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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 Introduction


treatment of hepatic encephalopathy (HE) is the lack of a
well-validated, standardized assessment method. The pur- Hepatic encephalopathy (HE) is a clinically significant
pose of this study was to present preliminary validity data neuropsychiatric syndrome that occurs frequently in pa-
on a new method of grading HE, the Hepatic Encepha- tients with end stage liver disease (ESLD). Not only is HE
lopathy Scoring Algorithm (HESA), which combines associated with considerable reductions in overall quality
clinical impressions with neuropsychological performances of life [1], it also is a strong prognosticator of death, as over
to characterize HE. Participants were 49 inpatients admit- 75% of patients die within 3 years of their first HE episode
ted for complications of end stage liver disease. Each [2]. Thus, early identification and treatment of HE is crit-
participant’s level of HE was graded using HESA and the ical to improving quality of life and may aid in preventing
West Haven Criteria (WHC) by independent raters blinded death in patients with ESLD.
to each other’s rating. A moderately strong association was A primary obstacle to early diagnosis and treatment of
found between the two grading methods (r = 0.60), and HE is the lack of a well-validated, standardized method
individual HESA clinical and neuropsychological indica- for detecting and characterizing HE. The absence of an
tors were good discriminators among grades. The results objective and sensitive HE grading method also has
also suggest HESA may be more sensitive to mental status contributed to our limited understanding of the epidemi-
impairment in the middle grades of HE than WHC. These ology and pathogenesis of HE and the difficulty in eval-
findings suggest HESA holds promise as a multi-method uating the efficacy of HE-targeted treatments [3, 4]. This
approach to grading all levels of HE. has led several members of the field to suggest that an HE
grading ‘‘gold standard’’ is needed and would benefit
Keywords Chronic liver disease  Cognitive impairment  researchers, clinicians, and most importantly, patients
End stage liver disease  Hepatitis C  Hepatic with ESLD [3].
encephalopathy  Neuropsychological assessment 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
T. I. Hassanein (&) of HE due to difficulties in detecting subtle neurocognitive
Department of Medicine, Hepatology Neurobehavioral Research impairments [7, 8]. To overcome this limitation, neuro-
Program, UCSD Liver Center, University of California,
psychological and/or neurophysiological measures have
200 West Arbor Drive, San Diego, CA 92108-8707, USA
e-mail: thassanein@ucsd.edu been recommended, as they provide sensitive and objective
indicators of cerebral dysfunction [3, 4, 9]. The relative
R. C. Hilsabeck  W. Perry utility of one method over the other has not been deter-
Department of Psychiatry, Hepatology Neurobehavioral
mined, however, due to the lack of a ‘‘gold standard’’
Research Program, UCSD Liver Center,
University of California, 200 West Arbor Drive, against which sensitivity and specificity of each can be
San Diego, CA 92108-8707, USA compared.

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A potentially improved method for increasing the reli- 12% Asian American, and 4% other ethnicities. All
able grading of HE is a combination of clinical judgment participants were fluent in English. The etiology of
and neuropsychological testing. Neuropsychological mea- ESLD was the hepatitis C virus (HCV) in 20% of the
sures may be preferable to neurophysiological measures for patients, alcohol-related liver disease in 29%, a combi-
practical reasons; that is, they are less expensive, more nation of HCV and alcohol-related liver disease in 25%,
portable, and quicker and easier to administer and score. and various other etiologies in the remaining 26%. Most
The purpose of the present study was to introduce a new patients (61%) had documentation of previous episodes
method of grading HE, the Hepatic Encephalopathy Scor- of HE.
ing Algorithm (HESA), and to present preliminary findings
supporting its construct validity.
Measures

