, Padova, Italy, 28
April to 1 May 2008. The members of the commission gratefully
acknowledge the direction and assistance of Professor Piero
Amodio in the completion of this assignment.
Disclosures: Christopher Randolph is the author of the
RBANS, and receives royalties on the sales of that instrument.
None of the other commission members report any potential
conflicts of interest.

References
1. Li YY, Nie YQ, Sha WH, et al. Prevalence of subclinical hepatic
encephalopathy in cirrhotic patients in China. World J Gastroenterol
2004; 10: 2397401.
2. Poordad FF. Review article: the burden of hepatic encephalopathy.
Aliment Pharmacol Ther 2007; 25(Suppl. 1): 39.
3. Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic
encephalopathy impairs fitness to drive. Hepatology 2004; 39:
73945.
4. Groeneweg M, Quero JC, De Bruijn I, et al. Subclinical hepatic
encephalopathy impairs daily functioning. Hepatology 1998; 28:
459.
5. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of
hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;
30: 8905.
6. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose
and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977;
72(Part 1): 57383.
7. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy
definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of
Gastroenterology, Vienna, 1998. Hepatology 2002; 35: 71621.
8. Amodio P, Montagnese S, Gatta A, Morgan MY. Characteristics of
minimal hepatic encephalopathy. Metab Brain Dis 2004; 19:
25367.
9. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with
poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001; 120: 1708.
10. Schomerus H, Hamster W. Quality of life in cirrhotics with
minimal hepatic encephalopathy. Metab Brain Dis 2001; 16: 3741.
11. Watanabe A, Tuchida T, Yata Y, Kuwabara Y. Evaluation of
neuropsychological function in patients with liver cirrhosis with
special reference to their driving ability. Metab Brain Dis 1995; 10:
23948.
12. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence
and natural history of subclinical hepatic encephalopathy in
cirrhosis. J Gastroenterol Hepatol 2001; 16: 5315.
13. 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: 271823.
14. Romero-Gomez M, Grande L, Camacho I, et al. Altered response to
oral glutamine challenge as prognostic factor for overt episodes in
patients with minimal hepatic encephalopathy. J Hepatol 2002; 37:
7817.
15. Saxena N, Bhatia M, Joshi YK, et al. Electrophysiological and
neuropsychological tests for the diagnosis of subclinical hepatic

634

16.

17.

18.
19.

20.

21.
22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

encephalopathy and prediction of overt encephalopathy. Liver 2002;

22: 1907.
Tarter RE, Switala J, Plail J, Havrilla J, Van Thiel DH. Severity of
hepatic encephalopathy before liver transplantation is associated
with quality of life after transplantation. Arch Intern Med 1992; 152:
2097101.
Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive
functions and health-related quality of life in patients with cirrhosis
who have minimal hepatic encephalopathy. Hepatology 2007; 45:
54959.
Amodio P, Gatta A. Neurophysiological investigation of hepatic
encephalopathy. Metab Brain Dis 2005; 20: 36979.
Amodio P, Valenti P, Del Piccolo F, et al. P300 latency for the
diagnosis of minimal hepatic encephalopathy: evidence that spectral EEG analysis and psychometric tests are enough. Dig Liver Dis
2005; 37: 8618.
Zeneroli ML, Pinelli G, Gollini G, et al. Visual evoked potential: a
diagnostic tool for the assessment of hepatic encephalopathy. Gut
1984; 25: 2919.
Yang SS, Chu NS, Liaw YF. Somatosensory evoked potentials in
hepatic encephalopathy. Gastroenterology 1985; 89: 62530.
Sandford NL, Saul RE. Assessment of hepatic encephalopathy with
visual evoked potentials compared with conventional methods.
Hepatology 1988; 8: 10948.
Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency:
diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007;
47: 6773.
Romero-Gomez M, Cordoba J, Jover R, et al. Value of the critical
flicker frequency in patients with minimal hepatic encephalopathy.
Hepatology 2007; 45: 87985.
Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger
D. Critical flicker frequency for quantification of low-grade hepatic
encephalopathy. Hepatology 2002; 35: 35766.
Zeneroli ML, Cioni G, Crisi G, Vezzelli C, Ventura E. Globus
pallidus alterations and brain atrophy in liver cirrhosis patients
with encephalopathy: an MR imaging study. Magn Reson Imaging
1991; 9: 295302.
Kulisevsky J, Pujol J, Deus J, Balanzo J, Pujol A. Magnetic resonance
imaging pallidal hypersignal in cirrhotic subjects. Hepatology 1996;
24: 2823.
Inoue E, Hori S, Narumi Y, et al. Portal-systemic encephalopathy:
presence of basal ganglia lesions with high signal intensity on MR
images. Radiology 1991; 179: 5515.
Taylor-Robinson SD, Oatridge A, Hajnal JV, et al. MR imaging of
the basal ganglia in chronic liver disease: correlation of T1-weighted
and magnetisation transfer contrast measurements with liver dysfunction and neuropsychiatric status. Metab Brain Dis 1995; 10:
17588.
Miese F, Kircheis G, Wittsack HJ, et al. 1H-MR spectroscopy,
magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy. Am J Neuroradiol 2006; 27: 101926.
Weissenborn K, Bokemeyer M, Ahl B, et al. Functional imaging of
the brain in patients with liver cirrhosis. Metab Brain Dis 2004; 19:
26980.
Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H.
Neuropsychological characterization of hepatic encephalopathy.
J Hepatol 2001; 34: 76873.
McCrea M, Cordoba J, Vessey G, Blei AT, Randolph C. Neuropsychological characterization and detection of subclinical hepatic
encephalopathy. Arch Neurol 1996; 53: 75863.
Bahceci F, Yildirim B, Karincaoglu M, Dogan I, Sipahi B. Memory
impairment in patients with cirrhosis. J Natl Med Assoc 2005; 97:
2136.

