Q J Med 2003; 96:623633

doi:10.1093/qjmed/hcg110

Review
The neurology of liver failure
M. LEWIS and P.D. HOWDLE
From the Academic Unit of Medicine, St Jamess University Hospital, Leeds, UK

Introduction

Overt hepatic encephalopathy

Overt hepatic encephalopathy is generally taken to
refer to a syndrome of neuropsychiatric, neuropsychological and neurological disturbances that may
arise as a complication of liver disease, and which is
reversible.2 This definition is not entirely consistent
with the current state of knowledge, however, as

there is growing evidence that the reversibility of

the syndrome is not complete.11,12
A recent consensus statement, published following the World Congress of Gastroenterology in
1998, suggested that hepatic encephalopathy be
divided into three main types, with further subdivisions within one of the categories (Table 1).13
Between 10 and 50% of patients with cirrhosis
and/or porto-caval shunts will experience an episode of overt hepatic encephalopathy at some time
during their illness, with the prevalence varying
across the spectrum of severity of the cirrhosis.14,15
The true incidence and prevalence of overt hepatic
encephalopathy in these patients is difficult to
establish, because of the considerable heterogeneity
in aetiology and disease severity. It is also difficult to
diagnose the more subtle forms of hepatic encephalopathy such as stage 1 (Table 2) and minimal
hepatic encephalopathy. The lack of a gold standard
for assessing the presence of hepatic encephalopathy means that the incidence of these more minor
forms is difficult to ascertain.13
The factors that can precipitate overt hepatic
encephalopathy are well recognized, and include
an oral protein load, gastrointestinal bleeding,
electrolyte imbalance, infection and deteriorating
liver function.2,16
It is unlikely that a single mechanism underlies
the whole syndrome of hepatic encephalopathy in
all its various forms; a multifactorial pathogenesis is
much more likely.1720 Current thinking suggests
that a combination of chronic low-grade glial
oedema17 and potentiation of the effects of gamma
amino butyric acid (GABA) on the central nervous

Address correspondence to Dr M. Lewis, 68 Savile Road, Methley, Leeds LS26 9HW.

e-mail: m-k-lewis@email.msn.com
! Association of Physicians 2003; all rights reserved

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That there is a relationship between the brain and

the liver has been known for many years,1 and
patients with chronic liver disease frequently experience neurological problems. The commonest and
most widely recognized is the reversible syndrome
of hepatic encephalopathy,2 and we will deal with
this in some detail. There are also of course many
conditions that affect both the liver and the nervous
system, Wilsons disease being one of the best
known.28 This condition is a genetic disorder of
copper metabolism; the abnormal gene is located
on chromosome 139 and most of the symptoms
seem to be due directly to the deposition of copper
in various organs. Patients typically present early
with liver disease or later with the neurological
syndrome,2 which consists of various subtle neuropsychiatric symptoms such as a change in behaviour
or performance at school10 and abnormality of
movement.3,4 There are many other conditions
where the brain and liver are damaged by the same
or similar mechanisms,2 but these will not be
examined by this review, which concentrates on
the effect of a poorly functioning liver on the nervous
system.

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M. Lewis and P.D. Howdle

Table 1 Proposed nomenclature of hepatic encephalopathy (HE)13
HE type

Nomenclature

Subcategory

Subdivisions

Encephalopathy associated with

acute liver failure
Encephalopathy associated with
portal-systemic bypass, but no
intrinsic hepatocellular disease
Encephalopathy associated with
cirrhosis and portal hypertension or
portal-systemic shunts

Episodic HE
Persistent HE
Minimal HE

Precipitated
Spontaneous
Recurrent
Mild
Severe
Treatment-dependent

Table 2 The clinical stages of hepatic encephalopathy2,20

Mental state

Mild confusion, euphoria or depression, decreased attention, mental

slowing, untidiness, slurred speech, irritability, reversal of sleep pattern,
possible asterixis.
Drowsiness, lethargy, gross mental slowing, obvious personality changes,
inappropriate behaviour, intermittent disorientation, lack of sphincter
control, obvious asterixis.
Somnolent but rousable, unable to perform mental tasks, persistent
disorientation, amnesia, occasional attacks of rage, incoherent speech,
pronounced confusion, asterixis probably absent.
Coma.