Methods West Haven criteria

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


relies solely on the clinician’s judgment to determine the
The participants were 49 patients (36 men and 13 wo- presence and severity of HE. Neuropsychiatric abnormal-
men) admitted to a university medical center for com- ities associated with HE are graded on a 0–4 scale, with
plications of ESLD. Average age of the sample was 50.5 ‘‘grade 0’’ indicating minimal HE (i.e., no overt neuro-
years (SD = 9.0 years), and average education was psychiatric or neurological symptoms) and ‘‘grade 4’’
11.9 years (SD = 3.5 years). The ethnic composition of indicating severe HE (i.e., coma). Total evaluation time is
the study cohort was 63% Caucasian, 21% Hispanic, 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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Hepatic encephalopathy scoring algorithm response in these areas is representative of coma. All three
indicators must be judged present by the clinician for the
HESA is an adaptation of the WHC that utilizes both patient to be rated grade 4 HE; if even one criterion is
subjective and objective indicators to assess neuropsychi- false, stage 4 is not assumed. In grade 3 HE, five clinical
atric symptoms associated with HE (see Table 1). The first indicators are considered: somnolence, confusion, disori-
step in the development of HESA was to determine which entation to place, bizarre behavior or anger/rage, and
neuropsychiatric abnormalities were most characteristic of motor abnormalities, including clonus, rigidity, nystag-
each grade. The HE grading table in Blei [10] was used as a mus, and/or positive Babinski sign. If three or more are
reference in this regard as it provided a comprehensive list applicable, including an objective indicator of confusion
of symptoms commonly associated with each grade. Next, described below (i.e., Mental Control), the patient is
symptoms considered highly characteristic, distinct, and considered to be grade 3. Five clinical indicators are also
capable of being operationalized were retained and, when considered in grade 2 HE: lethargy, inappropriate behav-
possible, neuropsychological measures (see description ior, disorientation to time, slurred speech, and hyperactive
below) were applied to objectively assess different signs of reflexes. A patient is rated as grade 2 if two or more of
mental status change. A graduated approach was utilized so these indicators are present, along with three or more
that more severe grades of HE required minimal neuro- neuropsychological indicators. In grade 1, only two clin-
psychological assessment and less severe grades required ical indicators are assessed – sleep disorder and tremor –
more. Determination of how much neuropsychological but neither is imperative for rating a patient in this grade if
testing to perform and, ultimately, the patient’s HE grade is all four neuropsychological indicators are positive.
based on a decision tree (see Fig. 1). Accordingly, Table 2 shows the definitions of the clinical indicators
administration time varies but does not exceed 15 min. used in HESA.

HESA clinical indicators HESA neuropsychological indicators

In HE grade 4, three clinical indicators – no opening of the The primary criteria in choosing neuropsychological tasks
eyes, no verbalizations, and no responses to simple com- for measuring mental status indicators were that they had to
mands – were chosen as necessary markers since lack of be: (1) well validated and standardized; (2) brief; (3) easy

Fig. 1 Decision tree for All Grade 4 indicators marked.


determining hepatic
encephalopathy (HE) grade
using HESA Yes, stop. No, continue.

Patient is Grade 4.
Three or more Grade 3 indicators marked.

Yes, stop. No, continue.

Patient is Grade 3.
Two or more and three or more in Grade 2 marked.

Yes, stop. No, continue.

Patient is Grade 2.
Four or more Grade 1 indicators marked.

Yes, stop. No, stop.

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

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Table 3 Indicators of impairment on neuropsychological measures


Impaired Not impaired

Grade 3
Mental Control Score = 0 Score >0
Grade 2
Slow responses Mental control <4 Mental control ‡4
Amnesia for recent events HVLT or BVMT-R Recognition <100% HVLT or BVMT-R Recognition = 100%
Anxiety Score >4 Score £4
Simple computations First three problems <100% First three problems = 100%
Grade 1
Complex computations Second three problems <100% Second three problems = 100%
Shortened attention span Letter-Number Sequencing raw score = 0 or number Letter-Number Sequencing raw score >0 or number
of digits correctly repeated on Digit Span <5 of digits correctly repeated on Digit Span ‡5
Construction ability BVMT-R Copy Trial <6 or cannot write name legibly BVMT-R Copy Trial ‡6 or can write name legibly
Depression Score >4 Score £4
HVLT, Hopkins Verbal Learning Test, shortened version; BVMT-R, Brief Visuospatial Memory Test – Revised

