Dig Dis Sci (2008) 53:529–538
DOI 10.1007/s10620-007-9895-0
ORIGINAL PAPER
Introduction to the Hepatic Encephalopathy Scoring Algorithm
(HESA)
Tarek I. Hassanein Æ Robin C. Hilsabeck Æ
William Perry
Received: 10 November 2006 / Accepted: 4 June 2007 / Published online: 21 August 2007

Springer Science+Business Media, LLC 2007
Abstract A primary obstacle to early diagnosis and
treatment of hepatic encephalopathy (HE) is the lack of a
well-validated, standardized assessment method. The pur-
pose of this study was to present preliminary validity data
on a new method of grading HE, the Hepatic Encepha-
lopathy Scoring Algorithm (HESA), which combines
clinical impressions with neuropsychological performances
to characterize HE. Participants were 49 inpatients admit-
ted for complications of end stage liver disease. Each
participant’s level of HE was graded using HESA and the
West Haven Criteria (WHC) by independent raters blinded
to each other’s rating. A moderately strong association was
found between the two grading methods (r = 0.60), and
individual HESA clinical and neuropsychological indica-
tors were good discriminators among grades. The results
also suggest HESA may be more sensitive to mental status
impairment in the middle grades of HE than WHC. These
findings suggest HESA holds promise as a multi-method
approach to grading all levels of HE.
Keywords Chronic liver disease
Cognitive impairment

End stage liver disease
Hepatitis C
Hepatic
encephalopathy
Neuropsychological assessment
T. I. Hassanein (&)
Department of Medicine, Hepatology Neurobehavioral Research
Program, UCSD Liver Center, University of California,
200 West Arbor Drive, San Diego, CA 92108-8707, USA
e-mail: thassanein@ucsd.edu
R. C. Hilsabeck
W. Perry
Department of Psychiatry, Hepatology Neurobehavioral
Research Program, UCSD Liver Center,
University of California, 200 West Arbor Drive,
San Diego, CA 92108-8707, USA
Introduction
Hepatic encephalopathy (HE) is a clinically significant
neuropsychiatric syndrome that occurs frequently in pa-
tients with end stage liver disease (ESLD). Not only is HE
associated with considerable reductions in overall quality
of life [1], it also is a strong prognosticator of death, as over
75% of patients die within 3 years of their first HE episode
[2]. Thus, early identification and treatment of HE is crit-
ical to improving quality of life and may aid in preventing
death in patients with ESLD.
A primary obstacle to early diagnosis and treatment of
HE is the lack of a well-validated, standardized method
for detecting and characterizing HE. The absence of an
objective and sensitive HE grading method also has
contributed to our limited understanding of the epidemi-
ology and pathogenesis of HE and the difficulty in eval-
uating the efficacy of HE-targeted treatments [3, 4]. This
has led several members of the field to suggest that an HE
grading ‘‘gold standard’’ is needed and would benefit
researchers, clinicians, and most importantly, patients
with ESLD [3].
At present, the most widely used HE grading method is
the West Haven Criteria (WHC) [5, 6], which relies solely
on clinical judgment. As such, this method has been criti-
cized for its poor sensitivity in differentiating milder forms
of HE due to difficulties in detecting subtle neurocognitive
impairments [7, 8]. To overcome this limitation, neuro-
psychological and/or neurophysiological measures have
been recommended, as they provide sensitive and objective
indicators of cerebral dysfunction [3, 4, 9]. The relative
utility of one method over the other has not been deter-
mined, however, due to the lack of a ‘‘gold standard’’
against which sensitivity and specificity of each can be
compared.
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A potentially improved method for increasing the reli-
able grading of HE is a combination of clinical judgment
and neuropsychological testing. Neuropsychological mea-
sures may be preferable to neurophysiological measures for
practical reasons; that is, they are less expensive, more
portable, and quicker and easier to administer and score.
The purpose of the present study was to introduce a new
method of grading HE, the Hepatic Encephalopathy Scor-
ing Algorithm (HESA), and to present preliminary findings
supporting its construct validity.
12% Asian American, and 4% other ethnicities. All
participants were fluent in English. The etiology of
ESLD was the hepatitis C virus (HCV) in 20% of the
patients, alcohol-related liver disease in 29%, a combi-
nation of HCV and alcohol-related liver disease in 25%,
and various other etiologies in the remaining 26%. Most
patients (61%) had documentation of previous episodes
of HE.
Measures

