Journal of Gastroenterology and Hepatology (1994) 9, 366-372

LIVER A N D BILIARY

Effects of an infusion of branched-chain amino acids on

neurophysiological and psychometric testings in cirrhotic patients with
mild hepatic encephalopathy
KIYOHIRO H I G U C H I , YUKIHIRO SHIMIZU, S H U J I N A M B U , C H I H A R U MIYABAYASHI,
T E R U M I TAKAHARA, SEI J I SAITO, OSAMU HIOKI, YOSHIHIRO KUWABARA A N D
AKIHARU WATANABE
Third Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University,
Toyama, Japan

Abstract Psychotropic action of a branched-chain-enriched amino acid solution (Aminoleban) was

quantitatively and visually examined in six cirrhotic patients with mild hepatic encephalopathy (grades I and
11) using electrophysiological and psychometric methods. Neurophysiological effects of the amino acid
solution were observed by comparing topographic spectrum analyses of electroencephalography (EEG)
before and immediately after an intravenous 3 h infusion of the solution. The delta wave in the frontal
region diminished from 61 k 13 to 12 +4% (P < 0.01) and the alpha wave in the occipital region increased
from 1 1 & 3 to 51 f 11% (P < 0.01). Latencies of the P3 wave in visual evoked potentials, which were
* *
topographically recorded in the occipital region, shortened from 220 32 to 148 19 ms (P < 0.01).
Latencies of the P300 wave in event-related potentials, which were topographically recorded in the
centro-temporal region, shortened from 493 zt 81 to 360 5z 93 ms (P < 0.05). Topographic reaction pattern
of P300 was irregular toward the occipital or parietal region in cirrhotic patients. T h e EEG frequency power
spectrum, illustrated by the colour density spectral array of computer-aided polysomnography analysis,
clearly showed a gradual increase of the alpha wave spectrum and a gradual decrease of the delta wave
spectrum after initiation of the infusion. These immediate neurophysiological changes were confirmed by
improvement of quantitative psychometric tests including number connection test, reaction time to sound,
and digit symbol and block design tests of Wechsler Adult Intelligence Scale.
From the results, it was concluded that branched-chain amino acids functioned as psychotropic drug for
cirrhotic patients with mild hepatic encephalopathy.

Key words: blood-brain barrier, branched-chain amino acid, hepatic encephalopathy, liver cirrhosis,
psychotropic drug.