components of memory functioning (i.e., learning, deemed ‘‘complex’’ (e.g., 23 · 3), and addition and
retention, and recognition), which are needed to in- subtraction items were deemed ‘‘simple’’ (e.g., 5 – 1).
crease sensitivity for detecting change in neurocog- Relatively simple items for each set of computations
nitive status. The HVLT was shortened from ten to were used to minimize the likelihood that an ‘‘im-
six items to make it easier for patients with HE to paired’’ performance might be due to educational and/
tolerate and equate the number of items to that of the or cultural variables rather than HE. Since only three
BVMT-R. Recognition memory was chosen as the ‘‘simple’’ items were used, an incorrect answer on any
best measure of ‘‘amnesia for recent events’’ in Grade one of the three items is considered indicative of
2 because it is least sensitive to memory impairment impaired ‘‘simple computations’’ in Grade 2. Like-
due to emotional (e.g., depression) rather than neu- wise, an incorrect response on any one of the three
rocognitive factors, but it may be insensitive to ‘‘complex’’ items is considered indicative of impaired
memory problems in less severe stages of HE. A cut- ‘‘complex computations’’ in Grade 1.
off score of <12 was considered to be indicative of (6) Letter–Number Sequencing/Digit Span: Repetition of
‘‘amnesia for recent events’’ because it corresponds to a string of digits and/or numbers is a widely used
discriminability of <92%, which is less £1 standard measure of attention span. Letter–Number Sequenc-
deviation below the normative mean in persons ing (LNS) was chosen to measure attention since it is
younger than 61 years of age. a subtest of the Wechsler Adult Intelligence Scale –
(4) Depression and anxiety ratings: A 7-point Likert 3rd Edition [18], the ‘‘gold standard’’ in the assess-
scale was chosen for assessment of both depression ment of intelligence. In this task, patients are read a
and anxiety for two reasons – brevity and ease of string of letters and numbers intermixed randomly
administration and scoring. The use of one-item and asked to recite back the string with one caveat;
Likert rating scales is common throughout medical they are to repeat the numbers first in numerical order
practice (e.g., pain, fatigue) and requires minimal and then the letters in alphabetical order. A raw score
effort and reading skill from patients. These types of of £7 was chosen as the cut-off score indicative of
scales consistently have been shown to be valid ‘‘shortened attention span’’ since it corresponds to a
measures of the construct in question [14–16]. A cut- performance below the 16th percentile in persons
off score >4 was chosen as a positive indicator of aged 45–64 years and below the 10th percentile in
depression and/or anxiety since these scores suggest persons aged 25–44 years. In cases where the patient
the problem is mostly present versus mostly absent. is unable to grasp the instructions for LNS, Digit Span
(5) Computations: Computation items were extracted is used as an alternative method for assessing atten-
from the Arithmetic subtest of the Wide Range tion span. The administration procedure of the Digit
Achievement Test – 3rd Revision [17], which is a Span subtest of the Repeatable Battery for the
widely used screening measure of academic Assessment of Neuropsychological Status (RBANS)
achievement. Multiplication and division items were [19] was chosen for its brevity. Patients unable to