Methods West Haven criteria

Participants The WHC [5, 6] is a widely used HE grading method that

The participants were 49 patients (36 men and 13 wo-
men) admitted to a university medical center for com-
plications of ESLD. Average age of the sample was 50.5
years (SD = 9.0 years), and average education was
11.9 years (SD = 3.5 years). The ethnic composition of
the study cohort was 63% Caucasian, 21% Hispanic,
relies solely on the clinician’s judgment to determine the
presence and severity of HE. Neuropsychiatric abnormal-
ities associated with HE are graded on a 0–4 scale, with
‘‘grade 0’’ indicating minimal HE (i.e., no overt neuro-
psychiatric or neurological symptoms) and ‘‘grade 4’’
indicating severe HE (i.e., coma). Total evaluation time is
approximately 15 min.

Table 1 Hepatic Encephalopathy Scoring Algorithm (HESA)

Time |__|__| :|__|__| 24 Hour Clock

4 No eyes opening No verbal/voice response

No reaction to simple commands

All applicable Grade 4 otherwise continue examination

3 Somnolence Confusion Disoriented to place

Bizarre Behavior / Anger/Rage Clonus/Rigidity / Nysatgmus / Babinsky

Mental Control = 0

3 or more applicable Grade 3 otherwise continue examination

2 Lethargy Loss of time Slurred Speech

Hyperactive Reflexes Inappropriate Behavior

Slow Responses Amnesia of recent events

Anxiety Impaired Simple Computations

2 or more and 3 or more applicable Grade 2 otherwise continue

1 Sleep disorder / Impaired Sleep Pattern Tremor

Impaired complex computations Shortened attention span

Impaired Construction ability Euphoria or Depression

4 or more applicable Grade 1 otherwise Grade 0

HE Grade |__|
NOTE: indicates symptoms assessed using clinical judgment and indicates symptoms
assessed using neuropsychological measures.

Copyright © 2006 The Regents of the University of California

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Dig Dis Sci (2008) 53:529–538
Hepatic encephalopathy scoring algorithm
HESA is an adaptation of the WHC that utilizes both
subjective and objective indicators to assess neuropsychi-
atric symptoms associated with HE (see Table 1). The first
step in the development of HESA was to determine which
neuropsychiatric abnormalities were most characteristic of
each grade. The HE grading table in Blei [10] was used as a
reference in this regard as it provided a comprehensive list
of symptoms commonly associated with each grade. Next,
symptoms considered highly characteristic, distinct, and
capable of being operationalized were retained and, when
possible, neuropsychological measures (see description
below) were applied to objectively assess different signs of
mental status change. A graduated approach was utilized so
that more severe grades of HE required minimal neuro-
psychological assessment and less severe grades required
more. Determination of how much neuropsychological
testing to perform and, ultimately, the patient’s HE grade is
based on a decision tree (see Fig. 1). Accordingly,
administration time varies but does not exceed 15 min.
HESA clinical indicators
In HE grade 4, three clinical indicators – no opening of the
eyes, no verbalizations, and no responses to simple com-
mands – were chosen as necessary markers since lack of
Fig. 1 Decision tree for
determining hepatic
encephalopathy (HE) grade
using HESA Yes, stop.
Patient is Grade 4.
Yes, stop.
Patient is Grade 3.
Yes, stop.
Patient is Grade 2.
Patient is Grade 1.
531
response in these areas is representative of coma. All three
indicators must be judged present by the clinician for the
patient to be rated grade 4 HE; if even one criterion is
false, stage 4 is not assumed. In grade 3 HE, five clinical
indicators are considered: somnolence, confusion, disori-
entation to place, bizarre behavior or anger/rage, and
motor abnormalities, including clonus, rigidity, nystag-
mus, and/or positive Babinski sign. If three or more are
applicable, including an objective indicator of confusion
described below (i.e., Mental Control), the patient is
considered to be grade 3. Five clinical indicators are also
considered in grade 2 HE: lethargy, inappropriate behav-
ior, disorientation to time, slurred speech, and hyperactive
reflexes. A patient is rated as grade 2 if two or more of
these indicators are present, along with three or more
neuropsychological indicators. In grade 1, only two clin-
ical indicators are assessed – sleep disorder and tremor –
but neither is imperative for rating a patient in this grade if
all four neuropsychological indicators are positive.
Table 2 shows the definitions of the clinical indicators
used in HESA.
HESA neuropsychological indicators
The primary criteria in choosing neuropsychological tasks
for measuring mental status indicators were that they had to
be: (1) well validated and standardized; (2) brief; (3) easy
All Grade 4 indicators marked.
No, continue.
Three or more Grade 3 indicators marked.
No, continue.
Two or more and three or more in Grade 2 marked.
No, continue.
Four or more Grade 1 indicators marked.
Yes, stop. No, stop.
Patient is Grade 0.
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Table 2 Descriptions of the HESA clinical indicators