INTRODUCTION We have already reported that branched-chain amino

Prospective, randomized controlled trials of a branched-
chain-enriched amino acid solution in cirrhotic patients
with hepatic encephalopathy have been extensively per-
formed with respect to improvement of malnutrition,
arousal effect of hepatic encephalopathy, and improve-
ment of survival rates.'** However, the results are still
controversial at p r e ~ e n t ,probably
~ because the clinical
backgrounds of cirrhotic patients studied and amino acid
composition of the test solutions have varied widely
among studies. Furthermore, many different protocols
have been used, including control treatment and efficacy
judgement.
Correspondence: Akiharu Watanabe, Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University,
2630 Sugitani, Toyama 930-01, Japan.
Accepted for publication 17 January 1994.
acids infused to cirrhotic patients can be well transported
into the brain via the blood-brain barrier4 where detoxifi-
cation of ammonia takes place by supplying glutamic acid
from branched-chain amino acids.5 Nine per cent of total
leucine infused to cirrhotic patients was taken up by the
brain.6 These results suggest that branched-chain amino
acids may directly accelerate ammonia detoxification in
brain of cirrhotic patients and result in ameliorating
hepatic encephalopathy.
Quantitative and visual methods of medical electronics
such as topographic (brain mapping) and polygraphic
analyses were used to quantify directly the influence of
the intravenous infusion of a branched-chain-enriched
amino acid solution on brain dysfunction seen in hepatic
Branched-chain aa as psychotropic drug
encephalopathy. Visual evoked potentials (VEP) and
event-related potentials (ERP; the auditory P300) were
also analysed by colour topography. The quantitative
psychometric tests were also performed to confirm the
changes of cognitive motor abilities.
The present report describes immediate and direct
psychotropic effects of a branched-chain-enriched amino
acid solution (Aminoleban) in cirrhotic patients with mild
hepatic encephalopathy.
PATIENTS AND METHODS
Patients
Six patients with cirrhosis of the liver (five men and one
woman, 50-70 years old, average age 59.0) and five
control subjects without liver dysfunction (three men and
two women, 48-68 years old, average age 57.2) were
examined in the present study (Table 1).
Each patient with cirrhosis was assigned a clinical
grade based on the Child-Pugh scale' from the clinical
and biochemical data; four were grade B and two grade C.
All patients were studied as inpatients of Toyama Medical
and Pharmaceutical University Hospital and had histolog-
ical evidence of liver cirrhosis. Five patients had oesoph-
ageal varices, and two had peviously documented
episodes of clinical encephalopathy.
At the time of entry into the study, all patients were
classified as grade I or I1 of the encephalopathy scale;8
grade was assessed by two attending doctors in terms of
altered sleep rhythm, slow and slurred speech, altered
affect, constructional apraxia or psychiatric manifesta-
tions. Electroencephalography (EEG) topographic and
polygraphic analyses, and quantitative psychometric tests
were carried out during 0-2 days after patients had been
admitted because of mild hepatic encephalopathy. They
were treated by low-protein diet during these test periods.
No patient had gastrointestinal bleeding within 2 weeks
prior to the admission.
Control subjects were selected from inpatients with
non-hepatic disorders such as gastric and duodenal ulcers,
colon polyps, and non-specific colitis (Table 1).
Infusion of a branched-chain-enriched amino
acid solution
Aminoleban (Otsuka Pharmaceutical Co. Ltd, Tokyo,
Japan) was used as a branched-chain-enriched amino acid
solution. The solution contained 40 g amino acid per
500 mL vial, and each vial contained 14.2 g of branched-
chain amino acid (4.2 g valine, 5.5 g leucine and 4.5 g
isoleucine); 0.9 g of aromatic amino acid (phenylalanine
and tryptophan); and 0.5 g of methionine. No tyrosine
was included. The molar ratio of branched-chain amino
acid/aromatic amino acid was 37.1 to 1. This solution was
infused intravenously via an anticubital vein for 3 h by
means of an infusion pump (Atto AC-2110, Atto Corp.,
Tokyo, Japan) to cirrhotic patients with hepatic encephal-
opathy.
367
The following examinations were performed immedi-
ately before and 0-2 h after the end of infusion. The same
examinations were performed only once in control sub-
jects without infusing an amino acid solution (equivalent
to the condition immediately before the infusion to
cirrhotic patients).
Informed consent was obtained from the patients be-
fore performing these tests.
Topographic analysis of cerebral electrical
activity (brain mapping)
A 20-channel EEG machine (EEG-4418; Nihon Kohden
Kogyo Co., Tokyo, Japan) was used with a signal pro-
cessor (Type 7T 18, Nippon Denki Sanei, Tokyo, Japan)
and a telemeter of polygraphy (WEE-6124, Nihon
Kohden Kogyo Co) for recording EEG data from Fpl,
Fp2, F3, F4, F7, F8, T3, T4, T5, T6, C3, C4, P3, P4, 0 1
and 0 2 . Disc electrodes were placed according to the
10-20 International System. Linked earlobes were used
as reference. The other detailed procedures were de-
scribed previo~sly.~ The spectra were divided into four
different bands: delta (0.5-4 Hz), theta (4-8 Hz), alpha
(8-12Hz) and beta (12-32Hz). The alpha band was
subdivided into three ranges: alpha 1 (8-9.3 Hz), alpha 2
(9.4-10.6 Hz) and alpha 3 (10.7-12 Hz). Topograms were
expressed as two-dimensional colour maps using a signal
processor for topography (Topography System 71 1, Nip-
pon Denki Sanei).
Visual evoked potential
The VEP to unpatterned flash stimuli (flashlamp at a
distance of 30 cm from the eyes) was recorded from the
midline occipital area, Oz (international 10-20 system,
with a central Cz, reference electrode).1° Each eye was
stimulated separately (the other eye was covered) and at
least two stimulation series were recorded for each eye.
The responses were recorded with an X-Y plotter, and
the latency to the first positive wave (Pl) and the
following potentials (N2, P2, N3, and P3) were mea-
sured. Topographic analysis of P3 wave latency was
performed as described above.
P300
The P300 wave was elicited using the auditory oddball
paradigm."J2 The subject's task was to push a button as
quickly as possible whenever the rare low tone (1000 Hz,
20%) occurred and to ignore the frequent high tone (2000
Hz, 80%). The EEG was recorded at Pz referred to the
mastoid (time constant 10 s, low pass filter 35 Hz, sensi-
tivity 7 pV/mm). Electroencephalography recording in
each trial began 200 ms before stimulus onset and lasted
about 1 s after stimulus presentation. The P300 was
defined as the first positive-going peak after the N100-
P200-N300 complex between 250 and 500ms after
stimulus presentation. Topographic analysis of P300
wave latency was performed as described above.
 W
m
W

