Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines

Article (PDF Available)inLiver international: official journal of the International Association for the Study of the Liver 29(6):789-96 · July 2009with112 Reads
DOI: 10.1111/j.1478-3231.2009.02030.x · Source: PubMed
By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow-up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug-induced disturbances, non-convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow-up period.
Neurop hysiological investigations of hepatic encephalopathy:
ISHEN practice guidelines
Jean-Michel Guerit
, Aldo Amantini
, Catherine Fischer
, Peter W. Kaplan
, Oriano Mecarelli
, Alfons Schnitzler
Emilio Ubiali
, Piero Amodio
and the members of the ISHEN commission on Neurophysiological Investigations
1 Neurology Clinique Edith Cavell, Bruxelles, Belgium
2 Department of Neurological Sciences, Neurophysiopathology, University Hospital of Florence, Florence, Italy
3 Neurological and Neurosurgical Hospital, Lyon, France
4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Department of Neurological Sciences, Neurophysiopathology, Sapienza University, Rome, Italy
6 Department of Neurology, Heinrich-Heine University, D ¨usseldorf, Germany
7 Neurophysiology Unit, United Hospitals of Bergamo, Bergamo, Italy
8 Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
acute liver failure – cirrhosis – electro-
encephalogram – encephalopathy – evoked
potentials – neurophysiology
Piero Amodio, Department of Clinical and
Experimental Medicine, University of Padua, Via
Giustiniani 2, 35128 Padova, Italy
Tel: 139 0498218677
Fax: 139 0497960903
Received 14 December 2008
Accepted 16 February 2009
By studying neuronal activity through neuronal electrogenesis, neurophysio-
logical investigations provide a functional assessment of the nervous system
and, therefore, has been used for quantitative assessment and follow-up of
hepatic encephalopathy (HE). The different clinical neurophysiological ap-
proaches can be classified depending on the function to explore and their
sensitivity to HE. The reliable techniques are those that reflect cortical
function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroen-
cephalogram (EEG), visual EPs (latency 4 100 ms) and somatosensory EPs
(SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem
acoustic EPs, SEPs of a latency o 25 ms) are in principle insensitive to HE,
but can disclose brainstem conduction deficits due to oedema. SEPs and
motor EPs can disclose myelopathies. Because of its parallelism to the clinical
examination, clinical neurophysiology can complement the neurological
examination: (i) to provide evidence of HE in patients who have normal
consciousness; (ii) to rule out, at least under some conditions, disturbances of
consciousness due to other causes (e.g. drug-induced disturbances, non-
convulsive stat us epilepticus) with the reservation that the mildest degrees of
encephalopathy might be associated with an EEG pattern similar to that
induced by drugs; and (iii) to demonstrate the worsening or, conversely
improvement, of HE in the follow-up period.
By studying neuronal activity through central or periph-
eral neuronal electrogenesis, neurophysiological investi-
gations provide a functional asse ssment of the nervous
system. Therefore, their domain is similar to that of the
clinical examination and complementary to that of
neuroimaging. When compared with the clinical exam-
ination, they provide a more quantitative assessment,
potentially amenable for follow-up, and may remain
interpretable in patients under mu scle blockade, in
whom clinical examination is not feasible.
Because neuronal electrogenesis depends on neuronal
activity that is sensitive to the influence of energy-
providing metabolic systems as well as to the influence
of those systems that are involved in electrolyte homo-
eostasis and clearance of toxic substances, clinical neuro-
physiology has been used for quantitative assessment and
follow-up of metabolic encephalopathies (1).
Neurophysiological techniques
Two techniques are available for routine use, both in
clinical and in experimental settings: the electroencepha-
logram (EEG) and evoked potentials (EPs). Recommen-
dations for their execution are reported by Deuschl and
Eisen (2). The grading of recommendations in this ar ticle
was performed according to the EASL criteria (Table 1).
The EEG primarily reflects cortical neuronal activity
modulated by both physiological and pathological dien-
cephalic and brainstem influences and by metabolic
and toxic factors. Many abnormal EEG patterns are
Antonello Grippo (Florence), Franco Randi (Rome), Marco Senzolo
(Padova) and Sami Schiff (Padova).
Liver International (2009)
2009 John Wiley & Sons A/S 789
Liver International ISSN 1478-3223
non-specific and may reflect a wide variety of pathophy-
siological events, from transient, primary, subcortically
or metabolically induced cortical dysfunction to irrever-
sible cortical problems.
Evoked potentials are generated through the passive
reception of sensory stimu li (‘exogeneous’ EPs) or cog-
nitive treatment of sensory stimuli [‘endogenous’ EPs or
cognitive’ EPs (CEPs]. Exogeneous EPs may be classified
according to the type of stimulus used [visual (VEP) ,
auditory (AEP) or somatosensory (SEP)] or their analy-
sis time window (short-latency, middle-latency or long-
latency EPs). Contrary to the EEG that only assesses
cortical function, EPs may provide assessme nt of both
the brainstem [brainstem auditory EPs (BAEPs), short-
latency SEPs (SSEPs)] and the cerebral cortex (long-
latency VEP, SEP and AEP). They may also provide a
quantitative assessment of some cognitive processes
(CEPs). To improve communication with the intensiv ists
and to facilitate patient follow-up, all EP parameters can
be summarized into two indices: the index of global
cortical function (IGCF) and the index of brainstem
conduction (IBSC) (4). The IGCF is derived from flash
visual and cortical SSEPs; it is rated from Grade 0
(normal cortical function, never observed in truly coma-
tose patients) to Grade 4 (absence of cortical compo-
nents). Grades 1–3 correspond to intermediate stages of
increasing severity. The IGCF was shown to be correlated
with the Glasgow Coma Score (5). The IBSC is derived
from subcortical somatosensory and BAEPs: it may
reflect medullary, pontine and/or midbrain dysfunction.