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successfully repeat at least five digits forward on the Table 4 Overlap in HE Grade using two grading methods
RBANS Digit Span were considered to have ‘‘short- West Haven Hepatic Encephalopathy Scoring Algorithm
ened attention span’’ since this performance falls Criteria (WHC) (HESA)
below the 16th percentile for persons aged 40–
0 1 2 3 Total
69 years and below the 7th percentile in persons aged
20–39 years. 0 21 1 0 0 22
(7) BVMT-R Copy Trial: The BVMT-R Copy Trial was 1 11 3 3 1 18
chosen as a measure of constructional ability since the 2 2 2 3 2 9
BVMT-R already was included in HESA (see above), 3 0 0 0 0 0
and its six designs are relatively simple. One point is Total 34 6 6 3 49
awarded for the correct drawing of each design, and
one point is awarded for the proper location of each grade 0, six (12%) were assessed as grade 1, six (12%) were
design on the page. Thus, a total of 12 points is assessed as grade 2, and three (6%) were assessed as grade 3.
possible (i.e., 2 points for each of the six designs). A Spearman’s rho rank order correlation coefficient revealed a
raw score of <6 was deemed indicative of impaired significant association between the two grading methods
‘‘construction ability’’ since this score suggests, at a (r = 0.60, P < 0.001). As can be seen in Table 4, there was
minimum, that the patient was unable to place each complete agreement between the two methods in 27 patients
figure in its proper location on the page. (55%), with 21 patients rated as grade 0, three rated as grade
1, and three rated as grade 2. With regard to disagreement,
Procedure HE was graded as more severe using HESA in seven patients
(14%) and less severe using HESA in 15 patients (31%).
Written informed consent as approved by the university
IRB was obtained from each patient and/or an appropriate HESA clinical and neuropsychological indicators
surrogate. Following informed consent, the patient’s HE
grade was assessed by two raters blinded to each other’s Grade 4 indicators
rating. One rater graded HE using WHC and the other rater
graded HE using the HESA, usually within 1 h of one No patient exhibited any of the three indicators in HESA
another (i.e., 94% of the time). The order of HE grading Grade 4, i.e., no opening of the eyes, no verbalizations, and
methods was chosen randomly. In all cases, WHC ratings no responses to simple commands.
were completed by attending hepatology physicians or
Grade 3 indicators
their fellows, and HESA ratings were completed by a
neuropsychologist or trained psychometrician.
There are five clinical and one neuropsychological indi-
cator in HESA Grade 3. For the three patients assessed as
Statistical analyses grade 3, all were rated as confused and all met the criterion
for impairment on the neuropsychological indicator,
Spearman’s rho rank order correlation coefficient was used Mental Control. Two out of three displayed motor abnor-
to determine the relationship between the two rating malities and were somnolent and disoriented to place. One
methods. Proportions of HESA indicators by HE grade of the three exhibited bizarre behavior. Of those patients
were computed to illustrate the frequency of indicators assessed at grades lower than 3, very few exhibited som-
marked. Chi-square and Fisher’s Exact t-tests were used to nolence, confusion, disorientation to place, or bizarre
compare the percentage of impaired indicators across HE behavior. Motor abnormalities and impairment on Mental
grades. A P value of £0.05 was considered to be statisti- Control were seen more often but still infrequently. All
cally significant for all analyses. 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
Results assessed as grades 0–2 (see Table 5).

Agreement between grading methods Grade 2 indicators

Using WHC, 22 patients (45%) were rated as grade 0, 18 There are five clinical and four neuropsychological indi-
(37%) were rated as grade 1, and nine (18%) were rated as cators in HESA Grade 2. For the six patients rated as grade
grade 2. Using the HESA, 34 patients (69%) were assessed as 2, all were disoriented to time, slow to respond, and

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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 Discussion
impaired on simple computations. Slurred speech, inap-
propriate behavior, and anxiety were noted less often. The The HESA introduces a new method for assessing HE that
three patients rated as grade 3 showed similar amounts of capitalizes on the strengths of both clinical observation and
impairment on these indicators, whereas patients rated as objective indicators of cognitive impairment. This study is
grades 0 or 1 generally showed impairment less frequently among the first to develop and apply a systematic, multi-
on these indicators. One clinical (i.e., inappropriate method approach to grading HE that can be used to assess
behavior) and two neuropsychological indicators (i.e., all levels of severity. HESA combines data generated from
slowed responding and amnesia for recent events) did not clinical and neuropsychological examinations in a gradu-
differ significantly across grades (see Table 6). ated fashion so more objective neuropsychological testing
is performed in the less severe stages where neuropsychi-
Grade 1 indicators atric dysfunction is not reliably identified by clinical
examination alone. Results from the current study provide
There are two clinical and four neuropsychological indi- preliminary support for the validity of HESA, as it corre-
cators in HESA Grade 1. For the six patients assessed as lated significantly with WHC, and many of its individual
grade 1, at least half were impaired on all six indicators. clinical and neuropsychological indicators discriminated
Patients assessed as grades 2–3 showed similar rates of well among grades.
impairment, while significantly fewer patients assessed as Of the 49 patients assessed in the current study, dis-
grade 0 were impaired on one clinical (i.e., tremor) and two crepant ratings were made in 22 cases. In seven of these,
neuropsychological indicators (i.e., shortened attention HE was graded as more severe using HESA, and in six of
span and impaired constructions). The percentages of these seven instances, patients graded as 1 or 2 using WHC
impairment for each HESA Grade 1 indicator by HE grade were graded as either 2 or 3 using HESA. This finding
are shown in Table 7. 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) Grade 2 (n = 6) Grade 1 (n = 6) Grade 0 (n = 34) v2