Liver International (2009)

2009 John Wiley & Sons A/S

Randolph et al.

35. Tarter RE, Arria AM, Carra J, Van Thiel DH. Memory impairments
concomitant with nonalcoholic cirrhosis. Int J Neurosci 1987; 32:
8539.
36. Meyer T, Eshelman A, Abouljoud M. Neuropsychological changes
in a large sample of liver transplant candidates. Transplant Proc
2006; 38: 355960.
37. Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of
subclinical hepatic encephalopathy in apparently healthy, ambulant, non-shunted patients with cirrhosis. J Hepatol 1986; 3: 7582.
38. Sorrell JH, Zolnikov BJ, Sharma A, Jinnai I. Cognitive impairment
in people diagnosed with end-stage liver disease evaluated for liver
transplantation. Psychiatry Clin Neurosci 2006; 60: 17481.
39. Weissenborn K, Heidenreich S, Giewekemeyer K, Ruckert N,
Hecker H. Memory function in early hepatic encephalopathy.
J Hepatol 2003; 39: 3205.
40. Weissenborn K, Giewekemeyer K, Heidenreich S, et al. Attention,
memory, and cognitive function in hepatic encephalopathy. Metab
Brain Dis 2005; 20: 35967.
41. Tarter RE, Hegedus AM, Van Thiel DH, Edwards N, Schade RR.
Neurobehavioral correlates of cholestatic and hepatocellular disease: differentiation according to disease specific characteristics and
severity of the identified cerebral dysfunction. Int J Neurosci 1987;
32: 90110.
42. Sood GK, Sarin SK, Mahaptra J, Broor SL. Comparative efficacy of
psychometric tests in detection of subclinical hepatic encephalopathy in nonalcoholic cirrhotics: search for a rational approach. Am
J Gastroenterol 1989; 84: 1569.
43. Tarter RE, Hegedus AM, Van Thiel DH, et al. Nonalcoholic
cirrhosis associated with neuropsychological dysfunction in the
absence of overt evidence of hepatic encephalopathy. Gastroenterology 1984; 86: 14217.
44. Zeegen R, Drinkwater JE, Dawson AM. Method for measuring cerebral
dysfunction in patients with liver disease. Br Med J 1970; 2: 6336.
45. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of
ammonia and inflammation in minimal hepatic encephalopathy.
Metab Brain Dis 2007; 22: 12538.
46. Quero JC, Hartmann IJ, Meulstee J, Hop WC, Schalm SW. The
diagnosis of subclinical hepatic encephalopathy in patients with
cirrhosis using neuropsychological tests and automated electroencephalogram analysis. Hepatology 1996; 24: 55660.
47. Tarter RE, Van Thiel DH, Arria AM, Carra J, Moss H. Impact of
cirrhosis on the neuropsychological test performance of alcoholics.
Alcohol Clin Exp Res 1988; 12: 61921.
48. Binesh N, Huda A, Thomas MA, et al. Hepatic encephalopathy: a
neurochemical, neuroanatomical, and neuropsychological study.
J Appl Clin Med Phys 2006; 7: 8696.
49. Mattarozzi K, Stracciari A, Vignatelli L, et al. Minimal hepatic
encephalopathy: longitudinal effects of liver transplantation. Arch
Neurol 2004; 61: 2427.
50. Della Sala S, Lunghi A, Marini A, Nespoli A, Spinnler H. Neuropsychological evaluation of bleeding cirrhotic patients. Schweiz Arch
Neurol Psychiatr 1992; 143: 35569.
51. Bajaj JS, Saeian K, Verber MD, et al. Inhibitory control test is a
simple method to diagnose minimal hepatic encephalopathy and
predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007; 102: 75460.
52. Malaguarnera M, Greco F, Barone G, Gargante MP, Toscano MA.
Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, doubleblind, placebo-controlled study. Dig Dis Sci 2007; 52: 325965.