Motor EPs (MEPs) are recorded from muscles follow-
ing direct stimulation of the motor cortex, or from
transcranial stimulation of the motor cortex, either
electrical or magnetic, via transcranial magnetic stimula-
tion (TMS-MEPs). They provide information on motor
cortex excitability and cortico-spinal conduction time.
One clear advantage of the EEG is to provide on-line
assessment of brain function, in contrast to the EPs,
which summate the functional status of the correspond-
ing neural structures over the time needed for averaging.
This makes the EEG a unique tool for studying rapidly
changing activities (epileptic phenomena, triphasic
waves, periodic patterns and cortical reactivity to stimu-
In addition to providing straightforward brainstem
assessment, EPs benefit from their relative resistance to
the environmental electrical noise and levels of anaesthe-
sia, which may sometimes completely obscure the EEG in
the intensive care unit (ICU) environment (6).
Neurophysiological findings in hepatic
There is widespread evidence that both EEG and cortical
EPs worsen in parallel to the increasing severity of HE.
Hepatic encephalopathy of increasing severity is succes-
sively associated with a progressive slowing of the EEG,
an initial increase, followed by a decrease, in EEG ampli-
tude, a discontinuous pattern and an isoelectric EEG. A
remarkable finding is the appearance of triphasic waves.
Stupor is often, but not alwa ys, associated with triphasic
waves; coma is usually associated with d waves (7).
Although triphasic wa ves are frequent in HE, they are not
specific and can also be observed in other types of meta-
bolic encephalopathies (uraemic, hyponatremia) or in drug
intoxications (lithium, valproate and baclofen) (8, 9).
There is some debate on the initial changes in EEG,
consisting of either a frontal predominance of the a
rhythm or an increase in b waves (10–12). This observa-
tion is fully in keeping with the hypothesis of an
increased GABA-ergic receptor activity. Indeed, benzo-
diazepine (BZD) administration is known to give rise to
the initial appearance of anterior fast (b range) activities,
which eventually slows down (and transiently cross the a
range) with increasing dosages. Of note, stuporous HE
patients may transiently recover following the adminis-
tration of flumazenil, a BZD antagonist (13). At any rate,
research on this issue is still needed to confirm changes in
the spatial distribution of rhythms in the first stages of
HE, their frequency, pathophysiology and meaning.
Table 1. Grading of evidence and recommendations
Notes Symbol
Grading of evidence
Further research is very unlikely
to change our confidence in the
estimate of effect
Further research is likely to have
an important impact on our
confidence in the estimate of
effect and may change the estimate
Low- or very
Further research is very likely to
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
Factors influencing the strength
of the recommendation included
the quality of the evidence,
presumed patient-important
outcomes, and cost
Variability in preferences and
values, or more uncertainty: more
likely a weak recommendation is
Recommendation is made with less
certainty; higher cost or resource
Source: European Association for the Study of the Liver (3).
Liver International (2009)
2009 John Wiley & Sons A/S
Neurophysiological investigations of hepatic encephalopathy Guerit et al.
The grading of the severity of EEG alterations in
hepatic encephalopathy can be carried out on the basis
of visual pattern recognition, but this approach has
limited reliability (14). Grading on the basis of the simple
semiquantitative evaluation of the frequency of the basic
EEG rhythm improves the reliability of EEG evaluation
(15). On the basis of the relative power of frequency
bands and the mean dominant frequency, an EEG
classification can be obtained that has prognostic value
both in terms of survival and risk for development of
overt HE (16).
Evoked potentials
The IBSC might remain unaltered even in the presence of
a cortical dysfunction sufficient as to cause an isoelectric
EEG. In fact, IBSC alterations indicate brainstem dys-
function, which either may be the consequence of the
same or similar mechanisms as those causing HE, or
represent a concurrent pathological diso rder. Moreover,
SSEPs can detect myelopathy. By contrast, there is wide-
spread evidence that encephalic dysfun ction of increasing
severity is associated with a progressive worsening in
IGCF from Grades 0 to 3 (6). Finally, several studies
demonstrated changes in P300 latency and/or amplitudes
in patients with the mildest degrees of HE, which are
likely to parallel the early neuropsychologi cal changes
that can be observed in cirrhotic patients.
In a non-peer-reviewed study, Gu
erit (17) compared
EEG and IGCF, before liver transplantation, in a group of
18 patients with acute liver failure (ALF) who eventually
recovered after transplantation. EEG grading was per-
formed according to visual analysis of the dominant EEG
frequency (Grade 1: 7–8 Hz; Grade 2: 5–7 Hz; Grad e 3:
3–5 Hz and Grade 4: o 3 Hz) and the EP grading using
the IGCF. There was a highly significant relationship
between EEG and IGCF grades (P o 0.0001). However,
even the worst EEG alterations (Grade 4) were always
associated with preser vation of the primary cortical SEP
and VEP responses (Grade 3).
Motor-evoked potentials, as well as SSEPs and BAEPs,
may reveal signs of brainstem dysfunction or myelopa-
thy, even in patients considered to have minimal HE
(18–23), possibly linked to focal oedema occurring in
this syndrome, or to concurrent disorders.
