CURRENT CONCEPTS

Review Article

Current Concepts

T REATMENT OF H EPATIC
E NCEPHALOPATHY
STEPHEN M. RIORDAN, M.D.,

AND

ROGER WILLIAMS, M.D.

EPATIC encephalopathy is a complex neuropsychiatric syndrome that may occur in

such diverse clinical situations as inherited
errors of the urea cycle, acute or chronic liver disease,
and spontaneous or iatrogenic portosystemic venous
shunting, including that following procedures to
establish a transjugular intrahepatic portosystemic
shunt. The clinical manifestations of this syndrome
range from subtle abnormalities detectable only by
psychometric testing to deep coma. Several grading
systems have been proposed; one based on clinical
and electroencephalographic abnormalities is shown
in Table 1.1 Hepatic encephalopathy may be present
in 50 to 70 percent of all patients with cirrhosis, including those with abnormalities demonstrable only
by psychometric testing.2,3 Most manifestations of
hepatic encephalopathy are reversible with medical
treatment. Some patients with hepatic encephalopathy have progressive, debilitating syndromes, such as
dementia, spastic paraparesis, cerebellar degeneration,
and extrapyramidal movement disorders, associated
with structural abnormalities of the central nervous
system.1,4 These syndromes were formerly regarded as
irreversible, but there may be gradual improvement
after successful orthotopic liver transplantation.5
The accumulation of unmetabolized ammonia,
predominantly as a result of poor hepatic function
and portosystemic shunting, has traditionally been
considered to have an important role in the pathogenesis of hepatic encephalopathy. In addition, a
number of other possible mechanisms have recently
been proposed, including production of false neurotransmitters, activation of central g-aminobutyric
acidbenzodiazepine receptors by ligands of endogenous origin, altered cerebral metabolism, and dis-

From the Institute of Hepatology, University College London Medical

School, 6975 Chenies Mews, London WC1E 6HX, United Kingdom,
where reprint requests should be addressed to Dr. Williams.
1997, Massachusetts Medical Society.

turbed activity of Na/KATPase. Decreased activity of urea-cycle enzymes due to zinc deficiency and
the deposition of manganese in the basal ganglia
may also contribute to hepatic encephalopathy.1,6-11
These pathogenetic mechanisms are not necessarily
exclusive. Most treatment measures of proved value
are based on the ammonia hypothesis.
APPROACH TO MANAGEMENT

None of the manifestations of hepatic encephalopathy are specific to this disorder, and it is essential to exclude alternative diagnoses (Table 2).12 Although the level of ammonia in the arterial blood
tends to be elevated in patients with more advanced
hepatocellular dysfunction, especially when substantial portosystemic shunting is present, it is only poorly correlated with the grade of hepatic encephalopathy.13 Consequently, this measurement is of little
clinical value in establishing the diagnosis or following the progress of patients with hepatic encephalopathy. Conversely, practical bedside tests, such as the
number-connection and other trail-making tests,14,15
are easily administered and, in this era of cost-effective medicine, provide useful information, especially
in patients with subclinical hepatic encephalopathy
that would otherwise be overlooked.
The treatment of hepatic encephalopathy in patients with the rare condition of acute liver failure
and in those with the much more common chronic
liver disease should be considered separately. Hepatic
encephalopathy in patients with acute liver failure is
rapid in onset and progression and is almost always
complicated by cerebral edema in the later stages. It
is of paramount importance to consider orthotopic
liver transplantation for such patients on the basis of
the prognosis.16,17 Patients with acute liver failure and
grade 3 or 4 hepatic encephalopathy should undergo
elective ventilation, sedation with fentanyl, and paralysis with atracurium both to protect the airway and
to facilitate the management of cerebral edema by
preventing surges in intracranial pressure related to
psychomotor agitation. Monitoring of extradural
pressure is of value in these patients but carries some
risk.18 Mannitol given by repeated bolus injections
(0.5 g per kilogram of body weight over a period of
10 minutes) remains the main pharmacologic treatment of cerebral edema in this setting. Acetylcysteine
given by continuous infusion to patients with grade
4 hepatic encephalopathy has been reported to improve the cerebral blood flow and the cerebral metabolic rate for oxygen. Epoprostenol (prostaglandin
I2) also improves the cerebral metabolic rate for oxygen.19 Hypoglycemia can be a lethal complication of
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The New England Journal of Medicine