Table 1 Clinical features of cirrhotic patients with hepatic encephalopathy (grades I and 11) and control subjects without liver dysfunction

HBsAg/HCVAb/blood Serum Serum Plasma BCAA

History of transfusion /alcohol/history bilirubin albumin Blood ammonia concentration Child & Pugh
No. Age/sex disease (years) of ascites/encephalopathy (mg/dL) (g/dL) (ClgIdL) (pmol/L) BCAAIAAA Coma grade classification Diagnosis
Control subjects without liver dysfunction
1 56/M 0.1 -l-l-l+l-l- 0.6 3.6 ND 368 3.5 GU
2 61/M 0.4 -l-l-/+l-l- 0.9 4.1 ND 318 2.9 CP
3 68/F 1.2 -I-1-1-1-1- 0.6 4.6 ND 413 3.4 GU
4 48/M 0.3 -1-1+1-1-1- 0.7 3.9 46 400 3.1 DU
5 53/F 0.2 +l-l-l-l-l- 0.8 4.2 51 351 3.0 NC
Mean fs.d. 0.44 k 0.4 0.72k0.13 4.1k0.4 370+ 38 3.2 k0.3

Cirrhotic patients with hepatic encephalopathy

6 63/M 2 +l-l-l+l-l+ 1.2 3.0 110 180 0.7 I1 B - HCC
7 50/M 6 -1-1-/+1-/- 0.9 3.6 90 129 1.5 I1 B - HCC
8 60/M 7 -l+l-l-l-l- 1.1 3.1 83 98 0.8 I C + HCC
9 53/F 10 -l+l+l-/-l+ 1.8 2.9 76 96 0.5 I1 C + HCC
10 58/M 5 -l+l+l-l-l- 0.7 3.3 64 141 1.0 I B - HCC
11 70/M 4 +1-1-1-1-/- 0.9 3.3 58 130 0.9 I B - HCC
Mean ? s.d. 5.6k 2.7 1.10k0.38 3.2 ? 0.3** 80+ 19 129k31** 0.9 f0.3**
**P< 0.01.
HBsAg, surface antigen of hepatitis B virus; HCVAb, hepatitis C virus antibody (CIOO-3); BCAA, branchedchain amino acid (valine + leucine + isoleucine); GU, gastric ulcer;
DU, duodenal ulcer; CP, colon polyp; NC, non-specific colitis; HCC, hepatocellular carcinoma; ND, not determined.