Liver International (2009)

2009 John Wiley & Sons A/S

ISHEN MHE NP recommendations

53. Minguez B, Garcia-Pagan JC, Bosch J, et al. Noncirrhotic portal

vein thrombosis exhibits neuropsychological and MR changes
consistent with minimal hepatic encephalopathy. Hepatology 2006;
43: 70714.
54. Arria AM, Tarter RE, Starzl TE, Van Thiel DH. Improvement in
cognitive functioning of alcoholics following orthotopic liver
transplantation. Alcohol Clin Exp Res 1991; 15: 95662.
55. Schomerus H, Hamster W. Neuropsychological aspects of portalsystemic encephalopathy. Metab Brain Dis 1998; 13: 36177.
56. Kugler CF, Petter J, Taghavy A, et al. Dynamics of cognitive brain
dysfunction in patients with cirrhotic liver disease: an event-related
P300 potential perspective. Electroencephalogr Clin Neurophysiol
1994; 91: 3341.
57. Nomenclature AAHCoNL. The American College of Rheumatology
nomenclature and case definitions for neuropsychiatric lupus
syndromes. Arthritis Rheum 1999; 42: 559608.
58. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS
Consensus Cognitive Battery, part 1: test selection, reliability, and
validity. Am J Psychiatry 2008; 165: 20313.
59. Schomerus H, Weissenborn K, Hamster W, Ruckert N, Hecker H.
PSE-Syndrom-Test. Frankfurt: Swets & Zeitlinger B.V., 1999.
60. Randolph C. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). San Antonio: The Psychological Corporation, 1998.
61. Gold JM, Goldberg R, McNary S, Dixon L, Lehman A. Cognitive
correlates of job tenure among patients with severe mental illness.
Am J Psychiatry 2002; 159: 1395402.
62. Senzolo M, Amodio P, DAloiso MC, et al. Neuropsychological and
neurophysiological evaluation in cirrhotic patients with minimal
hepatic encephalopathy undergoing liver transplantation. Transplant Proc 2005; 37: 11047.
63. Weissenborn K, Ahl B, Fischer-Wasels D, et al. Correlations between
magnetic resonance spectroscopy alterations and cerebral ammonia
and glucose metabolism in cirrhotic patients with and without
hepatic encephalopathy. Gut 2007; 56: 173642.
64. Lockwood AH, Weissenborn K, Bokemeyer M, Tietge U, Burchert
W. Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics. Metab
Brain Dis 2002; 17: 2940.
65. Ahl B, Weissenborn K, van den Hoff J, et al. Regional differences in
cerebral blood flow and cerebral ammonia metabolism in patients
with cirrhosis. Hepatology 2004; 40: 739.
66. Amodio P, Campagna F, Olianas S, et al. Detection of minimal
hepatic encephalopathy: normalization and optimization of the
Psychometric Hepatic Encephalopathy Score. A neuropsychological
and quantified EEG study. J Hepatol 2008; 49: 34653.
67. Mooney S, Hasssanein TI, Hilsabeck RC, et al. Utility of the
repeatable battery for the assessment of neuropsychological status
(RBANS) in patients with end-stage liver disease awaiting liver
transplant. Arch Clin Neuropsychol 2007; 22: 17586.
68. Larson E, Kirschner K, Bode R, Heinemann A, Goodman R.
Construct and predictive validity of the repeatable battery for the
assessment of neuropsychological status in the evaluation of stroke
patients. J Clin Exp Neuropsychol 2005; 27: 1632.
69. Goldberg R, Lucksted A, McNary S, et al. Correlates of long-term
unemployment among inner-city adults with serious and persistent
mental illness. Psychiatr Serv 2001; 52: 1013.
70. Freilich BM, Hyer LA. Relation of the repeatable battery for
assessment of neuropsychological status to measures of daily
functioning in dementia. Psychol Rep 2007; 101: 11929.

635