TABLE 1. A GRADING SYSTEM

GRADE

LEVEL

0
Subclinical

Normal
Normal

1
2

3
4

OF

CONSCIOUSNESS

PERSONALITY

FOR

AND INTELLECT

HEPATIC ENCEPHALOPATHY.*

NEUROLOGIC SIGNS

Normal
Normal

None
Abnormalities only on psychometric analysis
Inverted sleep pattern, rest- Forgetfulness, mild confusion, Tremor, apraxia, incoordination,
lessness
agitation, irritability
impaired handwriting
Lethargy, slow responses
Disorientation as regards time, Asterixis, dysarthria, ataxia, hypoamnesia, decreased inhiactive reflexes
bitions, inappropriate
behavior
Somnolence but rousability, Disorientation as regards
Asterixis, hyperactive reflexes,
confusion
place, aggressive behavior
Babinski signs, muscle rigidity
Coma
None
Decerebration

ELECTROENCEPHALOGRAPHIC
ABNORMALITIES

None
None
Triphasic waves (5 cycles/sec)
Triphasic waves (5 cycles/sec)

Triphasic waves (5 cycles/sec)

Delta activity

*The system is based on clinical and electroencephalographic features suggested by Gitlin.1

TABLE 2. DIFFERENTIAL DIAGNOSIS

ENCEPHALOPATHY.*
DISORDER

OF

HEPATIC

DIAGNOSTIC TEST

Metabolic encephalopathies
Hypoglycemia
Electrolyte imbalance
Hypoxia
Carbon dioxide narcosis
Azotemia
Ketoacidosis
Toxic encephalopathies
Alcohol
Acute intoxication
Withdrawal syndrome
WernickeKorsakoff syndrome
Psychoactive drugs
Salicylates
Heavy metals
Intracranial lesions
Subarachnoid, subdural, or intracerebral
hemorrhage
Cerebral infarction
Cerebral tumor
Cerebral abscess
Meningitis
Encephalitis
Epilepsy or postseizure encephalopathy
Neuropsychiatric disorders

Blood chemical analysis

Measurement of blood
alcohol level, erythrocyte transketolase
activity, therapeutic
response to thiamine,
toxicologic screening

Computed tomogra phy, lumbar punc ture, arteriography,

electroencephalogra phy, virologic testing

Tests for organic brain

syndromes

*Data are adapted from Ferenci.12

This diagnosis is especially pertinent to patients with liver disease.

474 

acute liver failure, and monitoring of blood glucose

at least every four hours is mandatory.
The further treatment of patients with acute liver
failure is beyond the scope of this review, which focuses on the treatment options for patients with hepatic encephalopathy as a complication of chronic
liver disease, in whom cerebral edema is much less
frequent. Most episodes of hepatic encephalopathy
in patients with chronic liver disease are due to a
clinically apparent precipitating event or to the spontaneous development of portosystemic shunting (Table 3). Several factors may be operative in a given patient at the same time. For example, septicemia or
bacterial peritonitis, typically with gram-negative, colonic-type flora, develops within 48 hours in about
half of patients with ChildPugh class C cirrhosis
who have an acute gastrointestinal hemorrhage.20 Hypokalemia and systemic alkalosis, complicating the
use of diuretic agents to treat the ascites, in turn lead
to increased renal production of ammonia and increased diffusion of ammonia across the bloodbrain
barrier, respectively.21 Older age is generally considered to be an important influence on the prevalence
and severity of hepatic encephalopathy complicating
surgical creation of a portosystemic shunt.22 The
number of patients referred for surgical creation of a
shunt has fallen with the advent of the transjugular
intrahepatic portosystemic shunt, the establishment
of which has become a standard procedure in the
treatment of recurrent variceal hemorrhage in many
centers. This procedure is associated with a 25 percent overall incidence of chronic hepatic encephalopathy,23 which is more likely to occur in women,
patients over the age of 60 years, and patients with
marked hypoalbuminemia.23,24 Every effort should be
made to identify the precipitating factor and, if possible, correct it.
Other therapeutic measures are described below