Clinical indicator ( ) Description

Grade 4
No eyes opening Patient does not open eyes upon attempts to awaken (e.g., pinch)
No reaction to simple commands Patient does not react to simple commands, no motor responses
No verbal/voice response No audible response to stimulation
Grade 3
Somnolence Patient has extreme difficulty staying awake during assessment; difficult to re-awaken
Confusion Patient does not orient to or engage in assessment appropriately
Disoriented to place Patient unable to state location correctly
Bizarre behavior and/or anger/rage Displays strange behavior and/or inappropriate anger/rage
Clonus/rigidity/nystagmus/Babinsky Clonus/rigidity: Hand on calf muscle and flex foot up = repeatedly contracting muscle Nystagmus:
Hold pen out in front of eyes: Eyes appear ‘‘shaky’’ Babinsky: Toes flair out
Grade 2
Lethargy Patient is very sleepy but able to stay awake during assessment
Loss of time Patient is unable to state date correctly
Slurred speech Patient has slurred speech; difficult to understand
Hyperactive reflexes Fast up/down tendon response to hammer on elbow; Large response at knee
Inappropriate behavior Displays inappropriate behavior during assessment
Grade 1
Sleep disorder Patient’s sleep pattern is reversed; sleeps too much or too little; needs medicine to sleep
Tremor With arms stretched out, visible tremor (shaking) in hands

to administer and score. Tests with alternate forms were
preferred but not always available. The following is a brief
description of each measure.
(1) Orientation questionnaire: This questionnaire was
designed to allow for a graduated assessment of ori-
entation. Patients were first asked an open-ended
question (i.e., What is today’s date?) and then
prompted for missing or incorrect information, first
by asking a more specific open-ended question (e.g.,
What year is it?), followed by a randomized recog-
nition procedure with feedback (e.g., Is it 2004? If the
patient says ‘‘Yes’’, the examiner says ‘‘No, it is not
2004’’ and asks the next question or provides the
correct answer).
(2) Mental Control: This measure is a subtest of the well-
known Wechsler Memory Scale – Revised [11]. It
consists of three items: (1) counting backward from
20 to 1; (2) reciting the alphabet; (3) counting forward
by threes starting with 1 (i.e., 1, 4, 7, etc.). Each of
these items must be completed within a specified time
frame and without error to receive all possible points
(i.e., 2 points per item = 6 points total). Mental con-
trol was chosen as a measure of detecting ‘‘confu-
sion’’ and ‘‘slow responses’’ in HE Grades 3 and 2,
respectively. Mental Control possesses good face
validity as a measure for assessing confusion since
counting backward from 20 to 1 and reciting the
alphabet are over-learned skills resistant to deficits
even in patients with mild dementia. Patients who
cannot perform even one of these over-learned skills
(i.e., patients obtaining a score of ‘‘0’’) are considered
to be ‘‘confused’’ and thus meet this criterion in
Grade 3. In addition, given the necessity of com-
pleting each item within a certain time frame, this
subtest was considered an appropriate measure of
‘‘slow responses’’ in Grade 2. A cut-off score of <4
was chosen to indicate ‘‘slow responses’’ since this
score reflects an inability to perform two out of three
tasks quickly and accurately. Cut-off scores for
Mental Control and all neuropsychological measures
are shown in Table 3.
(3) Hopkins Verbal Learning Test (HVLT) or Brief Vi-
suospatial Memory Test – Revised (BVMT-R): The
HVLT [12] and BVMT-R [13] are well-known mea-
sures of learning and memory, each with six alternate
forms. Choosing memory tests with alternate forms
was critical in grading HE since assessments are
repeated frequently, sometimes more than once per
day. The HVLT is a measure of verbal memory, and
the BVMT-R is a measure of nonverbal memory. The
availability of both verbal and nonverbal memory
tests was necessary since there are some patients who
cannot draw (e.g., patients with significant tremor)
and others who cannot speak (e.g., patients who are
intubated). Moreover, both tests assess several