system by ammonia may be responsible for many

of the symptoms of hepatic encephalopathy.
GABA is the major inhibitory neurotransmitter in
the human brain.19 Increased GABA-mediated
neurotransmission is known to cause impaired
consciousness and psychomotor dysfunction.19
In animal models of hepatic encephalopathy, an
increase in GABA-ergic tone has been demonstrated
due to both an increase in GABA release and
enhanced activation of the GABA-A receptor complex.18 Benzodiazepines can act at the GABA-A
receptor complex, and increased concentrations of
endogenous benzodiazepines are found in the
brain in liver failure.18,21,22
Ammonia is known to be neurotoxic, but usually
at much higher levels than those found in liver
failure, and even then it does not produce a
syndrome like that seen in hepatic encephalopathy;
in fact, it tends to cause neuronal excitation.2,19
However, at the lower concentrations seen in
hepatic encephalopathy, ammonia potentiates the
actions of GABA, possibly by enhancing ligand
binding to the GABA-A receptor complex.19 It is

probably for this reason that some patients

with hepatic encephalopathy improve following
administration of the GABA-A receptor antagonist
flumazenil.20,23
In addition there is some evidence for involvement of the glutamatergic system in hepatic
encephalopathy. Glutamate is the major excitatory
neurotransmitter in the human brain, and ammonia
reduces its synthesis and down-regulates the glutamate receptor in vitro. This would result in reduced
excitatory transmission in the brain.18 The dopaminergic, serotonergic and opioid neurotransmitter
systems have also been implicated in the pathogenesis of hepatic encephalopathy, and it is likely
that all of them and possibly others are involved
in this complex syndrome.2,18
In fulminant hepatic failure where hepatic encephalopathy develops within 8 weeks of the onset of
liver disease,24 autopsy reveals brain oedema and
astrocyte swelling.20 In patients with cirrhosis and
portal-systemic shunts, the typical finding is the
Alzheimer type II astrocyte, which is the pathological hallmark of hepatic encephalopathy.2,20 They

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Stage

Neurology of liver failure

use. Arterial blood ammonia is usually raised in

hepatic encephalopathy, although not always, and
the absolute level bears little relation to the severity
of the encephalopathy.42 The use of the electroencephalogram is limited, as the alterations are
non-specific, and triphasic waves are found in
many other metabolic encephalopathies.43 The
role of evoked potentials in the diagnosis and
management of hepatic encephalopathy is controversial, and a complete discussion of these techniques is beyond the scope of this review. Visual
(VEP), sensory (SEP) and brainstem auditory (BAEP)
evoked potentials can all be recorded, and show
various abnormalities depending on the waveforms
analysed and the liver disease under examination.
Generally speaking, these tests demonstrate delayed
latencies (a slower response) which become more
prolonged in relation to the degree of encephalopathy.44 They may therefore be of use in detecting
minimal hepatic encephalopathy or monitoring
treatment in established encephalopathy.4452
In addition, marked prolongation or absence of
various waveforms can be an indicator of poor
prognosis.4,53,54 Other tests such as lumbar puncture and neuroimaging are not usually indicated in
overt hepatic encephalopathy unless the diagnosis
is in doubt.
Treatment is largely supportive. Precipitating
factors should be treated or removed, and absorption of nitrogenous substances from the bowel
should be reduced.2,20 Treatments aimed at reversing the neurotransmitter defects such as by the
use of flumazenil are unproven and remain experimental.23
The outlook for patients who develop overt
hepatic encephalopathy is grim.55,56 Following the
first episode of overt hepatic encephalopathy, the
1-year survival is about 40%, falling to about 15%
after 3 years.56,57 Interestingly, the studies by
Saunders et al. and Bustamante et al. show very
similar mortality rates, despite the improvements
in intensive medical support that have occurred
over the intervening 20 years.

