Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy

BACKGROUND: Subclinical hepatic encephalopathy (SHE) features in 30-84% of patients with cirrhosis of the liver. Its clinical significance with regards to progression to overt encephalopathy has however, not been established. AIMS: The present study was conducted (i) to compare the diagnostic usefulness of neuropsychological tests with that of electrophysiological (EP) tests in detection of SHE, and (ii) to examine the natural course of SHE. METHODS: Seventy-five-nonencephalopathic cirrhotics (11 females, 64 males; mean (+/- SD) age 43.6 (+/- 11.7) years; mean (+/- SD) education 11(+/- 3) years) were studied using a battery of tests for intelligence and memory, the number connection test (NCT), and EP tests viz. electroencephalogram (EEG) and auditory P300 event related potentials (P3ERP). All the patients were followed up for a period of 6 months to 2 years for development of overt encephalopathy. RESULTS: Thirty-five out of 75(47%) patients were diagnosed to have SHE based on at least one abnormal test result. The P3ERP latencies detected SHE in maximum number of patients (23%) followed by EEG (21%). Nearly 59% of patients with SHE progressed to overt encephalopathy within a mean duration of 4 months. Multivariate analysis showed that prior episode of encephalopathy (RR = 6.3; 95% CI = 2.0-19.7), abnormality on EEG (RR = 7.5; 95% CI = 2.2-25.3), abnormal performance on psychometric battery of tests (RR = 35.2; 95% CI = 4.3-287.3), occurrence of gastrointestinal bleed (RR = 19.3; 95% CI = 4.1-88.9), occurrence of dehydration (RR = 10.7; 95% CI = 2.5-45.4) and infection (RR = 11.4; 95% CI = 2.0-64.4) had significantly higher risk for development of overt encephalopathy. CONCLUSIONS: EP methods were more sensitive in detection of SHE. Amongst all the tests used, presence of only an abnormal EEG was significantly associated with development of overt encephalopathy along with the precipitating factors.     

Prevalence of subclinical hepatic encephalopathy in cirrhotic patients in China

AIM: Subclinical hepatic encephalopathy (SHE) is a common complication of liver diseases. The aim of this study was to find out the normal value of psychometric test and to investigate the prevalence of SHE in Chinese patients with stabilized hepatic cirrhosis.METHODS: Four hundred and nine consecutive cirrhotic patients without overt clinical encephalopathy were screened for SHE by using number connection test part A (NCT-A) and symbol digit test (SDT). SHE was defined as presence of at least one abnormal psychometric test. The age-corrected normal values were defined as the mean±2times standard deviation (2SD), and developed in 356 healthypersons as normal controls. Four hundred and sixteen patients with chronic viral hepatitis were tested as negative controls to assess the diagnostic validity of this test battery.RESULTS: There was no significant difference in NCT scores and SDT quotients between healthy controls and chronic hepatitis group (P>0.05). In all age subgroups,the NCT and SDT measurements of cirrhotic patients differed significantly from those of the controls (P<0.05).When mean±2SD of SDT and NCT measurements from healthy control group was set as the normal range, 119 cirrhotic patients (29.1%) were found to have abnormal NCT-A and SDT tests, 53 (13.0%) were abnormal only in SDT and 36 (8.8%) only in NCT-A. Taken together, SHE was diagnosed in 208 (50.9%) cirrhotic patients by this test battery. The prevalence of SHE increased from 39.9% and 55.2% in Child-Pugh‘s grade A and B groups to 71.8% in Child-Pugh‘s grade C group (P<0.05). After the adjustment of age and residential areas required from the tests, no correlation was found in the rate of SHE and causes of cirrhosis, education level and smoking habit.CONCLUSION: Psychometric tests are simple and reliable indicators for screening SHE among Chinese cirrhotic patients. By using a NCT and SDT battery, SHE could be found in 50.9% of cirrhotic patients without overt clinical encephalopathy. The prevalence of SHE is significantly correlated with the severity of liver functions.     

