Visual event-related P300 potentials in early portosystemic encephalopathy

GASTROENTEROLOGY 1992;103:302-310

Visual Event-Related P3OOPotentials in Earlvd Portosystemic Encephalopathy CHRISTIAN F. A. KijGLER, GEORG WENSING, AHMAD

and WOLFGANG First Department Germany

ERICH LOTTERER, JijRGEN PETTER, TAGHAVY, ECKHART G. HAHN,

E. FLEIG

of Medicine

and Department

of Neurology,

Visual event-related P300 potentials, conventional visual evoked potentials, and psychometric tests were applied to patients with noncirrhotic chronic liver disease and to clinically nonencephalopathic and encephalopathic cirrhotics to compare their diagnostic efficacy in detecting early portosystemic encephalopathy (PSE). Sixty-four investigations were performed in 58 patients. The latencies of the P~OO parameters were significantly longer in both the encephalopathic and nonencephalopathic cirrhotics than in the noncirrhotics, indicating distinctly abnormal cortical processing of visual stimuli in cirrhotic patients. The visual P3OOpotentials showed the highest sensitivity and specificity for grade I PSE. Abnormal P300 test results were also found in 78% of the clinically nonencephalopathic cirrhotics, while psychometric tests showed abnormalities in only 41%. The P300 latencies were similar in alcoholic and nonalcoholic cirrhotics. Significant inverse correlations were found between the P300 latencies and measures of quantitative liver function such as galactose-elimination capacity and aminopyrine breath test. It is concluded that visual event-related P~OOpotentials are a sensitive index of subclinical and grade I PSE. Furthermore, the degree of cognitive dysfunction detected by this method in patients with liver cirrhosis appears to be related to the reduction in hepatic metabolic capacity. he complex neuropsychiatric syndrome of hepatic encephalopathy that complicates severe acute as well as chronic liver disease becomes clinically manifest in its early stages by slight personality changes, discrete psychomotor dysfunction, and alterations of the sleep rhythm. The term of subclinical or latent hepatic encephalopathy is applied to patients with abnormal results of either psychometric tests or evoked potentials in the presence of normal clinical neurological examination results. So far, almost exclusively the early “exogenous,” i.e., stimu-

T

University

of Erlangen-Nttrnberg,

Erlangen,

lus-dependent, components of evoked potentials have been used in studies of hepatic encephalopathy with conflicting results. On the one hand, visual potentials evoked by homogenous flashes of light were reported to detect subclinical stages of hepatic encephalopathy with a high sensitivity of about 60%.‘*’ Comparable results were obtained using brain stem auditory evoked potential? and somatosensory evoked potentials,4 which showed sensitivity for detecting subclinical hepatic encephalopathy of 40% and SO%, respectively. In contrast, other investigators5-’ found the sensitivity of the visual and somatosensory evoked potentials to be only about 30% and Yang et a1.8 could not show any changes in the brain stem auditory evoked potentials throughout all stages of acute hepatic encephalopathy. Therefore, these authors concluded that visual, brain stem auditory, and somatosensory evoked potentials lacked the sensitivity required for the detection of subclinical hepatic encephalopathy, especially compared with psychometric tests such as the number-connection test. Beyond obvious methodological differences, this discrepancy may be attributable to the fact that conventional evoked potentials depend primarily on the physical properties of the evoking stimuli. Therefore, components of these potentials are not necessarily closely related to higher central nervous system function. In contrast to these stimulusdependent exogenous potentials, event-related endogenous potentials are dependent on the meaning of a stimulus to the subject in a given experimental context rather than on its physical qualities.g P300 potentials, for example, reflect stimulus discrimination and evaluation” and can even be elicited by the omission of an expected stimulus, i.e., with no physical stimulus present. We have recently developed a new method of eliciting visual P300 potentials by pattern flash stimuli (PFP300).” Because the PFP300 0