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CURRENT CONCEPTS

TABLE 3. FACTORS PRECIPITATING HEPATIC

ENCEPHALOPATHY IN PATIENTS WITH CHRONIC
LIVER DISEASE.
PRECIPITANT

Excess dietary protein*

Constipation*
Anorexia
Fluid restriction
Gastrointestinal hemorrhage*
Infection (including bacterial
peritonitis)*
Blood transfusion
Azotemia*
Hypokalemia*
Systemic alkalosis*

POSSIBLE MECHANISM

Increased ammonia
production

Increased diffusion of
ammonia across
bloodbrain barrier

Dehydration

Fluid restriction

Diuretic effect
Reduced metabolism
Excessive paracentesis

Diarrhea due to osmotic laxatives

toxins because of
of
Arterial hypotension
hepatic hypoxia

Gastrointestinal hemorrhage

Peripheral vascular dilatation

Arterial hypoxemia

Anemia
Use of benzodiazepines
Activation of central
g-aminobutyric
acidbenzodiazepine receptors
Use of other psychoactive drugs
Compounding of central nervous
system depressant
effect
Portosystemic shunts*
Reduced hepatic meSpontaneous
tabolism of toxins
Surgical
because of diversion
Transjugular intrahepatic
of portal blood
Progressive hepatic parenchymal
Reduced hepatic medamage*
tabolism of toxDevelopment of hepatoma*
ins because of decreased functional
reserve
*This is one of the more common precipitants.

according to the various hypotheses relating to the

pathogenesis of hepatic encephalopathy. The use of
these measures is not in every case currently supported by the results of controlled clinical trials (Table 4). Hepatic encephalopathy as a complication of
spontaneous or surgically created portosystemic anastomoses or transjugular intrahepatic portosystemic
shunts is usually successfully managed along conventional lines. Transhepatic embolization or surgical ligation of portosystemic shunts is occasionally of
benefit when hepatic encephalopathy is refractory to
other treatments.25,26 Refractory hepatic encephalopathy as a complication of transjugular intrahepatic portosystemic shunts can be successfully managed
by implanting a reducing stent.27

TABLE 4. RESULTS OF CONTROLLED TRIALS OF

TREATMENTS FOR HEPATIC ENCEPHALOPATHY AS
A COMPLICATION OF CHRONIC LIVER DISEASE.*
Ammonia hypothesis
Reduced ammonia production
Dietary protein restriction ()
Vegetable-protein diet ()
Carbohydrate enemas ()
Water enemas ()
Oral lactulose ()
Oral lactitol ()
Oral lactose in lactase deficiency ()
Oral antibiotics
Neomycin ()
Metronidazole ()
Rifaximin ()
Enterococcus faecium ()
Lactobacillus acidophilus
Alone ()
With neomycin ()
Helicobacter pylori eradication (NP)
Increased ammonia metabolism
Ornithine a-ketoglutarate ()
Ornithine aspartate ()
Sodium benzoate ()
Phenylacetate ()
Zinc supplementation ()
False-neurotransmitter hypothesis
Branched-chain amino acids
Enteral ()
Parenteral ()
Keto analogues ()
Levodopa ()
Bromocriptine ()
g-Aminobutyric acidbenzodiazepine
receptor ligand hypothesis
Flumazenil ()
Manganese hypothesis
Edetate calcium disodium (NP)
Sodium para-aminosalicylic acid (NP)
*A plus sign indicates that controlled trials support
the treatment; a plusminus sign that results of controlled trials are conflicting; a minus sign that controlled trials do not support the treatment; and NP that
controlled trials have not been performed.