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Table 3 Indicators of impairment on neuropsychological measures
Impaired
Grade 3
Mental Control Score = 0
Grade 2
Slow responses Mental control <4
Amnesia for recent events HVLT or BVMT-R Recognition <100%
Anxiety Score >4
Simple computations First three problems <100%
Grade 1
Complex computations Second three problems <100%
Shortened attention span Letter-Number Sequencing raw score = 0 or number
of digits correctly repeated on Digit Span <5
Construction ability BVMT-R Copy Trial <6 or cannot write name legibly
Depression Score >4
HVLT, Hopkins Verbal Learning Test, shortened version; BVMT-R, Brief Visuospatial Memory Test – Revised
components of memory functioning (i.e., learning,
retention, and recognition), which are needed to in-
crease sensitivity for detecting change in neurocog-
nitive status. The HVLT was shortened from ten to
six items to make it easier for patients with HE to
tolerate and equate the number of items to that of the
BVMT-R. Recognition memory was chosen as the
best measure of ‘‘amnesia for recent events’’ in Grade
2 because it is least sensitive to memory impairment
due to emotional (e.g., depression) rather than neu-
rocognitive factors, but it may be insensitive to
memory problems in less severe stages of HE. A cut-
off score of <12 was considered to be indicative of
‘‘amnesia for recent events’’ because it corresponds to
discriminability of <92%, which is less £1 standard
deviation below the normative mean in persons
younger than 61 years of age.
(4) Depression and anxiety ratings: A 7-point Likert
scale was chosen for assessment of both depression
and anxiety for two reasons – brevity and ease of
administration and scoring. The use of one-item
Likert rating scales is common throughout medical
practice (e.g., pain, fatigue) and requires minimal
effort and reading skill from patients. These types of
scales consistently have been shown to be valid
measures of the construct in question [14–16]. A cut-
off score >4 was chosen as a positive indicator of
depression and/or anxiety since these scores suggest
the problem is mostly present versus mostly absent.
(5) Computations: Computation items were extracted
from the Arithmetic subtest of the Wide Range
Achievement Test – 3rd Revision [17], which is a
widely used screening measure of academic
achievement. Multiplication and division items were
533
Not impaired
Score >0
Mental control ‡4
HVLT or BVMT-R Recognition = 100%
Score £4
First three problems = 100%
Second three problems = 100%
Letter-Number Sequencing raw score >0 or number
of digits correctly repeated on Digit Span ‡5
BVMT-R Copy Trial ‡6 or can write name legibly
Score £4
deemed ‘‘complex’’ (e.g., 23 · 3), and addition and
subtraction items were deemed ‘‘simple’’ (e.g., 5 – 1).
Relatively simple items for each set of computations
were used to minimize the likelihood that an ‘‘im-
paired’’ performance might be due to educational and/
or cultural variables rather than HE. Since only three
‘‘simple’’ items were used, an incorrect answer on any
one of the three items is considered indicative of
impaired ‘‘simple computations’’ in Grade 2. Like-
wise, an incorrect response on any one of the three
‘‘complex’’ items is considered indicative of impaired
‘‘complex computations’’ in Grade 1.
(6) Letter–Number Sequencing/Digit Span: Repetition of
a string of digits and/or numbers is a widely used
measure of attention span. Letter–Number Sequenc-
ing (LNS) was chosen to measure attention since it is
a subtest of the Wechsler Adult Intelligence Scale –
3rd Edition [18], the ‘‘gold standard’’ in the assess-
ment of intelligence. In this task, patients are read a
string of letters and numbers intermixed randomly
and asked to recite back the string with one caveat;
they are to repeat the numbers first in numerical order
and then the letters in alphabetical order. A raw score
of £7 was chosen as the cut-off score indicative of
‘‘shortened attention span’’ since it corresponds to a
performance below the 16th percentile in persons
aged 45–64 years and below the 10th percentile in
persons aged 25–44 years. In cases where the patient
is unable to grasp the instructions for LNS, Digit Span
is used as an alternative method for assessing atten-
tion span. The administration procedure of the Digit
Span subtest of the Repeatable Battery for the
Assessment of Neuropsychological Status (RBANS)