1992 by the American Gastroenterological 0016~5085/92/$3.00

Association

July 1992

VISUAL

parameters were found to reflect very closely the cognitive dysfunction induced by minute doses of alcohol,” we investigated the validity of this method for the detection of early encephalopathy in chronic liver disease and related it to quantitative measures of liver function. Materials and Methods Patient Selection Patients with chronic liver disease with or without cirrhosis were eligible for this study if their visual acuity as assessed by a conventional sight-testing chart was sufficient to see the visual patterns used for electrophysiological testing clearly. Urine and blood samples were routinely screened for the possible presence of centrally active substances such as benzodiazepines, barbiturates, and ethanol and had to be negative. Patients with clinical encephalopathy of grade II or greaterI were excluded, as were patients with other severe diseases or malignancies unrelated to the existing liver disease. Additional exclusion criteria were diseases that may directly or indirectly disturb visual acuity (such as multiple sclerosis and longlasting diabetes mellitus) and unwillingness to give written informed consent. The study protocol was approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Ntirnberg. According to these criteria, 4 of the 62 consecutive patients included the study had to be excluded from the analysis: z because of highly positive benzodiazepine tests (12,590 and 650 ng/mL, both with a positive history ofbenzodiazepine ingestion), 1 because of the unexpected proof of malignant ascites due to ovarian carcinoma, and 1 because of severe chronic pancreatitis. Thus, this report includes 64 investigations on 58 subjects, 6 of whom underwent a repeat investigation after several weeks. Characteristics

of Patient

Groups

All patients underwent a thorough general physical and neurological work-up. Testing for clinical PSE was carried out according to the criteria proposed by ParsonsSmith et a1.13All subjects underwent psychometric testing by means of the number-connection test and a line-drawing test14; this testing was performed immediately before or after the electrophysiological session to avoid possible bias due to increasing fatigue. The presence or absence of cirrhosis was proved histologically within 3 months before the study. Based on these data, the patients were grouped into three categories: 1. Patients with chronic noncirrhotic liver disease (NC; n = 20, 13 males, 7 female). This group comprised 2 patients with alcoholic liver disease (1 each with alcoholic hepatitis and alcoholic fibrosis) and 18 with liver disease of nonalcoholic etiology (5 with chronic active hepatitis B, z with chronic active hepatitis C, 2 with chronic persistent hepatitis of unknown cause, 3 with stage I primary biliary cirrhosis, 3 with primary sclerosing cholangitis associated with ulcerative colitis, 2 with chronic cholestatic hepatitis, and 1 with granulomatous hepatitis).

P300 AND EARLY

PSE

303

Patients with liver cirrhosis but no clinical encephalopathy (Cl; n = 33, 26 male, 7 female). The etiology of cirrhosis was alcoholic in 19 patients, chronic hepatitis B in 6, and hepatitis C in 1 patient. Primary biliary cir-

rhosis with a distal splenorenal shunt was found in 1 patient, secondary biliary cirrhosis in 2, and cryptogenie cirrhosis in another 4. In 15 of these 33 patients cirrhosis was compensated (Cl.l), and signs of hepatic decompensation other than encephalopathy were found in 18 patients (C1.2). Patients with clinically manifest PSE grade II3 and therefore decompensated liver cirrhosis (C2; n = 5, 2 male, 3 female). Two of these patients had alcoholic cirrhosis, 1 had primary biliary cirrhosis with a portocaval shunt, 1 had cirrhosis due to chronic non-A, non-B hepatitis, and 1 had cryptogenic cirrhosis. Detailed clinical and biochemical are given in Table 1. Electrophysiological