Prevalence of subclinical hepatic encephalopathy in patients with cirrhosis determined by psychometric tests

OBJECTIVE: To investigate the prevalence of subclinical hepatic encephalopathy (SHE) in patients with stable hepatic cirrhosis. METHODS: One hundred and seventy‐five consecutive cirrhotic patients (mean age 53 years, range 27?72 years) without overt clinical encephalopathy were screened for SHE using the number connection test (NCT) part A and symbol digit test (SDT). Subclinical hepatic encephalopathy was defined as the presence of at least one abnormal psychometric test. The age‐corrected normal value was defined as the mean ± 2SD obtained from 356 subjects without liver disease and in normal mental condition. Illiterate patients and patients with concurrent use of alcohol or psychotropic drugs, and those with previous portosystemic shunt and were excluded. RESULTS: In different age subgroups, the NCT scores and SDT quotients for cirrhotic patients were significantly different compared with those for controls (P < 0.05?0.001). Fifty patients (28.6%) were found to be abnormal in both the NCT and SDT, 16 (9.1%) patients were abnormal only in the SDT and 34 patients (19.4%) only in the NCT. Taken together, SHE was diagnosed in 100 patients (57.1%) by using the two tests. The prevalence of SHE increased from 46.8% and 53.0% in Child?Pugh grades A and B, to 76.6% in Child?Pugh grade C (P < 0.05). No significant correlation was found between the development of SHE and the etiology of cirrhosis, patient age and smoking habit. CONCLUSION: By using a combination of NCT and SDT, SHE was diagnosed in 57.1% of cirrhotic patients without overt clinical encephalopathy. The prevalence of SHE was significantly correlated with the severity of liver cirrhosis.     

肝硬化患者亚临床肝性脑病的诱发电位检测

目的 了解不同严重程度肝硬化患者亚临床肝性脑病的发生率及其临床意义。方法 对３０例无临床肝性脑病的肝炎后肝硬化患者同时进行脑干听觉、视觉和短潜伏期体感诱发电位（ＢＡＥＰ、ＶＥＰ、ＳＳＥＰ）检测。结果 三种脑诱发电位检测以ＢＡＥＰ异常率（４６．７％）高于ＶＥＰ和ＳＳＥＰ（均为３６．７％）;随着肝病程度加重,ＢＡＥＰ和ＳＳＥＰ异常率逐渐增高,分别为Ｃｈｉｌｄ－Ｐｕｇｈ Ａ级４１．７％和８．３％,Ｂ级４     

Visual Event-Related Potentials in Cirrhotic Patients without Overt Encephalopathy

Ambulant patients with cirrhosis and no clinical evidence of encephalopathy were screened for impaired brain function by neuroelectrophysiological testing dependent on cognitive function. Infrequent large checkerboard visual stimuli were randomly interleaved with frequent small ones to elicit P300 event-related potentials (ERPs). Three ERP components, N200, P3a and P3b, were derived from the electroencephalogram (EEG) by computer averaging. The use of 10% contrast and a minimum of four precisely placed scalp electrodes were found to be necessary for optimal separation of ERPs from sensory evoked potentials. Visual ERPs, onset/offset and pattern-reversal visual evoked potentials (VEPs), the spontaneous EEG and the time taken to complete a standard number connection test (NCT) were obtained from 20 normal adult subjects and 19 age-matched patients with histologically-confirmed cirrhosis and no clinical evidence of encephalopathy. The latencies and amplitudes of evoked potentials and the alpha rhythm of the EEG were determined. In 6 of the 19 patients the latencies of P3a and/or P3b exceeded the corresponding mean for controls+2 standard deviations of that mean. In 4 other patients the NCT was prolonged. In all of the patients the N200, VEPs and alpha rhythm of the EEG were normal. In conclusion: (i) Optimal isolation of ERPs is critically dependent on stimulus contrast and electrode placement; (ii) ERPs appear to be more sensitive than primary sensory evoked potentials or the EEG in detecting impaired brain neuroelectrophysiological function; and (iii) Cirrhotic patients without overt encephalopathy in whom P3a and/or P3b latencies are prolonged may have subclinical hepatic encephalopathy.     

Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis

BACKGROUND AND AIMS: The natural history of subclinical hepatic encephalopathy (SHE) is unknown. The present study was conducted to study the prevalence and the natural history of SHE in patients with cirrhosis of the liver. METHODS: One hundred and sixty-five patients with cirrhosis of the liver were studied. A total of nine psychometric tests (trail making and Wechsler adult intelligence scale-performance (WAIS-P) tests) were administered. Subclinical hepatic encephalopathy was present if two or more psychometric tests were abnormal. Seventy-two patients (SHE 40, without SHE 32) also underwent serial psychometric testing on follow-up visits at 6-8 week intervals. RESULTS: Subclinical hepatic encephalopathy was present in 103 (62.4%) patients. The number and figure connection, block design and picture completion tests were the most useful in the detection of SHE. Severity of SHE, as assessed by the number of abnormal tests, was greater in patients with more severe liver disease. During follow up, SHE tended to persist or worsen in patients with poorer liver function. Although other clinical complications were similar in different groups, overt hepatic encephalopathy developed more commonly in those patients who had SHE at entry compared to those who did not (22.6 vs 5.6%, P = 0.044). Among the patients with SHE, the development of overt hepatic encephalopathy was more common in patients with Child's score of > 6 than with Child's score of 相似文献   

幽门螺杆菌感染对高氨血症和肝性脑病发病的影响

目的了解幽门螺杆菌(Hp)感染和血氨水平、肝性脑病(HE)发病的关系,并探讨根除Hp对血氨水平和HE发生的影响。方法2003年7月-2005年1月在浙江省5个地区收集肝硬化住院患者,记录患者的一般资料、数字连接试验结果、Hp感染情况、肝功能Child-Pugh分级、血氨水平和HE情况。Hp(+)患者予“奥美拉唑+克拉霉素+替硝唑”1周根除治疗,1个月后查~(14)C尿素呼气试验,并记录患者的神经精神症状和血氨水平。结果(1)共收集肝硬化住院患者457例,Hp感染率60．6%,HE发生率47．5%。检出亚临床肝性脑病(SHE)患者55例,SHE占未发生HE肝硬化患者的47．0%(55/117)。(2)Hp(+)和Hp(-)肝硬化患者血氨浓度分别为(78．4±63．6)μmoL/L和(53．8±51．4)μmol/L(P＜0．01);根除Hp后血氨显著下降至(53．5±37．7)μmol/L(P＜0．01)。Hp(+)和Hp(-)肝硬化患者HE发生率差异有统计学意义(58．5%比30．6%,P＜0．01);根除Hp后HE发生率下降至34．1%(P＜0．01)。(3)HE、SHE和肝硬化患者的Hp感染率分别为74．4%、69．1%和53．2%(P＜0．05)。三组患者的血氨水平分别为(94．5±75．6)μmol/L、(59．9±49．2)μmol/L和(47．3±33．5)μmol/L(P＜0．05)。结论Hp感染是引起肝硬化高氨血症和并发HE的重要因素,根除Hp有利于治疗和预防HE的发生。     

Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy

OBJECTIVES: In patients with compensated liver cirrhosis the clinical repercussions of detecting subclinical hepatic encephalopathy (SHE) are unclear. We present a long-term follow-up study in cirrhotic patients to examine the relationship between SHE and subsequent episodes of overt hepatic encephalopathy. METHODS: A total of 63 cirrhotic patients were studied by Number Connection Test and auditory evoked potentials. We determined glutamine, ammonia, zinc, glutamate, urea, and ratio of branched chain amino acids to aromatic amino acids, and Child-Pugh classification. RESULTS: Of 63 patients, 34 (53%) exhibited SHE. Nineteen out of 63 (30%) developed overt hepatic encephalopathy during follow-up. Hepatic encephalopathy in follow-up was related to alcoholic etiology, ammonia, glutamine, zinc, ratio of branched chain amino acids to aromatic amino acids, liver function, presence of esophageal varices, and detection of SHE (84% of patients who exhibited hepatic encephalopathy in follow-up showed SHE). In Cox-regression, glutamine levels, SHE, esophageal varices, and Child-Pugh class were the independent variables related to hepatic encephalopathy in follow-up. CONCLUSIONS: SHE (defined on the basis of number connection test or auditory evoked potentials alteration) could predict a subsequent episode of overt hepatic encephalopathy. Lower glutamine levels, presence of esophageal varices, and liver dysfunction were also related to the development of overt hepatic encephalopathy.     

Cerebral changes in hepatic encephalopathy

Hepatic encephalopathy (HE) accompanied by an impairment of consciousness from orientation disorder (grade II) to coma (grade IV) is considered to be overt HE and is treated as an emergency. However, subclinical hepatic encephalopathy (SHE) can be detected by sensitive and quantitative neuropsychological examinations in cirrhotic patients without overt HE. The introduction of the SHE concept is clinically important for preventing the deterioration of SHE (grades 0 and I) to overt HE (grade II and more severe), prolonging the compensated state of cirrhosis without its deterioration to hepatic failure, and the continuation of patient treatment at home. We developed a new diagnostic method for SHE using a quantitative neuropsychological test, with the computerization of all operations. Evaluations of cerebral function and morphology are useful for the determination of the patho-physiology of HE, and assist the diagnosis of SHE. The latencies of the P3 wave in the visually evoked potential and the P300 wave in the event-related potential are prolonged in cirrhotic patients with SHE and are well expressed in three-dimensional coloured topograms (brain mapping). Automated polysomnographic analysis is useful for continuous-monitoring electroencephalograms (EEG) and for the detection of the sleep disturbance observed in cirrhotic patients with SHE. Brain atrophy in computed tomography (CT), magnetic resonance imaging (MRI) and high signals in the basal ganglia in the MR-T1-weighted images have frequently been observed in patients with SHE. The reduction of regional cerebral blood flow (rCBF) by ^99mtechnetium-1, 1-ethylcysteinate dimer (^99mTc-ECD)-single photon emission computed tomography (SPECT) and the choline/N-acetylaspartic acid ratio by ¹proton-magnetic resonance spectroscopy (¹H-MRS) were observed in the hippocampus in patients with SHE. These approaches (cerebral function tests and imaging diagnoses of the brain) can also be used to evaluate the effectiveness of treatments for HE; for example, branched-chain amino acid (BCAA) was shown by automated continuous polysomnographic analysis to be a psychotropic drug which acts directly on the central nervous system and the clinical significance of choline administration to HE patients is now being evaluated by ¹H-MRS and neuropsychological tests.     

Event-related brain potentials in male hypogonadism.

Several studies based on psychometric tests have determined an impairment of cognitive functions in patients with androgen deficiency. However, little is known about event-related potentials (ERPs) alterations in male hypogonadism. We investigated alterations of ERP in male hypogonadism before and 3 months after gonadotropin treatment. ERPs were elicited in 20 untreated male patients with idiopathic hypogonadotropic hypogonadism (IHH) (mean age: 21.1+/-1.4 years) and in a group of 30 male controls with comparable mean age and educational level. ERP recordings were repeated 3 months after hCG/hMG treatment. Untreated hypogonadal patients had longer mean P300 latencies and increased P300 amplitudes when compared to those in controls (321.6+/-18.5 vs 299.3+/-20.1 msec, p=0.0002; 12.15+/-4.47 vs 9.38+/-3.02 microV, p=0.011, respectively). The mean P300 latencies did not change significantly 3 months after gonadotropin treatment, while P300 amplitudes were decreased significantly. P300 latencies did not correlate with serum testosterone and other hormone levels. We conclude that prolongation of P300 latencies and increased P300 amplitudes are associated with male hypogonadism, but P300 prolongation is not reversed 3 months after gonadotropin treatment. These findings confirm the occurrence of cognitive defects in hypogonadal patients and would support the hypothesis that perinatal androgen deficiency contributes to an insufficient cognitive development.     