A
Branched-chain aa as psychotropic drug
Computer-aided polysomnography analysis
The polysomnographs were recorded for 10 h on mag-
netic tape according to the method of Horita et a1.I3 After
feeding the EEG data into the computer, the average
frequency power spectrum was calculated in the range
from 0.5 to 16 Hz with a resolution of 0.5 Hz at every 20 s
by using the fast Fourier transform. The EEG frequency
power spectrum was shown on a screen by the colour
density spectral array.
Quantitative psychometric tests
The following quantitative psychometric tests were per-
formed as described previ~usly.'~ Number connection
test (NCT) was performed by using one standard pattern,
showing randomly arranged circles, numbered consecu-
tively from 1 to 20. Reaction times against light (red) and
sound can be measured in ms using an apparatus of
reaction time (G 1355 Model RT-6, Gerbrands Co., MA,
USA). Two performance subtests of Wechsler Adult
Intelligence Scale (WAIS), block design test and digit
symbol test, were used as a measure of the visual spatial
motor functioning and a test of motor speed and accuracy,
respectively.
Statistical analysis
Data are given as meants.d. The significance of the
differences between the means was calculated using
Student's t-test, and P < 0.05 was considered significant.
RESULTS
Topographic analysis of EEG spectrum
In encephalopathic patients, a significant decrease in the
alpha power spectral density was observed diffusely but
particularly in the occipital region (Table 2). Delta power
spectral density increased diffusely in cirrhotic patients
with encephalopathy, and marked changes were observed
in the frontal region as well.
An intravenous 3 h infusion of Aminoleban resulted in
the diffuse diminution of the delta waves and in the
apparent diffuse increase of the alpha waves. The alpha
waves in the occipital region significaritly increased from
l l k 3 to 51 +11% (P<O.Ol), and the delta wave in the
frontal region significantly decreased from 61 f 13 to
12k49'0 ( P < 0.01).
Dynamic changes of the EEG spectrum induced by the
infusion of Aminoleban were shown as a subtraction
topogram (data not shown), suggesting the direct and
immediate efficacy of a branched-chain-enriched amino
acid solution for mild hepatic encephalopathy.
Visual evoked potential and event-related
potential
The latency of P3 wave in VEP was significantly pro-
longed in cirrhotic patients with mild encephalopathy
369
(132 k 2 6 ms in control vs 220k 32 ms in cirrhosis,
P < 0.01; Table 3). However, the observed prolongation
of latencies of other peaks, even including N3 wave, was
not significant (data not shown). Visual evoked potential
following the infusion of Aminoleban showed that the
latency of P3 wave had become significantly shortened
(from 2 2 0 t 32 to 148+ 19 ms, P < 0.01). The topo-
graphic observation revealed that P3 latency of VEP
recorded in the occipital region normalized following the
infusion (data not shown).
The latency of the P300 wave in ERP was significantly
prolonged in cirrhotic patients with mild encephalopathy
(350+52 ms in control vs 4 9 3 f 8 1 ms in cirrhosis,
P < 0.01, Table 3). However, significant prolongation of
N300 wave latency was not observed (data not shown).
The P300 wave shortened significantly from 493 t 8 1 to
360 t 93 ms (P < 0.05) following the infusion. Topo-
graphic observations of P300 showed a reaction pattern in
the centro-temporal region of the control subject but
irregular reaction patterns toward the parietal region were
observed in the cirrhotic patients (data not shown). The
infusion of Aminoleban induced topographically the
shortening of P300 wave latency.
Pol ysomnography
The EEG frequency power spectrum, illustrated by the
colour density spectral array of computer-aided polysom-
nography analysis, before and after the infusion of amino
acid to cirrhotic patients, showed a gradual increase of the
alpha wave spectrum from 1 6 f 4 % (before infusion) to
5 6 k 11% (4 h after the start of infusion; P < 0.01;
Table 4), and this effect could already be observed 1 h
after the start of infusion. The maximum effect was
observed 4 h after the start of the infusion (1 h after the
stop of infusion). The slow wave spectrum gradually
decreased 30min after the start of the infusion of the
branched chain-enriched amino acid solution. The maxi-
mum effect was observed in the 3rd hour of the infusion
(immediately before the end of the infusion; 65 f 12%
before the infusion vs 10 f 3% at the end of infusion,
P < 0.01). The slow wave gradually reappeared 1 h fol-
lowing the discontinuation of infusion, and an apparent
decrease of the alpha wave and increase of the delta wave
were observed 2 h following the end of infusion.
Quantitative psychometric tests
All tests among five items of quantitative psychometric
test were abnormal in cirrhotic patients compared to
those in control subjects (Table 5). However, number
+
connection tests (from 136 21 to 90 t 15 s, P < 0.05),
reaction time to sound (from 3 9 8 t 59 to 297k51 ms,
P < 0.05), digit symbol (from 2 8 k 8 to 45 k 7 points,
P < 0.05) and block design tests (from 2 2 + 7 to 3 6 t 8
points, P < 0.05), were significantly improved within 2 h
after the end of infusion to cirrhotic patients with mild
encephalopathy. Blood ammonia concentrations were
insignificantly decreased from 108 f 30 to 86 + 20 pg/dL.
The grade of encephalopathy was improved in all
cirrhotic patients 0-2 h after the infusion of branched-
370 K. Higuchi et al.