data of these patients

Testing

Electrophysiological testing was performed in a darkened room with the subjects sitting in a comfortable reclining chair 1 m in front of a television screen on which the visual stimuli were presented. For the visual event-related potentials, two different kinds of checkerboard stimuli (type A: check size 50’of visual angle, 16 X 16 checks; type B: check size 12.5’ of visual angle, 64 X 64 checks) were randomly flashed out of the grey background of the screen. Two hundred of the 250 stimuli generated by a Nicolet Compact Four System (Nicolet Company, Madison, WI) per derived set of potentials were type A and 50 were type B (A:B ratio, 80:20). The subjects’ task was to fixate a red dot in the center of the screen and make a running count in their minds of the infrequent B stimuli only. After each session the subjects had to report their counts to the experimenter, who compared them to the number actually presented. The percentage of stimuli counted incorrectly was 0.9% f 0.9% in noncirrhotic and 2.0% + 3.5% (mean + SD) in cirrhotic patients (not significantly different). The potentials elicited by each kind of stimulus were recorded electroencephalographically according to the international lo-20 system from Oz to Fz with Cz as mass electrode (bandpass, l-30 Hz; sensitivity, 100 pV). Every sweep of the electroencephalography (EEG) was analyzed for artifacts by an automated artifact-rejection program based on an amplitude-threshold discrimination. The sweeps following the A and B stimuli were then separately averaged and stored in different memory blocks of the Nicolet Compact Four system. Thus, A and B potentials corresponding to the A and B stimuli were obtained. The EEG processing used allowed simultaneous recording of both the early exogenous flash-evoked components and the late endogenous P~OO wave. This is very important for clinical applications of P300 potentials because the early flash-evoked components signal adequate stimulus conduction in subcortical and cortical areas of the visual system. They serve to indicate that the patient tested was cooperatively fixating the red dot in the center of the screen during the experiment. The PFP300 complex is present in both the A and B potentials although it is much larger in

304

Table

GASTROENTEROLOGY Vol. 103,No. 1

KiiGLER ET AL.

Z. Clinical

and Biochemical

Data of the Study Population NC

Cl.1

Cl.2

c2

20

41211

15 47 k16

18 51 + 8

5 55 + 7

13 7

11 4

15 3

2 3

15 5

15 3 8

3 2 8

7 8

11 7

2 3

N

Age (~4 Sex Male Female Child-Pugh grade A B C Median Pugh score Etiology of liver disease Alcoholic Nonalcoholic Blood chemistry Alanine aminotransferase (U/L1 Alkaline phosphatase (U/L1 Bilirubin [PmWL (mgldLl1 Albumin [g/L (g/dLll y-Globulins (%) Prothrombin time (quick) Venous ammonia [pmol/L kdL)l Fasting bile acids [pmol/L @w/L)1 Quantitative liver function tests No. of patients tested GEC (mg/min) ABT (U) ICG-k LBF (mL/min)

2 18

143 + 367

29f23

26 214

28 f35

197 f 188

160 f 84

160 f 63

223 f150

32 k 46 (1.9 f 2.7)

20 A 44

41 f 5 (4.1Itr 0.5) 17 f 4 98 + 5

39 f 4 (3.9+ 0.4) 19 T!T 5 83 f15

32 f 5 (3.2k 0.5) 30 f 6 62 k11

(3.4k 0.3) 34 f 3 26f13 77f 17

20 f 5

35 f15

55 + 35

50f 30

(33+ 8)

(1.2+ 2.6)

(60k 24)

58 k 44

(3.4+ 2.6)

(92f 63)

58 k14

(3.4+ 0.8)

(85f 50)

7.4f 7.6(2.9f 3.0)

16.9f 16.6(6.6f 6.5)

f 7.0) 33.9* 17.7(13.3

+ 6.8) 28.8?I17.3(11.3

13 443 + 59 0.56k 0.22 0.14k 0.04 1221f457

10 380f 75 0.30f 0.17 0.10f 0.07 969f 325

15 290 k 2 0.15k 0.08 0.05* 0.02 692 k 373

2 326 0.12 0.03 1322

NOTE. Age and biochemical

data are given as means + 1 SD. Normal ranges: alkaline phosphatase, 33-105 U/L; venous ammonia, 15-50 capacity (GEC), 370-600 mg/min; aminopyrine breath test, 0.6-1.0 U; indocyanine green elimination rate constant (ICG-k), >0.12; liver blood flow (LBF), 1000-1600 mL/min.