Because of its parallelism to the clinical examination,
clinical neurophysiology can complement the neurological
examination: (i) to provide evidence of HE in patients who
have normal consciousness; (ii) to rule out, at least under
some conditions, disturbances of consciousness due to other
causes (e.g. drug-induced disturbances, non-convulsive
status epilepticus) with the reservation that the mildest
degrees of encephalopathy might be associated with an EEG
pattern similar to that induced by drugs;and (iii) to
demonstrate the worsening or, conversely improvement, of
HE in the follow-up period. B
The usefulness of clinical neurophysiology in
evaluating hepatic encephalopathy
Clinical neurophysiology in HE can be considered for:
1. the detection of minimal/subclinical forms of HE,
2. the objective quantification of overt HE,
3. the management of ALF.
Detection of minimal hepatic encephalopathy
Quantitative EEG analysis shows an increase of the
relative power of the y band and a decrease of the mean
dominant frequency in the posterior derivations in
15–30% of patients with cirrhosis who do not have
clinical evidence of HE (16, 24–27).
In the absence of other causes, the EEG alterations that
are observed in this patient population are assumed to
reflect the presence of minimal HE. In fact, these altera-
tions (i) roughly correlate with the indices of hepatic
dysfunction, (ii) predict the development of overt HE
and liver-related death, at least in patients with advanced
liver disease (16) and (iii) appear or increase when an
amino acid oral challenge causing hyperammonemia is
given to pati ents at risk for HE (28).
The P300 wave, elicited by an active oddball paradigm,
was found to be alter ed in 20–80% of cirrhotic patients
with no clinical evidence of HE or with Grade I HE (29). In
follow-up studies, changes in P300 latency predicted the
occurrence of overt HE (29). However, the changes in the
EEG were found to have a higher value than P300 to predict
the development of overt HE (30). In fact, P300 reflects a
cognitive process, but the initial stage of HE causing
changes in the electrogenesis might even prec ede cognitive
dysfunction and more closely represent toxic brain dys-
function (31). At an y rate, in the model of minimal HE
induced by TIPPS, the delay of P300 latency was found to
be more sensitive than those of the late cortical components
of SSEPs (32).
Other kinds of CEPs can produce detailed information
on the elementary mechanisms underlying cognitive
processes in experimental settings (33, 34).
Objective quantification of overt hepatic encephalopathy
In the late 197 0s, Conn et al. (35) considered the main
background frequency of the EEG as one of the dimen-
sions for HE assessm ent, as well as the mental state,
asterixis and ammonia plasma levels. The use of the main
background frequency can be biased in case the mixture
of more rhythms that is common is overt HE (e.g. d and
y band), or in case of instability of the tracing. In
addition, it is not clear how to evaluate the presence of
transients such as intermittent rhythmic d activity or
triphasic waves and how to consider the reduction in
EEG amplitude occurring in severe coma. Despite these
problems and only the rough correspondence of the EEG
pattern with the behavioural features of HE on a popula-
tion basis, the EEG has a unique role in producing
Liver International (2009)
2009 John Wiley & Sons A/S 791
Guerit et al. Neurophysiological investigations of hepatic encephalopathy
objective data on brain functioning, especially in non-
cooperative patients. In the follow-up of single patients
the correspondence between the EEG pattern and the
clinical findings might be stricter than that on a popula-
tion basis.
In summary, the different clinical neurophysiological ap-
proaches can be classified depending on the function to
explore and their sensitivity to HE. The reliable techniques
are CEPs (P300 paradigm), EEG, VEPs (latency 4 100 ms)
and SSEPs (latency between 25 and 100 ms) , which reflect
cortical function. Short-latency EPs (BAEPs, SSEPs of a
latency o 25 ms) are in principle insensitive to HE, but can
disclose brainstem condu ction deficits due to oedema. SEPs
and MEPs can disclose myelopathies. B
Recommendation. The optimal choice of clinical neurophy-
siological testing, for both research and clinical purposes,
could be influenced by the anticipated degree of HE and the
dysfunction, which is being sought. The most sensitive
techniques (CEPs and quantitative EEG) are the best
choices for the mildest degrees of HE, but CEPs rapidly
saturate (in terms of change) for increasing degrees of
severity. In the case of severe HE, less sensitive techniques
can be used (IGCF). In extremely severe HE, the first
cortical components of SSEPs are still d etectable. The
absence of these primary responses should lead to an in-
depth assessment of other irreversible causes of brain
damage. 2
Management of acute liver failure
With regard to ALF (i.e. the rapid deterioration of liver
function in a subject without previous liver disease,
accompanied by encephalopathy), there can be a three-
fold potential purpose:
a. Detecting brain dysfunction in patients with rapidly
developing hepatic failure and, therefore, contributing
to the diagnosis of ALF and the selection for liver
b. Gauging the efficacy of ongoing therapy aimed at
delaying or reducing brain oedema, or preventing
and treating non-convulsive seizures, thereby gaining
time if a cadaver graft is not available or if the patient
is not a candidate for liver transplantation; and
c. Excluding from transplantation those patients who
have already developed brain lesion s as severe as to
compromise any hope of functional recovery and in
whom even a graft would not prevent death or
unacceptable neurological sequels.
These three goals will be dealt with initially. We then
offer some practical recommendations
a. Selecting those patients who need transplant, because
of the severity of hepatic encephalopathy
The criteria that are used to select the patients with
ALF who need transplantation are clinical. At present,
neither EEG nor the EP grading of HE has been used for
the selection for transplantation in ALF.
One small non-blinded retrospective study reported
the use of SEPs as a tool for OLTs selection (36), showing
that the disappearance of middle- to long-latency com-
ponents (N70) in non-sedated patients (which were
still dete ctable in 24% patients with Grade 4 HE) was
superior to the King’s College criteria for selection for
transplantation (correct classification: 0.96 vs. 0.72 re-
spectively). Such results, however, have been not repeated
in a blinded or a larger series of patients. Moreover, it is
hard to establish whether the use of sedative drugs would
have reduced the diagnostic value of the disappearance of
long-latency components of the SSEP.