Table2 Topographic distribution of alpha and delta power spectral density at the different scalp areas in control subjects and
cirrhotic patients with hepatic encephalopathy (grades I and 11),and alterations of the spectral density before and after the infusion of
branched-chain-enriched amino acid solution to cirrhotic patients
~~

Frontal Temporal Parietal Occipital

(% distribution)

Alpha
Control (4 cases) 42f12 45 f 10 4 6 k 12 6 0 f 15
Cirrhosis (5 cases)
Before infusion 15 f 5t +
10 2* 13*5* 11 f 3*
After infusion +
40 12** 43 f8** 40 f6** 51 f 11**

Delta
Control (4 cases) 7 f I* 6f2 6+3* 3+1*
Cirrhosis ( 5 cases)
Before infusion 61 f 13* 5 5 f 18* 47+11* *
43 9'
After infusion 12-t4** +
10 3** 9 -t 3** 7-t 2**
tP < 0.05, *P < 0.01 (control ws before in cirrhosis), **P < 0.01 (before in cirrhosis ws after in cirrhosis). After = immediately to 2 h
following the end of infusion.
Values are mean -t s.d.
Table 3 Latency of P3 wave in VEP and P300 wave in ERP in
control subjects and cirrhotic patients with hepatic encephalop- accentuated in encephalopathic cirrhotic patients as com-
athy (grades I and 11), and alterations of the latencies after the pared to the actual levels in the cerebrospinal fluid.4
infusion of branched-chain-enriched amino acid solution to When the branched-chain-enriched amino acid solution
cirrhotic patients is infused to cirrhotic patients with hepatic encephalopa-
thy, the Vpre values of branched-chain amino acids are
VEP ERP increased and those of aromatic amino acids conversely
P3 P300 decreased. Our previous experiments of leucine decar-
(ms) boxylation in the cell-free system also showed the close
relationship between accelerated metabolism of leucine
Control (4 cases) 132 f26 350 f52
Cirrhosis ( 5 cases) and ammonia metabolism in the brain. l5 Furthermore,
Before infusion 220 f32* 493k81t we already reported the ammonia detoxification by accel-
After infusion 148f 19** 360 f 93* erated oxidation of branched-chain amino acids in the
brain of rats with acute hepatic f a i l ~ r e .RSssle
~ er ~ 1 . ' ~
+P < 0.05, *P < 0.01 (control ws before in cirrhosis). reported that a rapid decrease of ammonia levels in the
* P i0.05, **P< 0.01 (before in cirrhosis ws after in cirrhosis). cerebrospinal fluid was obtained by the infusion of
After = immediately to 2 h following the end of infusion. branched-chain-enriched amino acid solution to cirrhotic
Values are mean fs.d. patients with hepatic encephalopathy. These results sug-
gest that branched-chain amino acid metabolism in the
chain-enriched amino acid solution. Four patients com- brain is closely linked to the detoxification of ammonia in
pletely recovered from encephalopathy (grade 0). the brain.
In the present study, the immediate and direct neural
effects of branched-chain-enriched amino acid solution
DISCUSSION (Aminoleban) was neurophysiologically confirmed by
comparing the results of quantitative and visual methods
T h e predicted velocity of branched-chain amino acid of medical electronics such as topographic and poly-
transport into the brain (V,,, nmol/min per g) is markedly graphic analyses, and quantitative psychometric tests.