Impairment of psychomotor responses after conscious sedation in cirrhotic patients undergoing therapeutic upper GI endoscopy

OBJECTIVES: The aim of this study was to determine whether the number connection test (NCT) times of a group of cirrhotic patients without clinically overt hepatic encephalopathy and a group of healthy patients without liver disease who were undergoing endoscopy were prolonged after sedation with short acting i.v. benzodiazepines. METHODS: All patients were administered the NCT in a standard fashion for 30 min before sedation for an upper GI endoscopy and then 2 h after sedation postprocedure. Two NCTs were carried out before and 2 h after sedation, and the mean of the tests pre- and postsedation calculated. Based on the upper limit of the 95% CI of the presedation NCT of patients without liver disease as the cut-off level for hepatic encephalopathy, the proportion of cirrhotic patients with subclinical encephalopathy before and after sedation were also determined. RESULTS: A total of 61 consecutive cirrhotic patients who underwent therapeutic upper GI endoscopy completed the study. The mean presedation NCT time was 43.5 s (95% CI = 39.0-48.1 s) and the mean postsedation NCT time 60.0 s (95% CI = 50.7-69.3 s). The difference between the mean pre- and postsedation NCT times was 16.4 s (95% CI = 9.8-23.1 s; p < 0.001). A total of 38 consecutive patients without clinical or biochemical evidence of liver disease who presented for upper GI endoscopy completed the NCT as described for the group of cirrhotic patients. The mean (+/- SD) baseline NCT time was 34.7+/-7.9 s (95% CI = 32.1-37.2 s), whereas the mean postsedation NCT time was 33.7+/-8.5 s (95% CI = 30.9-36.5 s). This difference was not statistically significant (p = 0.177). Using the upper limit of the 95% CI of the mean (37.4 s) of the presedation time in the patients without liver disease as the cut-off between normal and encephalopathy, the number of cirrhotic patients with abnormal presedation NCT times was 33 patients (54.1%), and this number rose to 46 patients (75.4%) after sedation with midazolam. This increase in proportion of cirrhotic patients with prolonged NCT time was statistically significant (p < 0.001).     

An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) is associated with poor quality of life and increased work disability. Treatment with lactulose and probiotics has shown some benefit. We compared lactulose with probiotics and a combination of lactulose plus probiotics in the treatment of MHE. PATIENTS AND METHODS: One hundred and ninety cirrhotic patients without overt encephalopathy [Child's A grade 71 patients (37.4%), Child's B grade 72 patients (37.9%), Child's C grade 47 patients (24.7%)] were evaluated by psychometry (number connection tests A and B or figure connection tests A and B) and P300 auditory event-related potential (P300ERP). MHE was diagnosed by abnormal psychometry and/or P300ERP. Patients were randomized to receive lactulose [group A (n=35): dose 30-60 ml/day], probiotics [group B (n=35): dose 1 capsule three times/day, each capsule contained Streptococcus faecalis 60 million, Clostridium butyricum 4 million, Bacillus mesentricus 2 million, lactic acid bacillus 100 million] and lactulose plus probiotics [group C (n=35)] for 1 month. Response was defined by normalization of the abnormal test parameters. RESULTS: MHE was diagnosed in 105 (55.2%) patients. Of the 105 patients, 75 (71%) had both abnormal psychometry and P300ERP, whereas 90 (86%) had abnormal psychometry alone, and 89 patients (85%) had abnormal P300ERP alone. Significant improvement was seen in abnormal psychometry tests (group A: n=31 vs. n=12, group B: n=29 vs. n=14, group C: n=30 vs. n=10), P300ERP (group A: 376.8+/-22.3 vs. 344.3+/-30.6 ms, group B: 385.4+/-28.5 vs. 355.5+/-27.9 ms, group C: 387.7+/-27.5 vs. 347.7+/-31.5 ms) and venous ammonia levels (group A: 102.3+/-63.1 vs. 69.3+/-33.3 micromol/l, group B: 108.2+/-37.5 vs. 75.7+/-33.0 micromol/l, group C: 96.3+/-27.7 vs. 68.7+/-28.4 micromol/l) in lactulose, probiotics and a combination of lactulose plus probiotics groups after treatment. Normalization of abnormal psychometry and P300ERP was seen in 54.8, 51.6 and 56.6% of patients treated with lactulose, probiotics and lactulose plus probiotics groups, respectively. CONCLUSION: A total of 55% of the patients with cirrhosis had MHE. Lactulose or probiotics or combinations of both are equally effective in the treatment of MHE.     

Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients

AIM： To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy （HE）, and the effect of Hpylori eradication in cirrhotic patients. METHODS： From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, Hpylori infection, liver impairment, blood ammonia concentration and HE. Patients with Hpylori infection were given I wk therapy with omeprazole plus clarithromycin and tinidazole. ^14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after RESULTS： Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE （SHE） was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative （n = 180） and positive （n = 277） cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 μmol/L, respectively （P 〈 0.01）, which was significantly reduced to 53.5 ± 37.7 μmol/L after bacterium eradication （n = 126） （P 〈 0.01）. Blood ammonia was 97.5 ± 81.0 μmol/L in H pylori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after Hpylori eradication （n = 11）. HE was more frequently observed in patients with H pylori infection than in those without （58.5% vs 30.6%, P 〈 0.01）. HE rate significantly dropped to 34.1% after H pylori eradiation （P 〈 0.01）. H pylori prevalence significantly differed among cirrhotic patients with HE （74.4%）, SHE （69.1%）, and those without HE （53.2%） （P 〈 0.05）. Blood ammonia level was significantly different among cirrhotic patients with HE （94.5 ± 75.6 μmol/L）, SHE （59.9 ± 49.2 μmol/L）, and without HE （47.3 ± 33.5 μmol/L） （P 〈 0.05）. Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nit     

Comparative Efficacy of Psychometric Tests in Detection of Subclinical Hepatic Encephalopathy in Nonalcoholic Cirrhotics: Search for a Rational Approach

To compare the efficacy of various psychometric tests in the detection of subclinical hepatic encephalopathy (SHE), cerebral functions were studied in 20 nonalcoholic cirrhotics without overt encephalopathy and in 18 matched healthy controls. Wechsler Adult Intelligence Scale (WAIS) indicated that verbal ability was preserved in all cirrhotics. Of the WAIS performance tests, block design test (BDT) was abnormal in 11 (55%), picture arrangement in 10 (50%), object assembly in eight (40%) and digit symbol in six (30%) patients. Taken together, these tests diagnosed SHE in 14 (70%) patients. Number connection test (NCT) alone, on the other hand, was abnormal in 13 (65%) patients. A combination of NCT and BDT yielded the diagnosis of SHE in 15 (75%) patients. An important measure of the reliability of the diagnosis of SHE was that NCT and BDT were independently abnormal in 10 of these patients. Both NCT and BDT were found easy and quick to administer. In conclusion, our results argue in favor of using a combination of NCT and BDT for a rapid and accurate diagnosis of SHE in patients with cirrhosis of the liver.     

Efficacy of Lactulose in Cirrhotic Patients with Subclinical Hepatic Encephalopathy

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.     

Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy

BACKGROUND/AIMS: Minimal hepatic encephalopathy (MHE) is associated with poorer quality of life and increased work disability. Diagnosis requires cumbersome psychometric and neurophysiological tests. We evaluated critical flicker frequency (CFF) to diagnose MHE. METHODS: 156 cirrhotic patients (age 41+/-12.5 yr) without overt encephalopathy (Child A 63, Child B 56, Child C 37) were evaluated by psychometric (number connection tests A, B or figure connection tests A, B), P300 auditory event related potential (ERP) and CFF. MHE was diagnosed by abnormal psychometric and/or P300 auditory event related potential. RESULTS: Prevalence of MHE was 53% with 27 (43%) in Child's A, 33 (59%) in Child's B and 23 (62%) in Child's C cirrhosis (p=NS). Of 83 patients, 72 (87%) had abnormal psychometry, 64 (77%) had abnormal P300 auditory event related potential (ERP) (380.6+/-28.8 ms) and in 66 (80%) CFF was below 39 Hz. 60 (83%) patients with abnormal psychometry and 51 (80%) with abnormal P300 auditory event related potential had CFF below 39 Hz. CFF sensitivity (96%), specificity (77%) and positive predictive value (68%), negative predictive value (98%) and diagnosis accuracy was 83.3% when compared to patients with both abnormal psychometry and P300ERP. CONCLUSIONS: Critical flicker frequency is a simple, reliable and accurate test without any age or literacy dependence for the diagnosis of MHE.     

Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests.

The prevalence and the clinical implications of subclinical cognitive alterations in cirrhotic patients have not been well defined as yet. Therefore, we performed a study to assess the clinical features and the survival of cirrhotic patients with cognitive alterations detected by the number connection test (NCT) and a set of computerized psychometric tests (Scan, Choice1, and Choice2) measuring the reaction times and the percentage of errors in performing specific tasks. Ninety-four cirrhotic patients (aged 58 +/- 9 years) without overt hepatic encephalopathy and 80 controls (aged 53 +/- 15 years) were consecutively enrolled. The median follow-up in cirrhotic patients was 426 days (lower quartile = 213 days; upper quartile = 718 days). Results of the NCT, Scan test, and Choice2 test were significantly worse in cirrhotic patients, whereas Choice1 did not differ significantly from the controls. In cirrhotic patients, the prevalence of altered psychometric tests was 21% (CI95% = 14%-31%) by NCT, 23% (CI95% =15%-33%) by Scan test, and 20% (CI95% =16%-30%) by Choice2 test. The alterations of NCT, Scan, and Choice2 were found to be related to the severity of liver disease, independently of its etiology. Increased risk of death was found to be associated with altered Scan test (hazard ratio = 2.4; CI95% =1. 1-5.3), or altered Choice2 test (hazard ratio = 2.8; CI95% = 1.2-6. 3). Multivariate regression showed that Scan and Choice2 tests had prognostic value on survival, in addition to Child-Pugh classes in the first year of follow-up.     

诱发电位对肝硬化患者轻微肝性脑病的诊断价值

目的 探讨诱发电位(EP)在没有症状性肝性脑病(OHE)的肝硬化患者中检测轻微肝性脑病(MHE)的价值.方法 对114例无OHE的肝硬化患者进行盲法、自身同步对照的数字连接试验A(NCT-A)、数字符号试验(DST)并检测视觉诱发电位(VEP)、脑干听觉诱发电位(BAEP)、体表感觉诱发电位(SSEP)、P300听觉事件相关诱发电位(P300ERP).NCT-A和DST检测中1项异常即诊断为MHE,比较各EP检测的异常率,评估其诊断MHE的价值.结果 114例肝硬化患者中诊断MHE 60例(52.6%),其阳性率与Child-Pugh分级呈等级正相关(r=0.278,P=0.003).VEP、BAEP、SSEP、P300ERP异常率分别为17.5%、29.8%、38.6%、57.0%.仅P300ERP的异常率与NCT-A+DST的阳性率差异无统计学意义(X2=0.432,P=0.511).VEP、BAEP、SSEP、P300ERP的诊断敏感度分别为13.3%、41.7%、46.7%、73.3%,特异度分别为77.8%、83.3%、70.4%、61.1%.P300ERP的受试者工作特征曲线(ROC)下面积最大(0.672,95%CI 0.572～0.773).VEP、BAEP、SSEP、P300ERP与NCT-A+DST的符合率分别为43.9%、61.4%、57.9%、67.5%.各EP检测的Kappa值均<0.39.结论 以P300ERP诊断无OHE的肝硬化患者MHE敏感度和特异度均较高.P300ERP不可替代NCT-A-4+DST,但可作为补充检测手段.     