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy is the term that has
replaced the old terms of latent or sub-clinical
hepatic encephalopathy. It was felt that these older
terms did not reflect the important effects of this
syndrome on patients lives.13 It has been recognized for some time that with appropriate neuropsychological tests, patients who were felt clinically
to be free from hepatic encephalopathy do in fact
demonstrate signs of cognitive impairment.58,59

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are found in many locations, including the cortex

and the lenticular, lateral thalamic, dentate and red
nuclei.24 In turn, these abnormal astrocytes have
been shown to be produced by ammonia.25 These
findings are similar to those in the acquired
hepatocerebral degeneration syndrome.2629
Recent studies have also shown increased levels
of manganese in the basal ganglia and to a lesser
extent other areas of the brain,3032 but the
relevance of these findings is undetermined.
Overt or symptomatic hepatic encephalopathy
is traditionally graded into four stages (Table 2).
The clinical picture is of a derangement of
consciousness accompanied by decreased (or occasionally increased) psychomotor activity that if left
untreated progresses through increasing drowsiness,
stupor and coma.33 Sleep disturbance is one of
the more common early signs and occurs in nearly
50% of cases.34
As the encephalopathy progresses along this path,
signs of pyramidal tract dysfunction such as
hypertonia, hyperreflexia and extensor plantar
responses are common, eventually being replaced
by hypotonia as coma develops.2 The familiar sign
of asterixis is well described in hepatic encephalopathy, but unfortunately also occurs in other
metabolic encephalopathies and is not therefore
pathognomonic.20 One of the areas in which
hepatic encephalopathy can differ from other
metabolic encephalopathies is in the early stages
when the psychomotor retardation that occurs can
produce a striking Parkinsonian syndrome.2 In one
study, these Parkinsonian features were shown to
correlate with the degree of T1 hyperintensity seen
in the basal ganglia on cerebral magnetic resonance
imaging and the changes in choline/creatine ratios
in the basal ganglia on cerebral magnetic resonance
spectroscopy.35
Focal neurological deficits and signs have been
described in hepatic encephalopathy, but are
probably rare,36,37 although a recent study has
described fairly subtle abnormal neurological signs
occurring quite frequently.38 Visual disturbances
have also been reported in association with hepatic
encephalopathy, both as a result of cortical39 and
retinal dysfunction. The retinal dysfunction has been
termed hepatic retinopathy and probably results
from damage to retinal glia or Muller cells.40,41
Although seizures may occur, they are unusual
outside the setting of fulminant hepatic failure, and
should prompt the search for an alternative explanation. This relative rarity probably represents the
balance of neurotransmitters being tipped in favour
of inhibition as discussed above.
The diagnosis of overt hepatic encephalopathy
is largely clinical, but some investigations are of

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M. Lewis and P.D. Howdle

absence of a gold standard, these comparisons
are very difficult. It could be that the neurophysiological tests are actually achieving the correct level
of sensitivity and specificity, and the neuropsychological tests are overdiagnosing the condition.
A recent study has suggested that using the
technique of critical flicker frequency might be
effective in identifying cases of minimal hepatic
encephalopathy.68 This technique establishes the
frequency at which a flashing light appears to stop
flashing and becomes continuous (fusion frequency). The authors plotted this against the severity
of hepatic encephalopathy and also for normal
controls, and showed that the fusion frequency
dropped with increasing cognitive impairment.
They went on to suggest appropriate cut-off scores
for identifying minimal and overt hepatic encephalopathy with varying degrees of sensitivity and
specificity. This is a promising technique, and
will probably have a role in screening patients
who may then need more formal neuropsychological assessment.61,69
Neuroimaging techniques such as magnetic
resonance spectroscopy (MRS) and positron emission tomography (PET) have been used in the
assessment of minimal hepatic encephalopathy,
but at the moment they are more useful in research
and in further establishing the pathophysiology of
the condition.13,70,71
How these patients should be treated is uncertain.14 Studies have shown an improvement in
cognitive functioning with dietary protein restriction
or lactulose treatment.58,69,72 If there is a scale of
neurological and cognitive dysfunction with minimal hepatic encephalopathy at one end and overt
hepatic encephalopathy at the other, it would
seem reasonable that similar treatments would
work in each condition.
The prognosis of minimal hepatic encephalopathy has recently been studied, and 30% of patients
who showed signs of minimal hepatic encephalopathy went on to develop overt hepatic encephalopathy.15 Unfortunately, in this study the authors
do not make it clear over what period this occurred,
as they followed patients until one of three endpoints occurred (death, transplantation or overt
hepatic encephalopathy). The mean time taken to
develop hepatic encephalopathy was about 2 years
from the initial assessment. This is of limited use, as
we can not know when these patients actually
developed their initial cognitive impairment. Other
studies have also shown that minimal hepatic
encephalopathy is an independent predictor of
poor survival in patients with liver disease.73
These findings are not consistent with another
study that showed that the presence of minimal