Sleep disturbance 33 17 50 44 1.88


Tremor 100a 83a 100a 21b 22.90*
Impaired complex computations 67 83 83 53 3.49
Shortened attention span 67 67a 83a 15b 16.72*
Impaired construction ability 67a 33a 67a 3b 20.30*
Depression 33 50 50 18 4.84
*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 these ten patients performed within normal limits for their
sensitivity of HESA in these cases is likely due to the use ages. These data suggest that although a patient may appear
of objective measures to identify mental status impairment inattentive and confused during a brief, unstructured
as well as to the availability of additional clinical indicators interaction, he or she can pay attention successfully when
(e.g., clonus/rigidity, slurred speech, tremor). This con- instructed to engage in and direct attention to a specific
clusion is illustrated more clearly by reviewing a case task, which would not be expected if the patient was
example, i.e., the one remaining case in which HE was acutely encephalopathic.
graded as more severe using HESA. In this case, the patient Another trend in these discrepant cases was that physi-
was graded as 0 using WHC but demonstrated impaired cians appeared to rely heavily on level of alertness when
performances on several HESA neuropsychological indi- grading HE using WHC. The reason for this may be that
cators. For example, the patient obtained a raw score of 0 level of alertness is easier to observe and identify as
on Mental Control, which means she was unable to recite problematic than many of the other WHC, such as lack of
the alphabet or count backward from 20 to 1 in 30 s. She awareness and inappropriate behavior. However, level of
also could not perform accurately three simple addition and alertness may not be defined the same across raters (e.g.,
subtraction problems and exhibited an impaired attention someone seen as lethargic by one physician may be viewed
span as she could repeat only four digits forward. This level as somnolent by another) or may not provide an accurate
of cognitive impairment is significant but was missed when indicator of level of HE, especially if the patient was not
using clinical judgment alone via WHC. engaged long enough to wake up and interact with the
In the remaining 15 discrepant cases, HE was graded as physician.
more severe using WHC. In 13 of the 15 cases, HE was It is also possible in some cases that both raters were
graded as 0 using HESA. Using WHC, 11 of these 13 were correct although they arrived at different ratings for HE
graded as 1 and two were graded as 2. Although mental grade. This may have been true in cases where patients
status impairment was identified in all of these cases using fluctuated from one grade to another before the second
HESA, it was not severe enough to meet full criteria for rater could assess HE grade. Lapses in time between ratings
grades 1–4. This is not an unexpected finding as cognitive could not be avoided, however, to keep raters blinded from
impairment has been well documented in patients without each other’s assessment. Since most of the ratings were
overt HE [20, 21]. An alternative explanation is that HESA performed within 1 h of one another (ten of them were
failed to identify patients with significant mental status performed immediately after one another), the likelihood
impairment that was evident on clinical exam. This of actual changes in HE grade accounting for discrepant
explanation seems unlikely, however, as it has been noted ratings in all cases is very low.
repeatedly that neuropsychological testing is more sensi- With regard to individual HESA indicators, some ap-
tive than clinical judgment [3, 22], and this was the case in peared to be more useful than others in determining HE
the current study when considering the middle grades of grade. In grade 3, all six indicators (i.e., five clinical and
HE as noted above. Closer examination of these discordant one neuropsychological) occurred at significantly greater
cases instead suggests that the opposite may occur; that is, percentages in individuals assessed as grade 3 compared
physicians may judge a cognitive function impaired when to those assessed as grades 0–2. However, bizarre
it is, in fact, intact. For example, in the current study, behavior was noted in only one of the 49 patients in this
physicians rated attention span as impaired in ten patients study, and clonus/rigidity/nystagmus/Babinski was present
using WHC and graded these patients as a 1. When as- in similar numbers of patients in all grades except 0. In
sessed formally using the HESA digit span task, eight of grade 2, four of five clinical indicators and two of four