The choice of a neurophysiological technique should
be guided by the severity of HE under investigation.
Because of their extreme sensitivity to any cognitive
disturbance, CEPs are unlikely to be a valuable tool in
the evaluation of ALF. Rather, we recommend using EEG
and, if there are significant EEG abnormalities (predo-
minant d pattern or suppressed low-voltage pattern), to
consider the IGCF, which would be analysed according to
the presence, abnormality or absence of individual re-
sponses and interpeak latencies, or according to Gu
classification (4).
b. Gauging the efficacy of ongoing therapy aimed at
delaying or reducing brain oedema or preventing epilepsy,
thereby gaining time in case of cadaver grafts are unavail-
able or the patient is not suitable for transplantation
The increase in intracranial pressure (ICP) is one of
the main problems in patients with ALF. The possibility
of substituting (or reducing the use of) invasive ICP
monitoring with non-invasive electrophysiological mon-
itoring would be an interesting clinical goal, given the
risk of invasive ICP procedures in subjects with ALF. Of
note, subclinical epileptic activity can increase ICP (37).
The EEG is the only method for the diagnosis of non-
convulsive seizures and the only tool available for mon-
itoring its treatment (38–43).
In principle, an increase in IC P can give rise to both
cortical (EEG, IGCF) and IBSC alterations. Despite the
fact that the EEG changes reflect the severity of ALF in
experimental animal models (44) and that a good
relationship between EEG changes and ICP/cerebral
perfusion pressure was also proven in humans (45), there
is no proof that EEG monitoring is superior to clinical
evaluation for non-sedated patients. With regard to EPs,
the latencies of the late components of flicker vision EPs
(fVEPs) (latency range 4 100 ms) were found to reflect
changes of ICP, but the time course of their changes w as
slower than that of ICP in an open non-blinded study
(45). The P1 component of fVEP proved to be an index
of HE in an open, non-blinded study comparing 10
patients with ALF and 10 patients w ith acute hepatitis
who did not develop ALF, despite the absence of formal
comparisons with other classifications (46). In the same
setting, BAEPs were found to detect mainly prolongation
of the III–V interpeak and, to a lesser extent, of the I–V
Liver International (2009)
2009 John Wiley & Sons A/S
Neurophysiological investigations of hepatic encephalopathy Guerit et al.
interpeak that did not correlate with HE or with its
outcome. Of note, an imperfect correlation between ICP
and clinical neurophysiological parameters should not
automatically be interpreted as a failure of clinical
neurophysiology, because it may also reflect the fact that
some increase in ICP may be neurologically irrelevant.
It may be difficult to differentia te those EEG and IGCF
alterations that are due to metabolic disturbances from
those that are due to increased ICP. Additional problems
occur by the concurrent use of sedative drugs in these
patients, or by hypothermia (47), which also influence
brain electric activity (48).
By contrast, because the relationships between body
temperature and subcortical conduction times are
known, any IBSC change, in conjunction with ICP
monitoring , can provide some help to detect the brain-
stem consequences of increased ICP. This is the basis of
systems designed for continuous monitoring of EEG
spectrum, BAEPs and SSEPs (49) or for continuous
monitoring of EEG and SSEP (50).
In summary, the use of EEG monitoring in patients with
ALF admitted in ICU is worth investigating, as EEG is the
only tool to monitor seizure activity. EEG, BAEPs and
SEPs can theoretically complement ICP monitoring by
establishing the neurological relevance of an increase in
ICP. The issue of whether the installation of an invasive
ICP monitoring system might be avoided or reduced based
on EEG, IGCF or IBSC findings, thereby avoiding an
increased risk of intracerebral bleeding, deserves further
clarificatio n. B
c. Excluding from transplantation those patients who have
de veloped brain lesions as severe as to compromise any hope
of functional recovery and in whom even a graft cannot
prevent death or unacceptable neurological sequel
The EEG may not provide useful information to
exclude patients from transplantation, because full EEG
recovery has been described in patients with ALF even
without transplant and flat EEG (51). In fact, the absence
of EEG activity does not prove the existence of severe
brain oedema and brainstem deficits (4, 6). Moreover, at
least in experimental settings, EEG activity was proved to
be absent in ALF even when fVEP still showed the
existence of cortical activity (44).
(IGCF Grade 4) or BAEP changes c onsistent with major
pontine in volv ement constitutes a sufficient criterion to
exclude an individual patient from transplantation deserves
further discussion.
Few uncontrolled studies have evaluated the applicabil-
ity of SSEPs in the detection of patients with ALF who
have excessively severe brain damage. Madl et al.(36)
found that all the three patients out of 25 with ALF in
which N20 disappeared died in a few hours. Similar results
were obtained by Yang et al. (52, 53), who observed that all
patients in whom N20 and P25 disappeared had died
within 24 h after SSEP recording. By contrast, data on
children with ALF due to Reye’s syndrome also indicated
possible recovery in subjects with absence of scalp SSEPs
components (54). However, this study was performed in
children and its applicability in adults is uncertain. More-
over, major signs of pontine involvement can also reflect a
pre-existing, pontine damage (multiple sclerosis, posterior
fossa tumour, etc.) which is prognostically irrelevant.