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Only quite recently, however, were these more

subtle deficits shown to affect patients lives,60 and
the current consensus is that they should be
treated.14,61 Depending on the tests used and the
population studied, minimal hepatic encephalopathy seems to affect between about 20% and
70% of patients with liver disease.15,6164
The pathogenesis of minimal hepatic encephalopathy is not understood. It would seem likely,
however, that the same mechanisms affecting
neurotransmission in overt hepatic encephalopathy
also underlie minimal hepatic encephalopathy.
There is no reason to think that hepatic encephalopathy is an all-or-nothing phenomenon, and a
continuous scale of impairment would seem more
likely.14,61 Alterations in the pattern of cerebral
blood flow have been demonstrated in patients with
minimal hepatic encephalopathy, and it would
seem likely that this also plays a role in its
pathogenesis.65
Because the syndrome of minimal hepatic encephalopathy has only recently been defined, its clinical
characteristics are poorly described. If different
neuropsychological tests are used to identify the
syndrome in each study, then different cognitive
deficits might be detected.64 A common finding in
most of the studies however, is impairment of visuospatial functioning, attention and psychomotor
speed.14,59,64 Unfortunately this is not universal,
and others have not demonstrated visuo-spatial
dysfunction.66 The causes of liver failure are
heterogeneous and the severity of liver disease
within even a single cause can vary hugely. This
could explain the difficulty in establishing the nature
of the cognitive dysfunction that exists in these
patients.
It is now generally agreed that neuropsychological tests offer the best option for diagnosing minimal
hepatic encephalopathy, but there is considerable
debate about which tests should be used and how
the results should be interpreted.13 Generally, any
battery of neuropsychological tests should assess
a broad range of cognitive functions,67 and in the
case of liver dysfunction, should probably include
tests of psychomotor speed, visuopraxis, attention
and concentration.13,64 It has been suggested that
tests of language and memory need not be included
in assessing minimal hepatic encephalopathy.64
We believe that at the moment we do not know
enough about the characteristics of the cognitive
impairment in these patients to exclude major areas
of cerebral function from any assessment.
The role of the EEG and evoked potentials in
making the diagnosis is also uncertain, but the
current feeling is that neuropsychological tests are
more sensitive and specific.13 However, in the

Neurology of liver failure

hepatic encephalopathy was of limited prognostic
significance.74 In this study however, patients with
minimal hepatic encephalopathy had more episodes of overt hepatic encephalopathy, and as we
know that overt hepatic encephalopathy is associated with a very poor prognosis,55,56 it could be
that the authors negative findings simply reflect a
lack of long-term follow-up.

Hepatic encephalopathy and

liver transplantation

Fulminant hepatic failure

Patients with fulminant hepatic failure form a
distinct group, compared to patients with chronic
liver disease. The syndrome is said to occur when
hepatic encephalopathy develops within 8 weeks
of the onset of liver disease.24 The most prominent
neurological problem is cerebral oedema and
subsequent raised intracranial pressure. The exact
mechanism by which the cerebral oedema occurs
is unknown, but once again ammonia is thought
to play a role. This time, levels of ammonia tend
to be higher, and may contribute to the neuroexcitatory symptoms seen in this state, such as
agitation, seizures and multifocal muscle twitching,
via direct toxicity. In these situations ammonia
also has an adverse effect on osmoregulation
via its reaction with glutamate to form glutamine,
thus exacerbating cerebral oedema.17,18 Mortality
is high at around 7080%,8083 but many of these
patients are now being transplanted, and survival
rates are improving.81,8487 In addition, there is
also evidence that if provided with support, the
native liver can regenerate, and auxiliary partial
liver transplantation is sometimes used to treat
these patients.88