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neuropsychological indicators were noted significantly offers an advantage over existing methods, as it incorpo-
more often in patients assessed as grade 2 compared to rates a multidimensional approach likely to increase sen-
other grades. Two clinical indicators (i.e., lethargy and sitivity and specificity in detecting all levels of HE due to
disorientation to time) and two neuropsychological indi- the use of both objective and subjective measures.
cators (i.e., slowed responding and impaired simple The HESA may provide another valuable contribution
computations) were particularly useful in discriminating by differentiating between ESLD patients who are cogni-
patients assessed as grade 2 from those assessed as grade 0 tively intact and those with minimal HE who may be at risk
or 1. Inappropriate behavior was not helpful because it for developing overt HE. Evidence for this assertion is
occurred too infrequently, and anxiety and amnesia for apparent in the current study as some patients rated as
recent events were not helpful because they occurred at grade 0 were impaired on many grade 1 indicators although
similar rates in grades 0 and 1, with the latter present in they did not meet the full criteria of the latter. On the other
over 65% of patients assessed as grade 0 or 1. Of note, hand, some grade 0 patients were not impaired or were
slurred speech and hyperactive reflexes occurred more impaired on only one to two grade 1 indicators. The former
often in patients assessed as grade 1 than those assessed as group of patients may represent those with minimal HE
grade 2, suggesting that these clinical indicators may not who need close monitoring and early intervention, while
be specific enough to be useful as markers of grade 2 HE. the latter group may represent those who are cognitively
With regard to grade 1 indicators, one clinical (i.e., tre- normal and not in need of current management. Further
mor) and two neuropsychological (i.e., shortened attention research is needed to determine HESA’s utility for this
span and impaired constructions) were present signifi- purpose and to explore the possibility of weighting certain
cantly more often in patients assessed as grade 1 than indicators in each grade more heavily than others to
other grades and were particularly useful in discriminating increase specificity.
patients in grade 1 from those in grade 0 or with minimal With further validation of the HESA, researchers and
HE. Sleep disturbance, depression, and impaired compu- clinicians will be positioned to use this tool to characterize
tations occurred in similar frequencies across HE grades, HE grade more accurately, thereby facilitating prevention
with the latter present in over half of patients in each and treatment of this potentially life-threatening syndrome.
grade. Improving the accuracy of HE grading in the early stages
Weissenborn and colleagues [22] also developed and of severity is critical for identifying patients who may be at
applied a standardized method for characterizing HE. risk for further deterioration. Careful monitoring of these
These researchers utilized five neuropsychological tests to patients would allow for more timely treatment when
derive a composite score, the psychometric hepatic necessary, possibly preventing hospitalization and death.
encephalopathy score (PHES), to classify patients as either
‘‘normal’’ or ‘‘pathological.’’ Although preliminary data on Acknowledgements The authors would like to express their deepest
gratitude to Elizabeth Ziegler, Meghan Carlson, Fatma Barakat, and
the PHES appear promising, this method was developed for
Scott Mooney for their invaluable help in assessing patients for this
detecting minimal HE and not for grading HE along a study, as well as to Deanna Oliver for organizing and facilitating
continuum of severity as does HESA. The neuropsycho- study completion.
logical measures used by these authors were normalized on
healthy volunteers from Germany, which may not gener-
alize to other populations. References
Further validation of HESA is clearly necessary,
1. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJC, Essink-Bot
including larger patient samples with the full spectrum of M, Hop WCJ, Schalm SW (1998) Subclinical hepatic encepha-
HE severity. Blei and colleagues [23] assessed the use of lopathy impairs daily functioning. Hepatology 28:45–49
HESA in a multi-center clinical trial of patients with severe 2. Bustamante J, Rimola A, Ventura PJ, Navasa M, Ciera I, Regg-
iardo V, Rodes J (1999) Prognostic significance of hepatic
HE undergoing extracorporeal albumin dialysis. They
encephalopathy in patients with cirrhosis. J Hepatol 30:890–895
concluded that HESA performed well in characterizing HE 3. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K,
in these patients and was reliable across eight centers. Blei AT and the Members of the Working Party (2002) Hepatic
Significant overlap was apparent in the clinical and neu- encephalopathy – definition, nomenclature, diagnosis, and quan-
tification: final report of the working party at the 11th World
ropsychological indicators found to be most useful in their
Congresses of Gastroenterology. Hepatology 35:716–721
sample of patients with severe HE and in those found to be 4. Montagnese S, Amodio P, Morgan MY (2004) Methods for
most useful in the current sample of patients, which was diagnosing hepatic encephalopathy in patients with cirrhosis: a
skewed toward the less severe end of HE. Comparing the multidimensional approach. Metab Brain Dis 19:281–312
5. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC,
HESA to neurophysiological measures, such as EEG,
Seeff L, Levy LL (1977) Comparison of lactulose and neomycin
would be another important means of establishing con- in the treatment of chronic portal-systemic encephalopathy.
vergent validity. However, we suggest that the HESA Gastroenterology 72:573–583