[19] was chosen for its brevity. Patients unable to
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successfully repeat at least five digits forward on the
RBANS Digit Span were considered to have ‘‘short-
ened attention span’’ since this performance falls
below the 16th percentile for persons aged 40–
69 years and below the 7th percentile in persons aged
20–39 years.
(7) BVMT-R Copy Trial: The BVMT-R Copy Trial was
chosen as a measure of constructional ability since the
BVMT-R already was included in HESA (see above),
and its six designs are relatively simple. One point is
awarded for the correct drawing of each design, and
one point is awarded for the proper location of each
design on the page. Thus, a total of 12 points is
possible (i.e., 2 points for each of the six designs). A
raw score of <6 was deemed indicative of impaired
‘‘construction ability’’ since this score suggests, at a
minimum, that the patient was unable to place each
figure in its proper location on the page.
Procedure
Written informed consent as approved by the university
IRB was obtained from each patient and/or an appropriate
surrogate. Following informed consent, the patient’s HE
grade was assessed by two raters blinded to each other’s
rating. One rater graded HE using WHC and the other rater
graded HE using the HESA, usually within 1 h of one
another (i.e., 94% of the time). The order of HE grading
methods was chosen randomly. In all cases, WHC ratings
were completed by attending hepatology physicians or
their fellows, and HESA ratings were completed by a
neuropsychologist or trained psychometrician.
Statistical analyses
Spearman’s rho rank order correlation coefficient was used
to determine the relationship between the two rating
methods. Proportions of HESA indicators by HE grade
were computed to illustrate the frequency of indicators
marked. Chi-square and Fisher’s Exact t-tests were used to
compare the percentage of impaired indicators across HE
grades. A P value of £0.05 was considered to be statisti-
cally significant for all analyses.
Results
Agreement between grading methods
Using WHC, 22 patients (45%) were rated as grade 0, 18
(37%) were rated as grade 1, and nine (18%) were rated as
grade 2. Using the HESA, 34 patients (69%) were assessed as
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Table 4 Overlap in HE Grade using two grading methods
West Haven Hepatic Encephalopathy Scoring Algorithm
Criteria (WHC) (HESA)
0 1 2 3 Total
0 21 1 0 0 22
1 11 3 3 1 18
2 2 2 3 2 9
3 0 0 0 0 0
Total 34 6 6 3 49
grade 0, six (12%) were assessed as grade 1, six (12%) were
assessed as grade 2, and three (6%) were assessed as grade 3.
Spearman’s rho rank order correlation coefficient revealed a
significant association between the two grading methods
(r = 0.60, P < 0.001). As can be seen in Table 4, there was
complete agreement between the two methods in 27 patients
(55%), with 21 patients rated as grade 0, three rated as grade
1, and three rated as grade 2. With regard to disagreement,
HE was graded as more severe using HESA in seven patients
(14%) and less severe using HESA in 15 patients (31%).
HESA clinical and neuropsychological indicators
Grade 4 indicators
No patient exhibited any of the three indicators in HESA
Grade 4, i.e., no opening of the eyes, no verbalizations, and
no responses to simple commands.
Grade 3 indicators
There are five clinical and one neuropsychological indi-
cator in HESA Grade 3. For the three patients assessed as
grade 3, all were rated as confused and all met the criterion
for impairment on the neuropsychological indicator,
Mental Control. Two out of three displayed motor abnor-
malities and were somnolent and disoriented to place. One
of the three exhibited bizarre behavior. Of those patients
assessed at grades lower than 3, very few exhibited som-
nolence, confusion, disorientation to place, or bizarre
behavior. Motor abnormalities and impairment on Mental
Control were seen more often but still infrequently. All
HESA Grade 3 indicators differed significantly in fre-
quency across grade, with significantly more patients as-
sessed as grade 3 rated as impaired compared to patients
assessed as grades 0–2 (see Table 5).
Grade 2 indicators
There are five clinical and four neuropsychological indi-
cators in HESA Grade 2. For the six patients rated as grade
2, all were disoriented to time, slow to respond, and
Dig Dis Sci (2008) 53:529–538 535