Acquired hepatocerebral
degeneration and hepatic
myelopathy
Acquired (non-Wilsonian) hepatocerebral degeneration (AHCD) is a clinico-pathological syndrome of
brain dysfunction associated with a variety of liver
diseases, originally characterised by Victor et al. in
1965.26 The typical clinical features of this chronic
and largely irreversible syndrome are dementia,
dysarthria, ataxia of gait, intention tremor and
choreoathetosis.26,29 The main neuropathological
findings include diffuse but patchy cortical necrosis,
diffuse proliferation of Alzheimer type II glial cells
and uneven neuronal loss in the cerebral cortex,
basal ganglia and cerebellum.2629
A hepatic or portal-systemic myelopathy (HM)
has also been described, initially by Zieve et al. in
1960,89 and is characterized clinically by a spastic
paraparesis with minimal sensory involvement.89,90
The pathology is somewhat different, however,
and consists mainly of symmetrical demyelination,
predominantly of the lateral pyramidal tracts,
sometimes associated with axonal loss, generally
going no higher than cervical cord level.89,90
The pathogenesis of both acquired hepatocerebral degeneration and hepatic myelopathy are poorly
understood, although it is usually thought that
nitrogenous products bypassing the liver through
the porto-caval shunt play an important role.90
There have been suggestions, however, that the
acquired hepatocerebral degeneration syndrome
simply represents the damage accumulated from
multiple episodes of hepatic encephalopathy.29
In most of the reported cases, episodes of overt
hepatic encephalopathy have preceded the development of the myelopathy or the hepatocerebral
degeneration.26,9194 However, there have been
cases where this has not occurred,90 and thus
another mechanism may be at work.
It would seem most likely that it is chronic
exposure to toxic substances bypassing the liver
that causes both AHCD and HM. Or more
specifically, that these toxins are resulting in one
pathological response in the brain and a different
pathological response in the spinal cord.2628,9295
Treatment of these patients is difficult. There have
been case reports of transplantation being used with
varying degrees of success,90,91,96,97 but if liver
transplantation does have a role to play in the
management of this condition, one needs to bear
the underlying pathology in mind. In the early
stages, demyelination seems to predominate, but as
the disease progresses axonal loss occurs, and this
is likely to be irreversible.26,94,95 This might go some

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The effect of liver transplantation in patients

with varying degrees of hepatic encephalopathy is
uncertain. There have been few studies in this area
and none in the UK. The work that has been done
suggests a significant improvement in cognitive
function following liver transplantation, but patients
do not return to normal.7579
A recent study has suggested that these improvements occur quickly after transplantation and are
maximal by about 3 months.75 In some respects
the fact that patients do not return to normal is not
surprising, but it is somewhat at odds with the
current theory regarding the complete reversibility
of hepatic encephalopathy.12,24

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M. Lewis and P.D. Howdle

Osmotic demyelination disorders

Central pontine myelinolysis and extrapontine
myelinolysis are now collected together under the
term osmotic demyelination disorders.102 These
syndromes are not exclusive to liver disease, and
can occur from a variety of causes.103 They are
however more common in association with liver
disease, particularly alcoholic liver disease.

Central pontine myelinolysis manifests as a

rapidly evolving paraparesis or quadraparesis, pseudobulbar palsy and impaired responsiveness. It is
characterized pathologically by loss of myelin in the
basis pontis, often in a strikingly symmetrical
fashion33,103 (Figure 1). The degree of neurological
impairment can range from minimal symptoms to a
full locked in syndrome, where the patient can
experience the horror of being fully aware but be
unable to move.104 The underlying cause is not fully
understood, but most cases involve a change in
osmolality, often rapid and often involving correction of hyponatraemia.33,103 This does not explain
all the cases, however,105 and in addition many
patients survive rapid correction of hyponatraemia
without developing signs and symptoms of central
pontine myelinolysis. Other conditions are likely to
predispose to development of the syndrome, and
liver disease and transplantation are commonly
described in this role.106108 The prognosis of this
condition has probably been described in overly
bleak terms, with many standard texts suggesting
that most patients die. However, this has not been
our experience, and in a recent large series, 32 out
of 44 patients with central pontine myelinolysis
survived. Twenty-one had various degrees of
permanent neurological impairment, but 11 recovered completely.109

Other neurological disorders

in liver disease
There has also been recent interest in two other
symptoms that can occur in liver disease and that

Figure 1. A T2-weighted MRI scan showing high signal in the brainstem (arrows) consistent with osmotic demyelination.