Visual Event-Related Potentials in Cirrhotic Patients Without Overt Encephalopathy: The Effects of Flumazenil

The P300 complex was derived from the electroencephalogram (EEG) as subjects mentally counted infrequent large checkerboard visual stimuli, presented randomly among frequent small checkerboard stimuli. Use of low contrast (10%) stimuli and four midline scalp electrodes, facilitated separation of cognitive and sensory components and enabled the P300 complex to be resolved into three distinct components—N200, P3a, and P3b. In 20 healthy adult subjects normative data were established and the P3a and P3b components were shown to depend on cognitive function. In 19 age-matched cirrhotic patients without overt hepatic encephalopathy (HE) the EEG and visual evoked potentials (VEPs) were normal, but latencies of P3a and/or P3b were prolonged in 9. Prolonged latencies were not associated with an abnormal number connection test. Ten additional age-matched cirrhotic patients without overt HE, who were alcohol, drug, and caffeine free, were randomized to receive flumazenil (1 mg) and placebo intravenously, double-blind. After flumazenil or placebo, latencies of P3a and P3b and psychometric test results did not change significantly. These findings suggest that in cirrhotic patients without overt HE (i) impaired cognitive sensory function may occur in the absence of abnormalities of a standard psychometric test, the EEG, or VEPs, and (ii) increased latencies of P3a and P3b may constitute a component of subclinical HE, which is not mediated by increased brain levels of central benzodiazepine receptor agonist ligands.     

Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy

BACKGROUND/AIMS: We assessed the usefulness of oral glutamine challenge (OGC) and minimal hepatic encephalopathy in evaluating risk of overt hepatic encephalopathy in cirrhotic patients.METHODS: Minimal hepatic encephalopathy (MHE) was inferred using neuro-psychological tests. Venous ammonia concentrations were measured pre- and post-60 min (NH(3)-60m) of a 10 g oral glutamine load. Receiver-operating-characteristic curve analysis indicated a pathological glutamine tolerance cut-off value of NH(3)-60m >128 microg/dl. RESULTS: In healthy control subjects (n=10) ammonia concentrations remained unchanged but increased significantly in cirrhotic patients (from 70.41+/-45.2 to 127.43+/-78.6; P<0.001). In multiple logistic regression analysis, altered OGC was related to Child-Pugh (odds ratio, OR=7.69; 95% confidence interval, CI=1.72-33.3; P<0.01) and MHE (OR=5.45; 95% CI=1.17-25.4; P<0.05). In the follow-up 11 patients (15%) developed overt hepatic encephalopathy (HE). In multivariate analysis OGC (OR=14.5; 95% CI=1.26-126.3) and MHE (OR=1.56; 95% CI=1.02-21.9) were independently related with HE in the follow-up. Patients with MHE and altered OGC showed significantly higher risk of overt HE in the follow-up (60%) than patients without MHE and normal OGC (2.8%) (Log rank test=21.60; P<0.0001). CONCLUSIONS: A pathological OGC in patients with MHE appears to be a prognostic factor for the development of overt hepatic encephalopathy, whereas a normal OGC in patients without MHE could exclude risk of overt HE.