pmol/L (25-85pg/dL); fasting bile acids, 5-10 pmol/L (2.0-3.9 mg/L); galactose-elimination

the B potentials. It is preceded by a marked negative wave peaking at about 250 milliseconds (N250; see Figure 1) that was shown to be primarily sensitive to different degrees of visual stimulus discrimination (“discrimination potential”). This is followed by a sharp positive shift of the potential peaking in the first component of the PFP300 complex (P~oo) that was terminated by a negative potential decay at about 400 milliseconds. The peak-to-peak amplitudes between N250 and P3OO (P300 amplitudes) were shown to be related to visual attention and task relevance.” Each PFP3OO recording lasted about 4 minutes and was repeated once to assess test-retest reliability. Furthermore, conventional pattern-reversal visual evoked potentials (PVEPs) were obtained (bandpass, l-30 Hz; sensitivity, 25 pV; number of averages, 100). The latencies (in milliseconds) and peak-to-peak amplitudes (in microvolts) of the N250 and P300 components of the PFP300 potentials as well as those of the PlOO component of the PVEPs were measured with the help of electronic cursors by one experienced investigator who had not performed the electrophysiological testing. For the latencies of the evoked potentials,

the upper limit of normal was defined as 2 SD above the mean, whereas the amplitudes were defined as abnormal if reduced by more than 75% of the corresponding mean value of a normal group of healthy volunteers we investigated previously.15 The reproducibility of the N250 and P300 latencies was examined by repeated measurements (two to three times) in 14 patients with chronic liver disease in stable clinical condition over a median period of 170 days. The coefficient of variation was only 4.3% for the N250 and 4.9% for the P300 latencies, while the P300 amplitudes reflecting visual attention varied by 24%. Quantification of Liver Function Other Chemical Methods

and

Routine laboratory tests included serum electrolytes, liver enzymes (aspartate aminotransferase, alanine aminotransferase, y-glutamyl transpeptidase, cholinesterase, alkaline phosphatase, bilirubin, albumin, prothromurea-nitrobin time, lactate d e h y d rogenase, creatinine,

VISUAL

July 1992

P300

AND EARLY

PSE

305

ing 1.5 pCi dimethylamine[14C]aminopyrine (specific radioactivity, 1.5 pCi/mg). The percentage of the administered dose exhaled in 1 mmol COJkg body wt was determined 30 minutes after IV injection of the radiolabel by means of a P-counting device.” Data are given as decimals (0.00-1.00). Indocyanine green was injected IV over 30 seconds in a dose of 0.5 mg/kg body wt. Plasma concentrations of the dye were measured photometrically from seven samples obtained in s-minute intervals from the third to the 21st minute after injection. The elimination rate constant k (ICG-k) was calculated from the extrapolated half-life according to the formula k = In 2/t,,,.” Liver blood flow was calculated from hepatic sorbitol clearance (Cl,,) at steady-state [Clss/(l - hematocrit)] during IV infusion of 50 mg sorbitol/min over 3 hours.lg Statistics Statistical analysis was done by Student’s t test, Wilcoxon’s test for unpaired samples, and the x2 test as applicable. The correlations between electrophysiological parameters and measures of quantitative liver function were calculated with regression analysis of the second degree according to Immich.zo The angle between the two regression lines resulting from this method is inversely related to the goodness of the correlation. A small angle indicates a close correlation, while regression lines perpendicular to each other indicate the absence of any correlation. Corrections for multiple testing were performed according to the method of Holm.‘l

Results

0

600 Latency (ms)

Figure 1. PFP300 potentials of the B stimuli for one person of each of the study groups. The N250 and PFP300 latencies are markedly prolonged in the patients of the C1.l, C1.2, and C2 groups compared with the potentials of the patient in the NC group; the amplitudes do not change significantly.

gen, blood glucose, serum protein electrophoresis, and venous ammonia). Fasting serum bile acid levels were determined using a commercial radioimmunoassay (Becton & Dickinson Immunodiagnostics, Orangeburg, NY). Benzodiazepines and barbiturates were measured in a morning urine sample using an immunofluorescence polarization assay (ADX; Abboth, Wiesbaden, Germany; limits of detectability, 40 ng/mL for benzodiazepines, 60 ng/mL for barbiturates). Ethanol was measured in blood samples by means of the ethanol dehydrogenase method. Forty patients also underwent quantitative liver function tests. Serial serum galactose concentrations were determined after the intravenous (IV) injection of a single dose of 0.5 g/kg body wt of galactose, and galactose-elimination capacity was calculated according to the method of Tygstrup.‘6 Aminopyrine breath testing was performed us-