REDUCTION OF PRODUCTION
AND ABSORPTION OF AMMONIA

The intestinal production of ammonia can be reduced by restricting the intake of dietary protein and
inhibiting urease-producing colonic bacteria. Although the restriction of dietary protein has long
been recognized as an effective treatment,12,28 patients
with cirrhosis often require minimal daily protein intakes of 0.8 to 1.0 g per kilogram to maintain nitrogen
balance.29 Long-term restriction to values below this
range should be avoided if possible. After dietary
protein has been initially limited to 20 g a day, the
intake should be increased by 10 g every three to five
days until the patients protein tolerance has been
established.
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The New England Journal of Medicine

Supplementation with vegetable, rather than animal, protein may be advantageous in patients whose
total daily dietary protein tolerance is less than 1 g per
kilogram, since controlled studies have suggested that
supplementation with vegetable protein may result
in a substantial improvement in nitrogen balance without precipitating or worsening hepatic encephalopathy.30 This beneficial effect may be due to the higher content of fiber in a vegetable diet than in an
animal diet with an equal amount of nitrogen. The
fiber increases the rate of transit of food through the
intestine and lowers the pH of the colonic lumen as
a result of its fermentation by colonic bacteria.29 Most
patients will accept a diet containing 30 to 40 g of
vegetable protein, although restriction of sodium will
render such a diet unpalatable.
The physiologic shedding of gut epithelial cells
provides additional luminal protein to be metabolized
to ammonia by bacteria. Both dietary and endogenous ammoniagenic substrates are removed from the
intestinal lumen by the osmotic cathartic action of
nonabsorbable disaccharides such as lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol).
These compounds are currently the main therapeutic
agents for chronic hepatic encephalopathy. The efficacy of oral lactulose for the treatment of hepatic encephalopathy has been established in controlled trials.31 The daily dose of lactulose should be titrated to
result in two to four soft, acidic (pH less than 6)
stools daily. For most patients the daily dose is between 30 and 60 g.
As well as having a cathartic effect, lactulose lowers the colonic pH as a result of the production of
organic acids by bacterial fermentation. The decrease
in pH creates an environment that is hostile to the
survival of urease-producing intestinal bacteria and
may promote the growth of nonurease-producing
lactobacilli, resulting in reduced production of ammonia in the colonic lumen. In addition, acidification of the colonic secretions not only reduces the
absorption of ammonia by nonionic diffusion, but
also results in the net movement of ammonia from
the blood into the bowel lumen.21 Enemas containing lactulose or other carbohydrates may be used if
oral or nasogastric administration of the carbohydrate
is impossible. Conversely, water enemas are ineffective, suggesting that acidification of the colonic lumen, rather than bowel cleansing alone, is responsible
for the therapeutic effect.32
Although it is not licensed for use in the United
States at present, oral lactitol at a dose of 30 to 45
g daily is as effective as lactulose for treating hepatic
encephalopathy and has the advantage of being more
palatable and associated with a lower incidence of
side effects, such as flatulence.33,34 Oral lactose at a
dose of 100 g daily is another proved alternative in
lactase-deficient patients.35
Antibiotics with activity against urease-producing
476 

bacteria, such as neomycin or metronidazole, also reduce the production of intestinal ammonia and have
proved value.31,36,37 The efficacy of neomycin (6 g daily) is similar to that of lactulose.37 A small percentage of this drug is absorbed from the gastrointestinal
tract and may cause ototoxic and nephrotoxic effects,
especially with continuous use over several months.38
This drug should be used with particular caution by
patients with renal insufficiency. The efficacy of metronidazole (800 mg daily) for one week is similar to
that of neomycin,36 although the possibility of gastrointestinal disturbance and other systemic side effects limits the use of this agent for longer periods.
Rifaximin, a nonabsorbed derivative of rifamycin, is
a proved alternative at a dose of 1200 mg daily.39
Since the therapeutic effects of nonabsorbable disaccharides depend on their metabolism by colonic
flora, a question of considerable clinical relevance is
whether combined treatment with lactulose and antibiotics is effective in patients with hepatic encephalopathy refractory to either agent alone. The effectiveness of combined therapy depends on whether
the lactulose can be metabolized by a population of
intestinal bacteria resistant to the antibiotic. The limited data available suggest that lactulose and neomycin may have an additive effect in reducing the intestinal production of ammonia, accompanied by an
enhanced clinical response, in the majority of patients who have an inadequate response to lactulose
alone.40,41 However, an increase in stool pH after the
addition of an antibiotic suggests that disaccharidemetabolizing intestinal bacteria have been eradicated;
combination therapy should then be discontinued.41
The idea of populating the colonic lumen with
nonurease-producing bacteria as a treatment for
hepatic encephalopathy was first raised more than
30 years ago, when an uncontrolled study suggested
that high oral doses of Lactobacillus acidophilus might
have a beneficial effect in patients with cirrhosis and
hepatic encephalopathy.42 Few controlled data are
available, although one small study showed that the
addition of L. acidophilus supplements for one to
four weeks produced clinical improvement in 71 percent of patients with hepatic encephalopathy refractory to neomycin alone. The results of a crossover
study in three patients suggested that treatment with
L. acidophilus alone was ineffective.43 Conversely,
oral administration of Enterococcus faecium for three
periods of four weeks, separated by two-week drugfree intervals, reduced systemic ammonia levels and
was at least as effective as lactulose in patients already on a restricted diet of 1 g of protein per kilogram. In contrast to the effect of lactulose, the therapeutic effect of E. faecium was sustained during
treatment-free intervals. No adverse effects have been
reported.44
Surgical approaches to reducing the intestinal production of ammonia, such as colectomy or colonic-