In the absence of any pre-existing pathology, a bilateral
absence of N20 or BAEPs indicating structural pontine
involvement provides firm evidence that the current
neurological status of the patient is not just due to HE
but that some secondar y complication occurred (brain-
stem haemorrhage or brainstem lesions due to an
increase in ICP). Although absent cortical SEPs indicate
a particularly severe neuronal dysfunction, usually of an
ominous prognosis, there is still some theoretical possi-
bility that this situation may be reversible. Indeed, while
there is now universal agreement that, in post-anoxic
coma, a bilateral loss of N20 heralds death or vegetative
state (54, 55), in head trauma a bilateral N20 loss after
midbrain dysfunction has been associated with recovery
in up to 15% of patients (56). An increase in ICP may
cause bilateral loss of the N20 because of midbrain
compression, thus interfering with subcortical conduc-
tion. Thus, even if unlikely, the possible reversibility
should be investigated with imaging (computerized to-
mography scan or, if negative, magnetic resonance ima-
ging or single photon emission computed tomography to
recognize whether blood flow is still detectable). Note-
worthy, such extreme alterations have never been de-
scribed as a mere consequence of sedative drugs.
That is to say that the actual prognosis in this situation
depends on its aetiology and pathophysiology, which
must be sought before taking any positive or negative
decision regarding transplantation.
Neurophysiological tools cannot be used in isolation to
exclude consideration for liver transplantation. Even the
bilateral absence of the N20 component of SSEPs is, in
itself, not sufficient to exclude transplantation. However, it
would be ethically unacceptable to offer t ransplantation to
such a patient without further examination aimed at
determining the irreversibility of the central ner vous system
compromise. B
The EEG, although unspecific, provides information
on the severity of HE (minimal to severe), indepen-
dent of patient cooperation. It is influenced by drugs,
electric noise and, when suppressed in severe coma,
cannot reliably provide information on residual cor-
tical or subcortical activity. A
The EEG can occasionally indicate the occurrence of
other kinds of brain damage alternative to HE, or
provide patterns highly suggestive of HE in confused/
stuporous patients (triphasic waves). A
The EEG classification based on visual pattern recog-
nition, although informati ve, does not allow reliable
Liver International (2009)
2009 John Wiley & Sons A/S 793
Guerit et al. Neurophysiological investigations of hepatic encephalopathy
grading. An estimate of the basic background fre-
quency should always be provided. Quantitative EEG
analysis may improve the reliability of EEG assess-
ment. B
Through the IGCF, sensory EPs can provide informa-
tion on cortical function in severe HE. C
Sensory EPs through the IBSC and MEPs, through the
study of the cortico-spinal conduction time, may
reflect conduction defects due to brainstem dysfunc-
tion or myelopathy. These can share same or similar
causal mechanisms with HE or reflect other concur-
rent conditions. B
Cognitive EPs require accurate methodological proce-
dures both regarding the stimulus paradigms, record-
ing and interpretation. Widespread clinical use may be
problematic. These tests may provide an insight into
the cognitive processes in research settings. 1
The use of neurophysiological monitoring tools for
acute HE due to ALF is reasonable and research in this
area is worthwhile. The EEG can detect non-convulsive
and/or subclinical epileptic activity that can occur in
these patients. 2
Practical issues
For diagnostic purpose, the 19 electrodes of the 10–20
International System are sug gested. For
monitoring pur-
poses, four electrodes (for instance, P3, P4, F3 and F4) may
be sufficient. No real agreement was found on the duration
of EEG recordings: from 20–30 min in order to display
possible variations in the vigilance levels to 5–10 min,
which are considered enough by some members of the
Commission. Eyes closed and eyes open recording was
suggested whenever possible; photic stimulation was not
considered necessary. Whenever possible, a polygraphic
recording was considered preferable to understand unusual
EEG patterns. The recording of the EEG at the same time of
the day (e.g. morning vs. morning) and feeding conditions
(e.g. fasting vs. fasting) was considered to be an ideal, but
sometimes impossible, practice. In the case of EEG quanti-
fied by spectral analysis, no real consensus was found on the
best measure to be considered: mean dominant frequency
or spectral bands. No real consensus was found concerning
the evaluation of fluctuating EEG: some members of the
Commission prefer to consider th e best segment, others the
worst one and others both. 2
Evoked potential
Consensus for the usefulness of median SSEPs and the
uselessness of BAEPs were expressed, with variable answers
for VEPs. A modification according to the problem to be
addressed (minor degrees of encephalopathy and for re-
search purpose: CEPs; minor degrees for clinical purpose:
VEPs; more severe degrees: SEPs). At any rate, EPs should
be elicited, recorded and interpreted according to standard
guidelines. Both latencies and amplitudes should be con-
sidered. The patient’s temperature should be considered in
EPs interpretation. 2
These guidelines have been prepared by the Commission
on Neurophysiological Investigations of Hepatic Ence-
phalopathy appointed be the International Society for
Hepatic Encephalopathy and Nitrogen Metabolism. The
content was discussed and approved in the 13th ISHEN
Symposium, Padova (Italy) 28 April to 1 May 2008.
1. Niedermeyer E. Metabolic central nervous system disor-
ders. In: Niedermeyer E, Lopes Da Silva F, eds. Electro-
encephalography. Basic Pr inciples, Clinical Applications,
and Related Fields. Baltimore: Williams & Wilkins, 1993;
2. Deuschl G, Eisen A. Recommendations for the practice of
clinical neurophysiology: guidelines of the International
Federation of Clinical Neurophysiology (2nd Revised and
Enlarged Edition). Electroencephalogr Clin Neurophysiol
1999; 52(Suppl.): 3–304.
3. European Association for the Study of the Liver. EASL
Clinical Practice Guidelines: Management of Chronic he-
patitis B. J Hepatol 2009; 50:227–42.