The PFP300 parameters of the group of noncirrhotic patients were not significantly different from those of a large group of normal subjects we have investigated previously (n = 72; age range, 1860 years; N250 latency, 260.7 +- 22.5 milliseconds; P300 latency, 322.0 + 15.5 milliseconds; P300 amplitudes, 14.0 + 6.6 pV; means + SD).15 This indicates that patients with noncirrhotic chronic liver disease do not show any cognitive deficits using the methods applied. However, the N250 and P300 latencies of both groups of clinically nonencephalopathic cirrhotics (Cl.1 and Cl.2) and of the group of encephalopathic cirrhotics (C2) were significantly prolonged compared with noncirrhotic patients (P < 0.005; Table 2; Figures 1 and 2). In contrast, the P3OO amplitudes did not differ significantly between these groups. The latencies and the amplitudes of the simultaneously recorded exogenous PVEPs were also similar in the different patient groups, although a slight tendency for longer PlOO latencies in the cirrhotics could be observed (P > 0.05; Table 2). When patients in group Cl were stratified according to the alcoholic or nonalcoholic etiology of liver cirrhosis, no significant differences in electrophysiological and psychometric parameters (Table 3) were found.

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Vol. 103, No. 1

Table 2. Electrophysiological Characteristics of the Different Patient Groups NC

Cl.1

Cl.2

C2

20

15

18

5

265 + 10

298 k 23”

314 -t 32”

315 k 16’

375 f 42’

389 + 37”

400 * 27”

@V)

332 k 18 12.8 k 6.3

11.6 f 7.2

10.7 k 6.0

12.4 IL 3.2

(ms) PlOO amplitude @V)

111 f 7 7.0 f 4.4

112 k 7 6.8 f 4.1

115 + 13 7.1 * 3.3

117 k 7 8.3 t 2.5

N PF-P300 N250 latency (ms) P300 latency (ms)

P300 amplitude PVEP PlOO latency

Data represent means f 1 SD. “P < 0.005 vs. NC.

To evaluate its diagnostic efficacy for the detection of encephalopathy in chronic liver disease, the PFPSOO was compared with other methods such as the PVEP and psychometric tests (Table 4; Figure 3). The PFP300 parameters (N250 as well as P300 laten-

P300 i

ties) were abnormal in all cases of grade I clinical portosystemic encephalopathy (PSE) (sensitivity, lOO%), whereas the number-connection test and line-drawing test detected 80% and the PVEPs (PlOO latency) only 20% of grade I PSE. On the other hand, the PFP300 parameters were normal in every patient of the noncirrhotic group (specificity, lOO%), and both the combination of the number-connection test and the line-drawing test and the PVEPs had specificities of 91% (Table 4). These data show that with regard to overt encephalopathy, the sensitivity and specificity of the visual P3OO are superior to those of both PVEP and the combination of the number-connection and line-drawing tests. In clinically nonencephalopathic cirrhotics (Cl), the PFP300 parameters showed cognitive dysfunction in 78% of patients. In contrast, number-connection and linedrawing tests detected psychomotor slowing in only 41%. The PVEPs were even less sensitive; only 14% of the patients had abnormal test results (Table 4). As expected, prothrombin time and albumin, bilirubin, and y-globulin levels were significantly altered in the cirrhotic compared with the noncirrhotic patients (P < 0.01). Quantitative measures of liver function (galactose-elimination capacity, aminopyrine breath test, indocyanine green clearance) and liver blood flow were significantly reduced in Cl and

Table 3. PFP300, PVEP, and NCT Results in Patients With Alcoholic of Group Cl

and Nonalcoholic

Cirrhosis

Etiology of cirrhosis Alcoholic

0

300

600,

,

Latency (ms) Figure 2. Average PFPBOOpotentials of the NC group and the and Cl.2 groups. These mean potentials were averaged from the potentials of 10 representative patients from each study group.