Table 4 Time-course of delta and alpha wave frequency of EEG polygraphy before, during and after the infusion of branched-
chain-enriched amino acid solution to cirrhotic patients with hepatic encephalopathy (grades I and 11)

Before During infusion After infusion

Time interval from the start of infusion (h) 0 1 3 4 5

Alpha 16+4 38+ lo** 48+ 13** 5 6 f 11** 3 5 f 10*

Delta 65+12 54+ 12 10 5 3** 15+8** 40+ 11*
Values are percentages. *P < 0.05, **P< 0.01 (before YS after the start of the infusion).
+
Values are mean sad.(five cases).
Branched-chain MI: as psychotropic drug 371

Table 5 Quantitative psychometric tests, blood ammonia and grade of encephalopathy in control subjects and cirrhotic patients with
hepatic encephalopathy (grades I and 11), and changes of these before and after the infusion of branched-chain-enriched amino acid
solution to cirrhotic patients

Reaction time (ms) WAIS (raw score) Grade of encephalopathys

Number connection test(s) Light Sound Digit symbol Block design 0 I I1
Control (4 cases) 43t10 276+62 261+46 65k10 42k6
Cirrhosis (4 cases)
Before infusion 136 f21* 436&91* 398+59t 28f8* 22 f7* 0 3 3
After infusion 90-t 15* 321+58 297-t51* 45+-7* 36 k 8* 4 2 0
tP c 0.05, *P < 0.01 (control ws before in cirrhosis patients). * P < 0.05 (before in cirrhosis ws after in cirrhosis).
After = immediately to 2 h following the end of infusion.
*Number of patients corresponding to each grade of encephalopathy.
Values are mean fs.d.