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CURRENT CONCEPTS

exclusion procedures, were used in the past for patients with hepatic encephalopathy refractory to other measures.25 The operative morbidity and mortality
were high, and today such patients should be considered for orthotopic liver transplantation.
In addition to ammonia produced in the intestinal
lumen, ammonia generated in the stomach by urease-producing Helicobacter pylori has recently been
suggested to contribute substantially to blood ammonia levels, especially in the presence of gastric hypochlorhydria, and to precipitate or exacerbate hepatic encephalopathy in patients with cirrhosis.45,46
Although the importance of H. pylori as a risk factor
for hepatic encephalopathy remains unclear and the
efficacy of eradication therapy has not been proved
in controlled trials, our current practice is to eradicate
this organism in patients with cirrhosis and a history
of hepatic encephalopathy.
INCREASED METABOLISM OF AMMONIA
IN THE TISSUES

Ornithine and aspartate are important substrates in

the metabolic conversion of ammonia to urea and
glutamine, respectively. Ornithine aspartate thus provides substrates for both of these ammonia-detoxification pathways. Controlled trials suggest that both
enteral and parenteral formulations of ornithine aspartate, but not ornithine a-ketoglutarate, significantly reduce ammonia levels and have useful therapeutic
effects in patients with cirrhosis and mild hepatic encephalopathy.47-50 In one study, an oral dose of 9 g
three times daily had an efficacy similar to that of
lactulose.48 Treatment with benzoate or phenylacetate,
which react with glycine to form hippurate and with
glutamine to form phenacetylglutamine, respectively, is also of proved value51,52; there is evidence that sodium benzoate at a dose of 10 g daily may be as effective as lactulose.52
Two of the five enzymes responsible for the metabolism of ammonia to urea in the urea cycle are
zinc-dependent. Zinc deficiency is common in patients with cirrhosis and is caused predominantly by
increased loss of zinc in the urine.53 There are reports of overt hepatic encephalopathy precipitated by
zinc deficiency and reversed by supplementation with
oral zinc.54 In a recent controlled trial, the rate of formation of urea from amino acids and ammonia was
increased in eight patients with cirrhosis, zinc deficiency, and mild hepatic encephalopathy who were
given 600 mg of oral zinc sulfate per day for three
months. A significant improvement in psychometric
test scores accompanied the resultant restoration of
plasma zinc levels and reduction in systemic ammonia levels.10 Similar beneficial effects of zinc supplementation for periods ranging from seven days to
three months have also been reported in other controlled studies,55,56 as well as some negative results.57,58
Although further studies are required, zinc-deficient

patients with cirrhosis should receive supplementation in view of the widespread importance of this
trace element for the synthesis of DNA and protein
and the function of metalloenzymes.
REDUCTION OF FALSE
NEUROTRANSMITTERS