123
538 Dig Dis Sci (2008) 53:529–538

6. Atterbury CE, Maddrey WC, Conn HO (1978) Neomycin-sorbitol visual-analog, and a Likert rating scale. Int J Method Psychiatric
and lactulose in the treatment of acute portal-systemic encepha- Res 6:123–127
lopathy. A controlled, double-blind clinical trail. Am J Dig Dis 15. Maurer TJ, Pierce HR (1998) A comparison of Likert scale and
23:398–406 traditional measures of self-efficacy. J Appl Psychol 83:324–329
7. Huda A, Guze BH, Thomas MA, Bugbee M, Fairbanks L, Strouse 16. Jensen MP, Turner JA, Romano JM, Fisher LD (1999) Com-
T, Fawzy FI (1998) Clinical correlation of neuropsychological parative reliability and validity of chronic pain intensity mea-
test with H magnetic resonance spectroscopy in hepatic enceph- sures. Pain 83:157–162
alopathy. Psychosom Med 60:550–556 17. Wilkinson GS (1993) Wide Range Achievement Test – 3rd
8. Quero Guillen JC, Soria IC, Garcia Montes JM, Jimenez Saenz revision: manual. The Psychological Corp, San Antonio
M, Herrarias Gutierrez JM (2003) Hepatic encephalopathy: 18. Wechsler D (1997) Wechsler Adult Intelligence Scale – 3rd
nomenclature, pathogenesis, and treatment. Rev Esp Enferm Dig edition: manual. The Psychological Corp, San Antonio
95:135–142 19. Randolph C (1998) Repeatable battery for the assessment of
9. Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Char- neuropsychological status: manual. The Psychological Corp, San
acteristics of minimal hepatic encephalopathy. Metab Brain Dis Antonio
19:253–267 20. Gilberstadt S, Gilberstadt H, Zieve L, Buegel B, Collier R, McC-
10. Blei AT (1996) Hepatic encephalopathy. In: Kaplowitz N (ed) lain C (1980) Psychomotor performance deficits in cirrhotic pa-
Liver and biliary diseases, 2nd edn. Williams & Wilkins, Balti- tients without overt encephalopathy. Arch Int Med 140:519–521
more, pp 615–628 21. McCrea M, Cordoba J, Vessey G, Blei AT, Randolph C (1996)
11. Wechsler D (1987) Wechsler Memory Scale – Revised: manual. Neuropsychological characterization and detection of subclinical
The Psychological Corp, San Antonio hepatic encephalopathy. Arch Neurol 53:758–763
12. Brandt J (1991) The Hopkins Verbal Learning Test: development 22. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H
of a new memory test with six equivalent forms. Clin Neuro- (2001) Neuropsychological characterization of hepatic encepha-
psychol 5:125–142 lopathy. J Hepatol 34:768–773
13. Benedict RHB (1997) Brief Visuospatial Memory Test – Re- 23. Hassanein T, Tofteng F, Brown RS, McGuire B, Lynch P, Mehta
vised: manual. The Psychological Corp, San Antonio R, Larsen FS, Gornbein J, Stange J, Blei AT (2007) Randomized
14. Tryon WW, Orr DA, Blumenfield M (1996) Psychometric controlled study of extracorporeal albumin dialysis for hepatic
equivalency of an electronic visual-analog (EVA), a conventional encephalopathy in advanced cirrhosis. Hepatology (in press)

123