Table 5 Percentage of impaired HESA Grade 3 indicators by HE Grade

HESA Grade 3 indicator Grade 3 (n = 3) Grade 2 (n = 6) Grade 1 (n = 6) Grade 0 (n = 34) v2

Somnolence 67a 0b 0b 0b 31.97*

Confusion 100a 17b 0b 0b 37.88*
Disoriented to place 67a 0b 17b 0b 22.90*
Bizarre behavior 33a 0b 0b 0b 15.65*
Motor abnormalitiesa 67a 33 33 9b 8.53**
Mental Control = 0 100a 17b 33b 3c 23.38*
*P £ 0.001; **P < 0.05. Values found by different letters indicate significant differences in a row (between groups)
a
Clonus, rigidity, nystagmus, or positive Babinski sign
Neuropsychological indicator is given in italics; all other indicators are clinical

Table 6 Percentage of impaired HESA Grade 2 indicators by HE Grade

HESA Grade 2 indicator Grade 3 (n = 3) Grade 2 (n = 6) Grade 1 (n = 6) Grade 0 (n = 34) v2

Lethargy 67a 67a 17 3b 21.16*

Disoriented to time 67 100a 17b 15b 20.75*
Slurred speech 67a 33a 50a 3b 16.26*
Hyperactive reflexes 0 17 50a 0b 17.88*
Inappropriate behavior 0 17 0 9 0.71
Slow responses 67 100a 33b 29b 11.50**
Amnesia for recent events 67 100 100 65 5.74
Anxiety 25 33 50 18 3.35
Impaired simple computations 67 83a 33 12b 16.36*
*P £ 0.001; **P < 0.05. Values found by different letters indicate significant differences in a row (between groups)
Neuropsychological indicators are given in italics; all other indicators are clinical

amnestic for recent events, and most were lethargic and
impaired on simple computations. Slurred speech, inap-
propriate behavior, and anxiety were noted less often. The
three patients rated as grade 3 showed similar amounts of
impairment on these indicators, whereas patients rated as
grades 0 or 1 generally showed impairment less frequently
on these indicators. One clinical (i.e., inappropriate
behavior) and two neuropsychological indicators (i.e.,
slowed responding and amnesia for recent events) did not
differ significantly across grades (see Table 6).
Grade 1 indicators
There are two clinical and four neuropsychological indi-
cators in HESA Grade 1. For the six patients assessed as
grade 1, at least half were impaired on all six indicators.
Patients assessed as grades 2–3 showed similar rates of
impairment, while significantly fewer patients assessed as
grade 0 were impaired on one clinical (i.e., tremor) and two
neuropsychological indicators (i.e., shortened attention
span and impaired constructions). The percentages of
impairment for each HESA Grade 1 indicator by HE grade
are shown in Table 7.
Discussion
The HESA introduces a new method for assessing HE that
capitalizes on the strengths of both clinical observation and
objective indicators of cognitive impairment. This study is
among the first to develop and apply a systematic, multi-
method approach to grading HE that can be used to assess
all levels of severity. HESA combines data generated from
clinical and neuropsychological examinations in a gradu-
ated fashion so more objective neuropsychological testing
is performed in the less severe stages where neuropsychi-
atric dysfunction is not reliably identified by clinical
examination alone. Results from the current study provide
preliminary support for the validity of HESA, as it corre-
lated significantly with WHC, and many of its individual
clinical and neuropsychological indicators discriminated
well among grades.
Of the 49 patients assessed in the current study, dis-
crepant ratings were made in 22 cases. In seven of these,
HE was graded as more severe using HESA, and in six of
these seven instances, patients graded as 1 or 2 using WHC
were graded as either 2 or 3 using HESA. This finding
suggests that HESA may be more sensitive to mental status