Treatment with formulas rich in branched-chain

amino acids but low in aromatic amino acids is based
on the hypothesis that reduced concentrations of
branched-chain amino acids (leucine, isoleucine, and
valine) and increased concentrations of aromatic amino acids (phenylalanine, tyrosine, and tryptophan)
may promote hepatic encephalopathy by causing the
production of false neurotransmitters.1,8,12 Randomized, controlled trials involving the parenteral administration of formulas enriched with branched-chain
amino acids demonstrated no benefit, improvement
in hepatic encephalopathy but not in mortality rates,
or improvement in both.59 Differences in the control
treatments, duration of therapy, selection of patients,
precipitating events, and exclusion criteria make the
interpretation of these conflicting results difficult.
Similar problems confound the interpretation of the
efficacy of enteral supplementation with formulas enriched with branched-chain amino acids.60 Ornithine
salts of branched-chain keto acids may be more effective than branched-chain amino acids themselves.30
Although current results do not support the general
use of branched-chain amino acids as a treatment for
hepatic encephalopathy, they have a specific role in
improving nitrogen balance without precipitating hepatic encephalopathy in malnourished patients with
cirrhosis who are intolerant of protein supplementation.61 However, most patients with cirrhosis who
require parenteral feeding tolerate standard synthetic
amino acid preparations.62
Decreased activity of dopaminergic neurotransmission has also been suggested to have a role in the
pathogenesis of hepatic encephalopathy.1,8,12 However, controlled trials in patients with cirrhosis and
hepatic encephalopathy failed to demonstrate any
beneficial effect of treatment with levodopa or bromocriptine.63,64
INHIBITION OF g-AMINOBUTYRIC ACID
BENZODIAZEPINE RECEPTORS

Benzodiazepines exert their depressant effects on

the central nervous system by interacting with highaffinity binding sites on the g-aminobutyric acid
benzodiazepine receptor complex. Binding to this receptor by a benzodiazepine-like ligand not present in
the normal brain has been proposed as an important
factor in the pathogenesis of hepatic encephalopathy.1,7,12 However, controlled trials of the efficacy of
treatment with the benzodiazepine-receptor antagonist flumazenil in small numbers of patients demonstrated typically incomplete improvement in the
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The New England Journal of Medicine

clinical grade of hepatic encephalopathy in 18 to 78

percent, which included only 50 percent of the patients who had recently received benzodiazepines.65-67
CORRECTION OF MANGANESE
DEPOSITION IN THE BASAL GANGLIA

Clinical observations suggest that manganese may

accumulate in the basal ganglia of patients with cirrhosis, as shown by hyperintensity of the globus pallidus on T1-weighted magnetic resonance images.11
It has been suggested that the deposition of manganese in the basal ganglia may contribute to the
pathogenesis of hepatic encephalopathy.11 This suggestion is based on similarities between aspects of
chronic hepatic encephalopathy and manganese intoxication68 and reports of the reversibility of hepatic
encephalopathy and this magnetic resonance imaging abnormality after liver transplantation.69 However, reports conflict as to whether the intensity of the
T1-weighted signal in the globus pallidus correlates
with either neuropsychiatric test scores or the clinical grade of hepatic encephalopathy.70,71 Longitudinal studies are needed to investigate the possible
therapeutic effects of chelation of manganese with
edetate calcium disodium or treatment with sodium
para-aminosalicylic acid, which has been reported to
be of value in chronic manganese poisoning from occupational exposure.72
ORTHOTOPIC LIVER TRANSPLANTATION

Orthotopic liver transplantation is increasingly being used in the treatment of patients with end-stage
cirrhosis, even older patients, many of whom have
hepatic encephalopathy along with other manifestations of severe hepatic decompensation. Liver transplantation is also indicated in the small group of
patients with severe, refractory hepatic encephalopathy, including such syndromes as dementia, spastic
paraparesis, cerebellar degeneration, and extrapyramidal disorders, even when hepatic encephalopathy is the sole manifestation of hepatic decompensation. In practice, therefore, medical management of
hepatic encephalopathy is mainly used for patients
who do not yet meet the criteria for liver transplantation and in whom hepatic encephalopathy is likely to
be mild, and for those in whom transplantation is
contraindicated because of other medical or social
problems. The latter group represents a substantial
number of patients, because of the increasing life expectancy of patients with cirrhosis and the comorbidity associated with advancing age.
There is some divergence of opinion as to whether
treatment is warranted for patients with subclinical
hepatic encephalopathy. We do not treat truly asymptomatic patients who have isolated abnormalities on
psychometric analysis. However, patients identified in
this way should be thoroughly assessed for functional
impairment, since intervention may enhance the ca478 

pacity to perform practical tasks such as driving an

automobile.73
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