Cl.1

N N250 latency (ms) P300 latency (ms) PlOO latency (ms) NCT (s)

303 382 112 41.8

Data represent means f 1 SD. NCT, number-connection test.

18 f 27 f 35 + 11 -t- 13.5

Nonalcoholic 15 307 f 381 f 116 f 36.5 f

32 45 10 9.5

VISUAL P300 AND EARLY PSE

July 1992

307

Table 4. Frequency of Abnormal Test Results in the Various Groups of Patients

N

Frequency ,~;~;;.

NC

Cl

Cl.1

Cl.2

c2

20

33

15

18

5

o/22 (0%) 2/22 (9%) 2/22 (9%)

29/37 (78%) 13/35n (37%) 5/37 (14%)

12/17 (71%) 5/17 (29%) o/17 (0%)

of abnormal test results of investigations)

NCT/LDT PVEP

The cirrhotic patients in groups Cl.1 and Cl.2, all clinically nonencephalopathic, “Two patients-of Cl.2 were excluded because of essential tremor. NCT. number-connection test; LDT, line-drawing test.

C2 compared with NC (Table 1). Fasting serum bile acid levels were significantly elevated in decompensated cirrhotics (Cl.2 and C2). This finding reflects the clinical grading of liver cirrhosis in these patients with a higher proportion of Child’s class B and C cases in Cl.2 and C2 than in Cl.1 (Table 1). To identify a potential relationship between the degree of cognitive and hepatic dysfunction, PFP300 parameters and quantitative measures of liver function were compared. The elimination rate constant of indocyanine green, parenchymal liver blood flow as well as the fasting serum bile acids did not show significant correlations with any of the PFP300 parameters. In contrast, both the galactose elimination capacity (rNzsD= -0.61; rpsoO= -0.53) and aminopyrine demethylation (rNz5,,= -0.46; rp3,,0= -0.60) were inversely related to the N250 and the P300 latencies (P < 0.02; Figure 4). The more cytosolic and microsomal liver function were reduced, the greater was the degree of cognitive dysfunction (Figure 4). Although the results of the number-connection test were positively correlated with the N250 (r = $0.46; P < 0.01) and P300 latencies (r = $0.45; P < O.Ol), we did not find any significant correlation between psychometric test results and parameters of quantitative liver function. Discussion To the best of our knowledge, this is the first application of visual event-related potentials for the assessment of cognitive dysfunction in early encephalopathy associated with chronic liver disease. To evaluate its diagnostic efficacy critically, we compared the PFP300 with other electrophysiological (PVEP) and conventional psychometric tests (number-connection test/line-drawing test) and related it to measures of quantitative liver function. The spontaneous EEG was not included in this comparison because it has been shown to be insensitive for the diagnosis of early PSE.22,23 Our data indicate that patients with chronic but noncirrhotic liver disease have normal cognitive function using the criteria applied in this study. In

were combined

17/20 a/la” 5/20

(85%) (44%) (25%)

s/5 (100%) 4/5 (80%) l/5 (20%)

into group Cl.

patients with cirrhosis, however, whether clinically encephalopathic or not, the latency of the N250 and P300 components is markedly prolonged. Seventyeight percent of nonencephalopathic cirrhotic patients (Cl.1 and Cl.2) showed subtle cognitive dysfunction. However, it is unknown whether the presence of such changes increases the risk of developing overt encephalopathy and might justify prophylactic treatment or reflects a degree of cognitive dysfunction that could affect important functions such as the ability to drive a car. Therefore, we do not feel that this large proportion of patients without overt clinical evidence of PSE should be treated presently. Interestingly, the P300 amplitudes remained unaltered in the different groups of patients. Thus, visual attention appears to remain intact at the earliest stages of PSE. This inference is consistent with our previous finding that the N250 and PFP300 latencies but not the PFP300 amplitudes are altered at very low blood ethanol concentrations (0.5 g/L) in experimental ethanol intoxication in humans.” The PFP300 amplitudes were reduced only at much higher blood ethanol levels and returned to normal earlier than the latencies. It would appear that the P3OO amplitude is the most stable parameter of the PFP300 complex. In the patients investigated in this study, the diagnostic accuracy of the visual P3OO parameters for detecting early clinically apparent encephalopathy was excellent. Cognitive deficits were observed in every patient with a diagnosis of having PSE grade I (sensitivity, loo%), and abnormalities were absent in every noncirrhotic patient in the control group (specificity, 100%). This discrimination was superior to that achieved by both the combination of the number-connection/line-drawing test (sensitivity, 80%; specificity, 91%) and the PVEPs (sensitivity, 20%; specificity, 91%). In the cirrhotic patients without clinical encephalopathy (Cl) the PFP300 showed subtle cognitive dysfunction in 78%, indicating some type of subclinical encephalopathy, whereas only 41% of the combination number-connection and