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Table 7 Percentage of impaired HESA Grade 1 indicators by HE Grade
HESA Grade 1 indicator Grade 3 (n = 3)
Sleep disturbance 33
Tremor 100a
Impaired complex computations 67
Shortened attention span 67
Impaired construction ability 67a
Depression 33
*P £ 0.001; **P < 0.05. Values found by different letters indicate significant differences in a row (between groups)
Neuropsychological indicators are given in italics; all other indicators are clinical
impairment in the middle grades than WHC. The increased
sensitivity of HESA in these cases is likely due to the use
of objective measures to identify mental status impairment
as well as to the availability of additional clinical indicators
(e.g., clonus/rigidity, slurred speech, tremor). This con-
clusion is illustrated more clearly by reviewing a case
example, i.e., the one remaining case in which HE was
graded as more severe using HESA. In this case, the patient
was graded as 0 using WHC but demonstrated impaired
performances on several HESA neuropsychological indi-
cators. For example, the patient obtained a raw score of 0
on Mental Control, which means she was unable to recite
the alphabet or count backward from 20 to 1 in 30 s. She
also could not perform accurately three simple addition and
subtraction problems and exhibited an impaired attention
span as she could repeat only four digits forward. This level
of cognitive impairment is significant but was missed when
using clinical judgment alone via WHC.
In the remaining 15 discrepant cases, HE was graded as
more severe using WHC. In 13 of the 15 cases, HE was
graded as 0 using HESA. Using WHC, 11 of these 13 were
graded as 1 and two were graded as 2. Although mental
status impairment was identified in all of these cases using
HESA, it was not severe enough to meet full criteria for
grades 1–4. This is not an unexpected finding as cognitive
impairment has been well documented in patients without
overt HE [20, 21]. An alternative explanation is that HESA
failed to identify patients with significant mental status
impairment that was evident on clinical exam. This
explanation seems unlikely, however, as it has been noted
repeatedly that neuropsychological testing is more sensi-
tive than clinical judgment [3, 22], and this was the case in
the current study when considering the middle grades of
HE as noted above. Closer examination of these discordant
cases instead suggests that the opposite may occur; that is,
physicians may judge a cognitive function impaired when
it is, in fact, intact. For example, in the current study,
physicians rated attention span as impaired in ten patients
using WHC and graded these patients as a 1. When as-
sessed formally using the HESA digit span task, eight of
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Dig Dis Sci (2008) 53:529–538
Grade 2 (n = 6) Grade 1 (n = 6) Grade 0 (n = 34) v2
17 50 44 1.88
83a 100a 21b 22.90*
83 83 53 3.49
67a 83a 15b 16.72*
33a 67a 3b 20.30*
50 50 18 4.84
these ten patients performed within normal limits for their
ages. These data suggest that although a patient may appear
inattentive and confused during a brief, unstructured
interaction, he or she can pay attention successfully when
instructed to engage in and direct attention to a specific
task, which would not be expected if the patient was
acutely encephalopathic.
Another trend in these discrepant cases was that physi-
cians appeared to rely heavily on level of alertness when
grading HE using WHC. The reason for this may be that
level of alertness is easier to observe and identify as
problematic than many of the other WHC, such as lack of
awareness and inappropriate behavior. However, level of
alertness may not be defined the same across raters (e.g.,
someone seen as lethargic by one physician may be viewed
as somnolent by another) or may not provide an accurate
indicator of level of HE, especially if the patient was not
engaged long enough to wake up and interact with the
physician.
It is also possible in some cases that both raters were
correct although they arrived at different ratings for HE
grade. This may have been true in cases where patients
fluctuated from one grade to another before the second
rater could assess HE grade. Lapses in time between ratings
could not be avoided, however, to keep raters blinded from
each other’s assessment. Since most of the ratings were
performed within 1 h of one another (ten of them were
performed immediately after one another), the likelihood
of actual changes in HE grade accounting for discrepant
ratings in all cases is very low.
With regard to individual HESA indicators, some ap-
peared to be more useful than others in determining HE
grade. In grade 3, all six indicators (i.e., five clinical and
one neuropsychological) occurred at significantly greater
percentages in individuals assessed as grade 3 compared
to those assessed as grades 0–2. However, bizarre
behavior was noted in only one of the 49 patients in this
study, and clonus/rigidity/nystagmus/Babinski was present