These effects may result in the rapid acceleration of 3. ERIKSSON L. S. 81 CONNH. 0. Branched-chain amino
ammonia detoxification in the brain by the administration acids in the management of hepatic encephalopathy: An
of branched-chain amino acids. Ammonia can induce the analysis of variants. Hepatology 1989; 10: 228-46.
metabolic impairment of neurotransmitter amino acids 4. HIGASHI T., WATANABE A., HAYASHI S., OBATAT., TAKEI
and energy production in the brain, morphological N. & NAGASHIMA H. Effect of branched chain amino acid
changes of astrocytes, and dysfunction of synaptosomal infusion on alterations in CSF neutral amino acids and
membranes, and thus interferes with the normal electro- their transport across the blood-brain barrier in hepatic
physiological properties of the brain.17 encephalopathy. In: Walser M., Williamson J.R., eds,
Although it would be of interest to see whether similar Metabolism and Clinical Implications of Branched Chain
effects can be observed in patients without liver cirrhosis Amino and Keto Acids. Elsevier/North-Holland, Amster-
or in healthy controls, this type of study was not under- dam, 1981; 465-70.
taken because of ethical problems and drug indication. 5. WATANABEA., SHIOTAT., TAKEI N., FUJIWARA M. &
However, it is assumed that the similar effects would not NAGASHIMA H. Ammonia detoxification by accelerated
be seen in non-encephalopathic subjects whose neuro- oxidation of branched chain amino acids in brains of
physiological and psychometric testings, as well as brain acute hepatic failure rats. Biochem. Med. Metabol. Biol.
ammonia levels, are within the normal range. Therefore, 1986; 35: 357-75.
the neurophysiological effect of branched-chain amino 6. SATOY., ERIKSSON S., HAGENFELDT L. & WAHRENJ.
acids might be specific for hepatic encephalopathy. Influence of branched-chain amino acid infusion on
One potential problem is that hepatic encephalopathy arterial concentrations and brain exchange of amino acids
may recur shortly after the end of the infusion, as shown in patients with hepatic cirrhosis. Clin. Physiol. 1981; 1:
by EEG polygraphy. Therefore, the continuous slow 151-65.
infusion of branched-chain amino acids to the patients 7. PUGHR. M. H., MURRAY L. I. M., DAWSON J. L., PIELSINI
should be considered for maintaining normal plasma M. L. & WILLIAMS R. Transection of the oesophagus for
levels of branched-chain amino acids. bleeding oesophageal varices. Br. J. Surg. 1973; 60:
Many different double-blind trials of branched-chain 646-9.
amino acid solution have concluded that branched-chain 8. SHERLOCK S. Disease of the Liver and Biliary System, 8th
amino acids are effective at least for ameliorating hepatic edn. Blackwell Scientific Publications, Oxford, 1989;
encephalopathy. Although the number of patients in 1-92.
the present study is small, the results directly support 9. SAGALES T., GIMENO V., DE LA CALZADA D., CASELLAS F.,
these findings from the neurophysiological aspect of MACIAD. & SORIANO M. V. Brain mapping analysis in
treatment. patients with hepatic encephalopathy. Brain Topogr.
1990; 2: 221-8.
10. JOHANSSON U., ANDERSONT., PERSON A. 19 ERIKSSON
REFERENCES L. S . Visual evoked potential - a tool in the diagnosis of
hepatic encephalopathy? J. Hepatol. 1989; 9: 227-33.
11. WEISSENBORN K., SCHOLZ M., HINRICHS H., WILTFANC J.,
CERRA F. B., CHEUNG N. K., FISCHER J. E. Disease-specific SCHMIDT F. W. & KUNKEL H. Neurophysiological assess-
amino acid infusion (FO 80) in hepatic encephalopathy: A ment of early hepatic encephalopathy. Electroencephal.
prospective, randomized, double-blind, controlled trial. J. Clin. Neurophysiol. 1990; 75: 289-95.
Parenter. Enteral Nutr. 1985; 9: 288-95. 12. DAVIES M. G., ROWAN M. J., MACMATHUNA P., KEELING
WAHRENJ., DENISJ., DESURMONT P. et al. Is intravenous P. W. N., WEIRD. G. & FEELY J. The auditory P300 event
administration of branched chain amino acids effective in related potential: An objective marker of the encephalop-
the treatment of hepatic encephalopathy? A multicenter athy of chronic liver disease. Hepatology 1990; 12:
study. Hepatology 1983; 3: 475-80. 688-94.
372 K. Niguchi et al.

13. HORITA M., KIMY.-O., MATSUURA K., YAMACUCHI N. & 16. ROSSLEM., LUFTM., HERZ,R., KLEINM., LEHMANN M. &
YAMAMOTO G. A computer-aided polysomnography analy- GEROKW. Amino acid, ammonia and neurotransmitter
sis system. Electroencephal. Electromyography 1988; 16: concentrations in hepatic encephalopathy: Serial analysis
346-53 (in Jpn.). in plasma and cerebrospinal fluid during treatment with
14. WATANABE A. & KUWABARA Y. Evaluation of neuropsycho- an adapted amino acid solution. Klin. Wochenschr. 1984;
logical function in patients with liver cirrhosis with 62: 867-75.
special reference to their driving ability. J. Gastroenterol. 17. COOPER A. J. L. & PLUMF. Biochemistry and physiology
Hepatol. (in press). of brain ammonia. Physiol. Reo. 1987; 2: 440-519.
15. SHIOTA T. Accelerated leucine decarboxylation in the rat 18. NAYLOR C. D., O’ROURKE K. & DETSKY A. S. Parenteral
brain in relation to increased blood ammonia levels nutrition with branched-chain amino acids in hepatic
during acute hepatic failure. Acta Med. Okayama 1984; encephalopathy. A meta-analysis. Gastroenterology 1989;
38: 219-25. 97: 1033-42.