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way towards explaining the different experiences

reported in the literature. In the case reported by
Counsell et al.,91 liver transplantation was performed at least 18 months after the onset of
symptoms, and there was no improvement in the
myelopathy. In a more recent case, the liver
transplant was performed after no more than 10
months of neurological symptoms, and the authors
documented good improvement.97
If, as seems likely, it is the portal-systemic venous
shunting that underlies these conditions, then with
the development of procedures such as transjugular
intrahepatic portal-systemic shunting (TIPSS), and
the increasing survival of these patients, such longterm neurological sequelae may be encountered
more often. In fact there is growing evidence that
this is already starting to occur, with several studies
reporting neurological and neuropsychological dysfunction in patients who have undergone shunting
procedures such as TIPSS.98101 As the time
between shunting and the development of AHCD
can be many years,90,95 we will need to wait and
see whether this syndrome becomes a common
and significant problem for these patients.

Neurology of liver failure

629

Figure 2. A T1-weighted MRI scan showing high signal in the basal ganglia (arrows).

Neuroimaging abnormalities
associated with liver disease
It is becoming widely recognized that patients with
chronic liver disease and portal-systemic shunts

exhibit typical abnormalities on cerebral magnetic

resonance imaging (MRI).114117 These consist of an
abnormally high signal on T1-weighted imaging in
the basal ganglia, particularly the globus pallidus
(Figure 2). This high signal is now believed to be
due to manganese deposition,30,32,118,119 and postmortem studies have shown levels up to seven times
normal in the globus pallidus.30,32 Interestingly,
chronic manganese poisoning produces a syndrome
very similar to the acquired hepatocerebral degeneration syndrome, with mental slowing, tremor and
bradykinesia. It also has very similar neuroimaging
characteristics, and chelation therapy has been
effective in improving both the clinical syndrome
and the globus pallidus high signal.120,121 With
successful liver transplantation, the abnormalities
seen in liver disease also resolve.118119
In the acquired hepatocerebral degeneration
syndrome, the typical findings described above are
found, often with more extensive high signal in the
white matter, best seen on T2-weighted imaging.90
In hepatic myelopathy, there are usually no MRI
abnormalities, and this probably represents the
current technical limitations of this technique and
the relatively small magnet strengths of current
clinical scanners.90,118,119

Conclusions
Neurological syndromes are common in patients
with liver failure, and are an important cause of
morbidity. Our understanding of their pathogenesis
is improving, but much work remains to be done,
particularly as regards management of these
problems. The link between the liver and the

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might have a neurological basis. The pruritus of

cholestasis may at least in part have its origins in the
central nervous system.110 The authors suggest
several mechanisms whereby this might be the
case: opioid agonists induce pruritus by a central
mechanism, central opioidergic tone is increased in
cholestasis and opioid antagonists can improve the
symptom. Clearly this theory remains to be proven.
Many patients with chronic liver disease also
complain of fatigue, and the mechanisms of this
symptom are poorly understood. It would seem
unlikely to have a single cause, but may be due in
part to altered central neurotransmission involving
the serotonergic system.2 Fatigue is a common
complaint in many medical and psychiatric conditions. It is particularly common in neurological
disorders such as multiple sclerosis, and the
mechanisms involved may be similar.111
There is an increased incidence of neuromuscular
dysfunction in patients with liver disease. Whether
the liver disease itself causes these problems is
difficult to establish. Many of the causes of liver
disease, such as alcohol, hepatitis C, porphyria and
so on, are also known to cause peripheral neuropathies and myopathies.103,112 There is some
evidence, however, that the worse the liver disease,
the worse the neuropathy, independent of the
aetiology of the liver disease.113 This suggests that
the liver disease itself is causing, or at least
contributing to, the neuropathy.

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M. Lewis and P.D. Howdle

brain, described many years ago by Dr Friedrich

Frerichs,1 is still only partially understood.

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