4. Gu
erit JM, Fischer C, Facco E, et al. Standards of clinical
practice of EEG and EPs in comatose and other unrespon-
sive states. The International Federation of Clinical Neuro-
physiology 3. Electroencephalogr Clin Neurophysiol 1999;
52(Suppl.): 117–31.
5. Guerit JM, De Tourtchaninoff M, Soveges L, Mahieu P. The
prognostic value of three-modality evoked potentials
(TMEPs) in anoxic and traumatic comas. Neurophysiol Clin
1993; 23: 209–26.
6. Guerit JM. Medical technology assessment EEG and evoked
potentials in the intensive care unit. Neurophysiol Clin
1999; 29: 301–17.
7. Ikeda A, Klem GH, L
uders HO. Metabolic, infectious, and
hereditary encephalopathies. In: Ebersole J, Pedley TA, eds.
Current Practice of Clinical Electroencephalography. Phila-
delphia, USA: Lippincot William & Wilkins, 2003; 348–77.
8. Blume WT. Drug effects on EEG. J Clin Neurophysiol 2006;
23: 306–11.
9. Kaplan PW. The EEG in metabolic encephalopathy and
coma. J Clin Neurophysiol 2004; 21: 307–18.
10. Kullmann F, Hollerbach S, Lock G, et al. Brain electrical
activity mapping of EEG for the diagnosis of (sub)clinical
hepatic encephalopathy in chronic liver disease. Eur J
Gastroenterol Hepatol 2001; 13: 513–22.
11. Montagnese S, Jackson C, Morgan MY. Spatio-temporal
decomposition of the electroencephalogram in patients
with cirrhosis. J Hepatol 2007; 46: 447–58.
12. Sagales T, Gimeno V, De LC, et al. Brain mapping analysis
in patients with hepatic encephalopathy. Brain Topogr 1990;
2: 221–8.
Liver International (2009)
2009 John Wiley & Sons A/S
Neurophysiological investigations of hepatic encephalopathy Guerit et al.
13. Barbaro G, Di Lorenzo G, Soldini M, et al. Flumazenil for
hepatic encephalopathy grade III and IVa in patients with
cirrhosis: an Italian multicenter double-blind, placebo-
controlled, cross-over study. Hepatology 1998; 28: 374–8.
14. Amodio P, Marchetti P, Del Piccolo F, et al. Spectral versus
visual EEG analysis in mild hepatic encephalopathy. Clin
Neurophysiol 1999; 110: 1334–44.
15. Amodio P, Pellegrini A, Ubiali E, et al. The EEG assessment
of low-grade hepatic encephalopathy: comparison of an
artificial neural network-expert system (ANNES) based
evaluation with visual EEG readings and EEG spectral
analysis. Clin Neurophysiol 2006; 117: 2243–51.
16. Amodio P, Del Piccolo F, Petteno E, et al. Prevalence
and prognostic value of quantified electroencephalogram
(EEG) alterations in cirrhotic patients. J Hepatol 2001; 35:
17. Gu
erit JM. Les potentiales E
es, 2nd edn. Paris: Masson,
18. Kono I, Ueda Y, Nakajima K, et al. Subcortical impairment
in subclinical hepatic encephalopathy. J Neurol Sci 1994;
126: 162–7.
19. Mehndiratta MM, Sood GK, Sarin SK, Gupta M. Compara-
tive evaluation of visual, somatosensory, and auditory
evoked potentials in the detection of subclinical hepatic
encephalopathy in patients with nonalcoholic cirrhosis. Am
J Gastroenterol 1990; 85: 799–803.
20. Nolano M, Guardascione MA, Amitrano L, et al. Cortico-
spinal pathways and inhibitory mechanisms in hepatic
encephalopathy. Electroencephalogr Clin Neurophysiol 1997;
105: 72–8.
21. Oria M, Raguer N, Chatauret N, et al. Functional abnorm-
alities of the motor tract in the rat after portocaval
anastomosis and after carbon tetrachloride induction of
cirrhosis. Metab Brain Dis 2006; 21: 297–308.
22. 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: 2718–23.
23. Utku U, Asil T, Balci K, Uzunca I, Celik Y. Hepatic
myelopathy with spastic paraparesis. Clin Neurol Neurosurg
2005; 107: 514–6.
24. Amodio P, Quero JC, Del Piccolo F, Gatta A, Schalm SW.
Diagnostic tools for the detection of subclinical hepatic
encephalopathy: comparison of standard and computer-
ized psychometric tests with spectral-EEG. Metab Brain Dis
1996; 11: 315–27.
25. Hartmann IJ, Groeneweg M, Quero JC, et al
. The prognos-
tic significance of subclinical hepatic encephalopathy. Am J
Gastroenterol 2000; 95: 2029–34.
26. 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: 556–60.
27. Van Der Rijt CC, Schalm SW, De Groot GH, De Vlieger M.
Objective measurement of hepatic encephalopathy by
means of automated EEG analysis. Electroencephalogr Clin
Neurophysiol 1984; 57: 423–6.
28. Douglass A, Al Mardini H, Record C. Amino acid challenge
in patients with cirrhosis: a model for the assessment of
treatments for hepatic encephalopathy. J Hepatol 2001; 34:
29. Saxena N, Bhatia M, Joshi YK, Garg PK, Tandon RK.
Auditory P300 event-related potentials and number con-
nection test for evaluation of subclinical hepatic encephalo-
pathy in patients with cirrhosis of the liver: a follow-up
study. J Gastroenterol Hepatol 2001; 16: 322–7.
30. Saxena N, Bhatia M, Joshi YK, et al. Electrophysiological
and neuropsychological tests for the diagnosis of subclini-
cal hepatic encephalopathy and prediction of overt ence-
phalopathy. Liver 2002; 22: 190–7.