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KijGLER ET AL

z 360

GASTROENTEROLOGY

A

.

-0-

-- -

8

b

l-i

T 280

0

O

A

0

QE $320

z z

b\

360

y--0.22x+375.25 x- - 1.65y+653.1 r=-0.6l

320 280 240

240

0

I

-

‘0

G

I

I

\

200

A

.

Vol. 103, No. 1

8-

A

6Ol GEC (mg/min

w E -360 5 5 320 5 & 280

\o

0 y= -59.6x+312.7 x P -O.O4y+ 1.42 r=-046

%I z 240

_

\

I

0

0.2

04

I

0.6

I

0.8 1.0 ABT (U)

Figure 4. Correlations between N250 latencies of the PFP300 complex and quantitative parameters of metabolic bepatic function. The smaller the angle between the two regression lines, the higher the correlation between the variables. GEC, galactose-elimination capacity; ABT, aminopyrine breath test; r, correlation coefficient.

100

A

tn

NC Cl.1 Cl.2 C2 Figure 3. N250 and P300 latencies (milliseconds), P300 amplitudes (microvolts), and number-connection test (NCT) scores (seconds) of patients in the NC and C1.l, Cl.2, and C2 groups. Individual values are given. Horizontal bars indicate mean f 1 SD.

line-drawing test results and only 14% of the PVEPs were abnormal. Alterations of the PFP300 complex are not specific for hepatic encephalopathy because they also occur in other types of encephalopathy such as Alzheimer’s disease,24~25Huntington’s disease, and Parkinson’s disease,25 or experimental intoxication with ethano1.l’ However, they appear to be an integral part of the spectrum of cognitive dysfunction in severe liver disease. We were recently able to observe the complete normalization after orthotopic liver transplantation of consistently prolonged PFP300 latencies in a patient with cirrhosis caused by non-A, non-B, non-C hepatitis and stage I encephalopathy.26 During the conduct of this study, two independent groups reported on the use of auditory P3OO potentials in patients with chronic liver disease.23*27However, Davies et a1.27 did not detect differences be-