in similar numbers of patients in all grades except 0. In
grade 2, four of five clinical indicators and two of four
Dig Dis Sci (2008) 53:529–538
neuropsychological indicators were noted significantly
more often in patients assessed as grade 2 compared to
other grades. Two clinical indicators (i.e., lethargy and
disorientation to time) and two neuropsychological indi-
cators (i.e., slowed responding and impaired simple
computations) were particularly useful in discriminating
patients assessed as grade 2 from those assessed as grade 0
or 1. Inappropriate behavior was not helpful because it
occurred too infrequently, and anxiety and amnesia for
recent events were not helpful because they occurred at
similar rates in grades 0 and 1, with the latter present in
over 65% of patients assessed as grade 0 or 1. Of note,
slurred speech and hyperactive reflexes occurred more
often in patients assessed as grade 1 than those assessed as
grade 2, suggesting that these clinical indicators may not
be specific enough to be useful as markers of grade 2 HE.
With regard to grade 1 indicators, one clinical (i.e., tre-
mor) and two neuropsychological (i.e., shortened attention
span and impaired constructions) were present signifi-
cantly more often in patients assessed as grade 1 than
other grades and were particularly useful in discriminating
patients in grade 1 from those in grade 0 or with minimal
HE. Sleep disturbance, depression, and impaired compu-
tations occurred in similar frequencies across HE grades,
with the latter present in over half of patients in each
grade.
Weissenborn and colleagues [22] also developed and
applied a standardized method for characterizing HE.
These researchers utilized five neuropsychological tests to
derive a composite score, the psychometric hepatic
encephalopathy score (PHES), to classify patients as either
‘‘normal’’ or ‘‘pathological.’’ Although preliminary data on
the PHES appear promising, this method was developed for
detecting minimal HE and not for grading HE along a
continuum of severity as does HESA. The neuropsycho-
logical measures used by these authors were normalized on
healthy volunteers from Germany, which may not gener-
alize to other populations.
Further validation of HESA is clearly necessary,
including larger patient samples with the full spectrum of
HE severity. Blei and colleagues [23] assessed the use of
HESA in a multi-center clinical trial of patients with severe
HE undergoing extracorporeal albumin dialysis. They
concluded that HESA performed well in characterizing HE
in these patients and was reliable across eight centers.
Significant overlap was apparent in the clinical and neu-
ropsychological indicators found to be most useful in their
sample of patients with severe HE and in those found to be
most useful in the current sample of patients, which was
skewed toward the less severe end of HE. Comparing the
HESA to neurophysiological measures, such as EEG,
would be another important means of establishing con-
vergent validity. However, we suggest that the HESA
537
offers an advantage over existing methods, as it incorpo-
rates a multidimensional approach likely to increase sen-
sitivity and specificity in detecting all levels of HE due to
the use of both objective and subjective measures.
The HESA may provide another valuable contribution
by differentiating between ESLD patients who are cogni-
tively intact and those with minimal HE who may be at risk
for developing overt HE. Evidence for this assertion is
apparent in the current study as some patients rated as
grade 0 were impaired on many grade 1 indicators although
they did not meet the full criteria of the latter. On the other
hand, some grade 0 patients were not impaired or were
impaired on only one to two grade 1 indicators. The former
group of patients may represent those with minimal HE
who need close monitoring and early intervention, while
the latter group may represent those who are cognitively
normal and not in need of current management. Further
research is needed to determine HESA’s utility for this
purpose and to explore the possibility of weighting certain
indicators in each grade more heavily than others to
increase specificity.
With further validation of the HESA, researchers and
clinicians will be positioned to use this tool to characterize
HE grade more accurately, thereby facilitating prevention
and treatment of this potentially life-threatening syndrome.
Improving the accuracy of HE grading in the early stages
of severity is critical for identifying patients who may be at
risk for further deterioration. Careful monitoring of these
patients would allow for more timely treatment when
necessary, possibly preventing hospitalization and death.
Acknowledgements The authors would like to express their deepest
gratitude to Elizabeth Ziegler, Meghan Carlson, Fatma Barakat, and
Scott Mooney for their invaluable help in assessing patients for this
study, as well as to Deanna Oliver for organizing and facilitating
study completion.
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