31. 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: 861–8.
32. Kramer L, Bauer E, Gendo A, et al. Neurophysiological
evidence of cognitive impairment in patients without
hepatic encephalopathy after transjugular intrahepatic por-
tosystemic shunts. Am J Gastroenterol 2002; 97: 162–6.
33. Schiff S, Vallesi A, Mapelli D, et al. Impairment of response
inhibition precedes motor alteration in the early stage of
liver cirrhosis: a behavioral and electrophysiological study.
Metab Brain Dis 2005; 20: 381–92.
34. Schiff S, Mapelli D, Vallesi A, et al. Top-down and bottom-
up processes in the extrastriate cortex of cirrhotic patients:
an ERP study. Clin Neurophysiol 2006; 117: 1728–36.
35. 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: 573–83.
36. Madl C, Grimm G, Ferenci P, et al. Serial recording of
sensory evoked potentials: a noninvasive prognostic indi-
cator in fulminant liver failure. Hepatology 1994; 20: 1487–94.
37. Shah AK, Fuerst D, Sood S, et al. Seizures lead to elevation
of intracranial pressure in children undergoing invasive
EEG monitoring. Epilepsia 2007; 48: 1097–103.
38. Claassen J, Mayer SA. Continuous electroencephalographic
monitoring in neurocritical car. Curr Neurol Neurosci Rep
2002; 2: 534–40.
39. Jordan KG. Continuous EEG and evoked potential mon-
itoring in the neuroscience intensive care unit. J Clin
Neurophysiol 1993; 10: 445–75.
40. Jordan KG. Nonconvulsive status epilepticus in acute brain
injury. J Clin Neurophysiol 1999; 16: 332–40.
41. Jordan KG. Continuous EEG monitoring in the neu-
roscience intensive care unit and emergency department.
J Clin Neurophysiol 1999; 16: 14–39.
42. Scheuer ML. Continuous EEG monitoring in the intensive
care unit. Epilepsia 2002; 43(Suppl. 3): 114–27.
43. Vespa PM, Nuwer MR, Nenov V, et al. Increased incidence
and impact of nonconvulsive and convulsive seizures
after traumatic brain injury as detected by continuous
electroencephalographic monitoring. J Neurosurg 1999; 91:
44. Tonnesen K, Balling H. Cerebral flow and metabolism
in experimental liver failure. A comparison between
Liver International (2009)
2009 John Wiley & Sons A/S 795
Guerit et al. Neurophysiological investigations of hepatic encephalopathy
hepatectomy and total hepatic devascularization in pigs.
Acta Chir Scand 1986; 152: 439–45.
45. Davenport A, Bramley PN. Cerebral function analyzing
monitor and visual evoked potentials as a noninvasive
method of detecting cerebral dysfunction in patients with
acute hepatic and renal failure treated with intermittent
machine hemofiltration. Ren Fail 1993; 15: 515–22.
46. Sawhney IM, Verma PK, Dhiman RK, et al. Visual and
auditory evoked responses in acute severe hepatitis. J
Gastroenterol Hepatol 1997; 12: 554–9.
47. Jalan R, Sw OD, Deutz NE, Lee A, Hayes PC. Moderate
hypothermia for uncontrolled intracranial hy pertension in
acute liver failure. Lancet 1999; 354: 1164–8.
48. Banoub M, Tetzlaff JE, Schubert A. Pharmacologic and
physiologic influences affecting sensory evoked potentials:
implications for perioperative monitoring. Anesthesiology
2003; 99: 716–37.
49. Pfurtscheller G, Schwarz G, Schroettner O, et al. Contin-
uous and simultaneous monitoring of EEG spectra and
brainstem auditory and somatosensory evoked potentials
in the intensive care unit and the operating room. J Clin
Neurophysiol 1987; 4: 389–96.
50. Fossi S, Amantini A, Grippo A, et al. Continuous EEG-SEP
monitoring of severely brain injured patients in NICU:
methods and feasibility. Neurophysiol Clin 2006; 36:
51. Rubik J, Pietraszek-Jezierska E, Kaminski A, et al. Success-
ful treatment of a child with fulminant liver failure and
coma caused by Amanita phalloides intoxication with
albumin dialysis without liver transplantation. Pediatr
Transpl 2004; 8 : 295–300.
52. Yang SS, Chu NS, Wu CH. Disappearance of N20 and P25
components of somatosensory evoked potential: an omi-
nous sign in severe acute hepatitis. J Formos Med Assoc
1993; 92: 46–9.
53. Yang SS, Chu NH, Wu CH. Subcortical somatosensory
evoked potentials in patients with hepatic encephalopathy
caused by severe acute hepatitis. J Gastroenterol Hepatol
1993; 8: 545–9.
54. Goff WR, Shaywitz BA, Goff GD, et al. Somatic evoked
potential evaluation of cerebral status in Reye syndrome.
Electroencephalogr Clin Neurophysiol 1983; 55: 388–98.
55. Zandbergen EG, De Haan RJ, Stoutenbeek CP, Koelman
JH, Hijdra A. Systematic review of early prediction of poor
outcome in anoxic-ischaemic coma. Lancet 1998; 352:
56. Guerit JM. Evoked potentials in severe brain injury. Prog
Brain Res 2005; 150
: 415–26.
Liver International (2009)
2009 John Wiley & Sons A/S
Neurophysiological investigations of hepatic encephalopathy Guerit et al.