VISUAL

July 1992

tween the P~OOS of their healthy control group and of nonencephalopathic cirrhotics. In both studies, the rate of abnormal results with the auditory P300 was much lower in subclinical encephalopathy (19%, 14%) and in grade I encephalopathy (90%, 92%) than in the present investigation using the visual P300. The results of Weissenborn et aLz3 were derived from nonalcoholic subjects exclusively. However, two lines of evidence argue against a possible explanation of these differences by the presence of alcoholic cirrhotics in our study. First, the electrophysiological (PFP300, PVEPs) and psychometric (number-connection and line-drawing) test results were virtually identical in alcoholic and nonalcoholic cirrhotics of group Cl (Table 3). Davies et alz7 were also unable to show differences in the auditory P3OO parameters between alcoholic and nonalcoholic cirrhotics. Second, the P3OO latencies in alcoholics who recently stopped drinking are shortened for some time after completion of ethanol withdrawal, presumably reflecting some type of a hyperexcitability state (Haan J, Sczepanski B, Schulz G, unpublished observations, October 1990). Thus, hidden ethanol consumption until some days before the investigation might have resulted in false-negative rather than false-positive results. Differences in the sex distribution among patient groups are a very unlikely reason for the prolonged P300 latencies in Cl because we have previously shown that PFP300 parameters are sex independent.l’ Although the patients with decompensated cirrhosis (Cl.2 and C2) were slightly older than those with compensated cirrhosis (Cl.l), the latency prolongations observed in these groups were similar. Furthermore, the effect of age on the PFP300 parameters is extremely small in the age range of 18-60 years 15,” and therefore does not confound our results. In addition, an effect on the results of hidden acute consumption of benzodiazepines, barbiturates, and ethanol was rendered unlikely by routine screening for these substances. The only remaining plausible reason for the higher rate of positive test results in the present study than in previous studies 23*27 is the use of visually rather than auditory elicited P300 waves. Several lines of evidence indicate that P3OOpotentials, although endogenous in nature, are not completely independent of the physical quality of the stimulus in both physiological and pathophysiological conditions. For example, healthy persons with absolute pitch do not have auditory P300 waves but have distinct visual P300 waves.” Autistic children show abnormal auditory P3OO waves but regular visual P300 waves30 Furthermore, Schomerus et a131 found that the most sensitive psychological tests for latent PSE investigate functions related to the visual system. Therefore, the higher rate

P300

AND

EARLY

PSE

309

of positive test results in cirrhotic patients without clinical encephalopathy in this study suggests that the visual P3OO reflects the disturbances of early encephalopathy more closely than the auditory P300. The superiority of visual event-related potentials over psychometric tests in detecting subclinical and early clinical encephalopathy is more pronounced than in the findings of Davies et al., who used auditory P300 potentialsz7 P300 potentials are electrophysiological markers of cognitive processes such as stimulus discrimination and evaluation and are therefore sensitive in reflecting subtle cognitive dysfunction. Furthermore, they are not influenced by nervous system dysfunction such as the various types of tremor which are not necessarily related to cognitive processes. In fact, two of our cirrhotic patients had essential tremor, making the line-drawing test unreliable for detection of encephalopathy. Objective measures of early encephalopathy in chronic liver disease such as event-related P3OO potentials have not previously been related to quantitative parameters of hepatic function. In the patients investigated here, the N250 and P300 latencies correlated inversely with galactose-elimination capacity and [l*C]aminopyrine breath test. The more the metabolic capacity of the liver is reduced, the greater the degree of cognitive dysfunction is in patients with chronic liver disease. In contrast, no such correlations were found between the number-connection test and quantitative liver function tests. The inverse correlation between PFP300 parameters and liver function may explain the findings of Weissenborn et aL3’ that P300 abnormalities but not psychometric tests have significant prognostic implications. Because the N250 and P300 latencies correlated significantly with indices of hepatic metabolic capacity but not with hepatic blood flow-dependent parameters, it seems likely that cognitive dysfunction in subclinical and early PSE is related to reduced metabolic capacity rather than to reduced liver blood flow or increased portal-systemic shunting. References Zeneroli ML, Pinelli G, Gollini G, Penne A, Messori E, Zani G, Ventura E. Visual evoked potential: a diagnostic tool for the assessment of hepatic encephalopathy. Gut 1984;25:291-299. Levy LJ, Bolton RP. Losowsky MS. The use of the visual evoked potential (VEP) in delineating a state of subclinical encephalopathy. A comparison with the number connection test (number connection test). J Hepatol 1987;5:211-217. Mehndiratta MM, Sood GK, Sarin SK, Gupta M. Comparative evaluation of visual, somatosensory and auditory evoked potentials in the detection of subclinical hepatic encephalopathy in patients with non-alcoholic cirrhosis, Am J Gastroenterol 1990;85:799-803. Yang SS, Chu NS, Liaw YF. Somatosensory

evoked

potentials

310

5.

6.

7.

8.

9. 10.

11.

12.

13.

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Received April 23, 1991. Accepted February 11, 1992. Address requests for reprints to: W. E. Fleig, M.D., First Department of Medicine, University of Erlangen-NOrnberg, KrankenhausstraBe12, D-8520 Erlangen, Germany.