    • "This indicates that using the MV ROC-derived threshold to evaluate EEG spectral variables provides information comparable to that produced using more advanced machine learning methods. Undertaking an EEG does not require patient co-operation and the recordings are not subject to learning effects—both problems which beset many other assessment tools used to diagnose hepatic encephalopathy (Guérit et al., 2009). This was recognised in the recent Practice Guideline on Hepatic Encephalopathy in Chronic Liver Disease published jointly by the American and European Associations for the Study of the Liver (Vilstrup et al., 2014 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: The utility of the electroencephalogram (EEG) for the diagnosis of hepatic encephalopathy, using conventional spectral thresholds, is open to question. The aim of this study was to optimise its diagnostic performance by defining new spectral thresholds. Methods: EEGs were recorded in 69 healthy controls and 113 patients with cirrhosis whose neuropsychiatric status was classified using clinical and psychometric criteria. New EEG spectral thresholds were calculated, on the parietal P3-P4 lead derivation, using an extended multivariable receiver operating characteristic curve analysis. Thresholds were validated in a separate cohort of 68 healthy controls and 113 patients with cirrhosis. The diagnostic performance of the newly derived spectral thresholds was further validated using a machine learning technique. Results: The diagnostic performance of the new thresholds (sensitivity 75.0%; specificity 77.4%) was better balanced than that of the conventional thresholds (58.3%; 93.2%) and comparable to the performance of a machine learning technique (72.9%; 76.8%). The diagnostic utility of the new thresholds was confirmed in the validation cohort. Conclusions: Adoption of the new spectral thresholds would significantly improve the utility of the EEG for the diagnosis of hepatic encephalopathy. Significance: These new spectral EEG thresholds optimise the performance of the EEG for the diagnosis of hepatic encephalopathy and can be adopted without the need to alter data recording or the initial processing of traces.
    Full-text · Article · Apr 2016
    • "Triphasic waves appear quite late in the progression of the disease, i.e. when the encephalopathy is quite severe with marked hyperammonemia, often responsible for stupor, whereas coma is most often associated with slowing (delta waves) or even a discontinuous EEG trace [75]. Focal abnormalities can be observed in the absence of underlying lesions [64]. In 15% of cases, one can find some focal spikes, or diffuse spike-and-waves [51]. "
    [Show abstract] [Hide abstract] ABSTRACT: Electroencephalogram (EEG) recording in the laboratory lasts at least 20minutes and uses 19 active electrodes. It includes rest periods, stimulation procedures, a 3-mn hyperventilation period and intermittent photic stimulation (IPS). Recorded at the bedside, the EEG uses at least eight electrodes; the stimulation procedures, duration of the EEG and need to repeat the examination depend on the indication. Simultaneous video recording is recommended. The EEG report describes the basic rhythm, its reactivity and pathological activities, whether epileptic or not, and their organization. The synthetic conclusion interprets the results while taking into account the clinical context and contributes, if possible, diagnostic and/or therapeutic help in patient management. EEG performed as soon as possible after a seizure is essential for the diagnosis and initial management of epilepsy. It is helpful to characterize the epileptic syndrome in order to initiate optimal treatment. EEG is also useful in managing the withdrawal of antiepileptic drugs. EEG is also extremely useful in case of impaired consciousness, confusional state or even acute or subacute cognitive disorders. It is the only available tool able to validate the diagnosis of non-convulsive status epilepticus presenting with confusional state. EEG helps in the diagnosis of toxic or metabolic encephalopathy and can assess its severity, especially in hepatic encephalopathy. Except in rare exceptions, EEG is not routinely indicated for the evaluation of typical vasovagal syncope, headaches, dizziness, typical transient global amnesia and transient ischemic attack. EEG is irreplaceable in the diagnosis and management of certain severe and frequent pathologies involving the cerebral cortex. Copyright © 2015. Published by Elsevier SAS.
    Article · Jan 2015
    • "As sedation, psychoactive drugs and hypothermia can produce EEG alterations not unlike those, which characterize HE, these should be considered as confounders in the diagnostic process. In severe coma, combinations of sensory evoked potential indices can obtain information on residual cortical or sub-cortical activity [83]. Neurophysiological monitoring of HE due to acute liver failure would seem reasonable but experience is limited. "
    [Show abstract] [Hide abstract] ABSTRACT: Hepatic encephalopathy in a hospitalized cirrhotic patient is associated with a high mortality rate and its presence adds further to the mortality of patients with acuteon- chronic liver failure (ACLF). The exact pathophysiological mechanisms of HE in this group of patients are unclear but hyperammonemia, systemic inflammation (including sepsis, bacterial translocation and insulin resistance) and oxidative stress modulated by glutaminase gene alteration remain as key factors. Moreover, alcohol misuse, hyponatremia, renal insufficiency and microbioma are actively explored. HE diagnosis requires exclusion of other causes of neurological, metabolic and psychiatric dysfunction. Hospitalisation in ICU should be considered in every patient with overt HE, but particularly if this is associated with ACLF. Precipitating factors should be identified and treated as required. Evidence-based specific management options are limited to bowel cleansing and non-absorbable antibiotics. Ammonia lowering drugs such as glycerol phenylbutyrate and ornithine phenylacetate show promise but are still in clinical trials. Albumin dialysis may be useful in refractory cases. Antibiotics, prebiotics and treatment of diabetes reduce systemic inflammation. Where possible and not contraindicated, large portal-systemic shunts may be embolised but liver transplantation is the most definitive step in the management of HE in this setting. HE in patients with ACLF appears to be clinically and pathophysiologically distinct from that of acute decompensation and requires further studies and characterization.
    Full-text · Article · Sep 2014
Show more

  • undefined · undefined
  • undefined · undefined
  • undefined · undefined

Recommended publications

Discover more