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Purpose of Review: The burden of hepatic encephalopathy on health services is increasing, and some degree of consensus in relation to drug therapy and prophylaxis has been reached. This review focuses on the role of nutritional interventions in the management of hepatic encephalopathy., Recent Findings: A number of relatively new pieces of evidence are emerging in relation to nutrition and hepatic encephalopathy as follows: first, reduction of protein intake is not useful for hepatic encephalopathy, but protein selection should be considered; second, oral supplementation with branched chain amino acids has a role not only for its nutritional effect in cirrhosis per se, but also for its effect in reducing the risk of recurrence of hepatic encephalopathy; third, alterations in gut microbiota develop in parallel with decompensation of cirrhosis, and modulation of gut microbiota may be effective for treating and preventing hepatic encephalopathy; fourth, prebiotics and probiotics are potentially useful in this aim, thus further research or trials on prebiotics and probiotics are required; fifth, micronutrient deficiency, which is common in end-stage liver disease, has adverse effects on the brain and may either directly cause encephalopathy per se, or interact with the mechanisms leading to hepatic encephalopathy., Summary: Properly performed nutritional interventions are likely to be useful for patients with hepatic encephalopathy, but well conducted clinical trials are required., Video Abstract: http://links.lww.com/COCN/A7.

Aim: To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices., Methods: A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices (Strategy 1) with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated (Strategy 2), for preventing variceal growth, bleeding and death in patients with cirrhosis and small esophageal varices. The basic nodes of the tree were gastrointestinal endoscopy, inpatient admission and treatment for bleeding, as required. All estimates were performed using a Monte Carlo microsimulation technique, consisting in simulating observations from known probability distributions depicted in the model. Eight-hundred-thousand simulations were performed to obtain the final estimates. All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis, to assess the impact of the variability of such estimates on the outcome distributions., Results: The event rate (considered as progression of varices or bleeding or death) in Strategy 1 [24.09% (95%CI: 14.89%-33.29%)] was significantly lower than in Strategy 2 [60.00% (95%CI: 48.91%-71.08%)]. The mean cost (up to the first event) associated with Strategy 1 [823 £ (95%CI: 106 £-2036 £)] was not significantly different from that of Strategy 2 [799 £ (95%CI: 0 £-3498 £)]. The cost-effectiveness ratio with respect to this endpoint was equal to 50.26 £ (95%CI: -504.37 £-604.89 £) per event avoided over the four-year follow-up. When bleeding episodes/deaths in subjects whose varices had grown were included, the mean cost associated with Strategy 1 was 1028 £ (95%CI: 122 £-2581 £), while 1699 £ (95%CI: 171 £-4674 £) in Strategy 2., Conclusion: Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.

The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups., (© 2014 American Association for the Study of Liver Diseases.)

Background/objectives: The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The aim of this study was to assess it in a large group of well-characterized outpatients with cirrhosis and no overt HE., Methods: One-hundred-and-ninety-one patients underwent clinical assessment, MMSE, electroencephalography (EEG) and paper-and-pencil psychometry (PHES); 117 were followed up for 8 ± 5 months in relation to the occurrence of HE-related hospitalizations., Results: On the day of study, 81 patients (42%) had abnormal EEG and 67 (35%) abnormal PHES; 103 (60%) had a history of HE. Average MMSE was 26.6 ± 3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal tests/negative history (25.7 ± 4.2 vs. 27.3 ± 2.7; P < 0.01; 25.5 ± 3.2 vs. 27.9 ± 1.8, P < 0.0001; 26.3 ± 3.7 vs. 27.4 ± 2.6, P < 0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed. An MMSE threshold of 26 was also a predictor of HE-related hospitalization (Cox-Mantel: P = 0.001); patients with MMSE <26 were significantly older than those with MMSE ≥26 but comparable in terms of liver dysfunction and ammonia levels. When MMSE items were considered separately, those which correlated most significantly with standard HE indices where spatial orientation and writing., Conclusion: In conclusion, an MMSE <26 identifies older patients with cirrhosis who are more prone to manifest HE signs.

Objective: The Inhibitory Control Task (ICT) was used to detect minimal hepatic encephalopathy (MHE). ICT assesses attention, working memory and inhibition by evaluating performance in detect, go and nogo trials, respectively. The event-related potentials (ERPs) elicited by the ICT provide insight into neural mechanisms underlying the cognitive alterations associated with MHE., Methods: The performance and the ERPs elicited by ICT were measured in 31 patients with cirrhosis (13 with and 18 without MHE) and in 17 controls. The latency and amplitude of the N2, P3a, P3b and nogo-P3 were compared among the groups., Results: Patients with MHE performed worse in all ICT trials compared to patients without MHE and controls. Cirrhotic patients, both with and without MHE, displayed a reduction in P3a amplitude, selectively in the detect trials. Patients without MHE exhibited greater N2 and nogo-P3 amplitudes compared to patients with MHE and controls., Conclusions: Both patients with and without MHE displayed neural alterations reflecting attentional deficits (i.e., P3a attenuation). However, patients without MHE coped with such dysfunctions by recruiting compensatory neural mechanisms, as suggested by the enhancement of the nogo-P3 and N2 amplitudes coupled with a normal ICT performance., Significance: The study suggests how initial brain dysfunction might be compensated for by recruitment of additional neurocognitive resources., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed., (© 2013 by the American Association for the Study of Liver Diseases.)

In a time-series, memory is a statistical feature that lasts for a period of time and distinguishes the time-series from a random, or memory-less, process. In the present study, the concept of "memory length" was used to define the time period, or scale over which rare events within a physiological time-series do not appear randomly. The method is based on inverse statistical analysis and provides empiric evidence that rare fluctuations in cardio-respiratory time-series are 'forgotten' quickly in healthy subjects while the memory for such events is significantly prolonged in pathological conditions such as asthma (respiratory time-series) and liver cirrhosis (heart-beat time-series). The memory length was significantly higher in patients with uncontrolled asthma compared to healthy volunteers. Likewise, it was significantly higher in patients with decompensated cirrhosis compared to those with compensated cirrhosis and healthy volunteers. We also observed that the cardio-respiratory system has simple low order dynamics and short memory around its average, and high order dynamics around rare fluctuations.

Prophylaxis of the first bleeding from esophageal varices became a clinical option more than 20 years ago, and gained a large diffusion in the following years. It is based on the use of nonselective beta-blockers, which decreases portal pressure, or on the eradication of esophageal varices by endoscopic band ligation of varices. In patients with medium or large varices either of these treatments is indicated. In patients with small varices only medical treatment is feasible, and in patients with medium and large varices with contraindication or side-effects due to beta-blockers, only endoscopic band ligation may be used. In this review the rationale and the results of the prophylaxis of bleeding from esophageal varices are discussed.

Unlabelled: Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly., Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE., (Copyright © 2013 American Association for the Study of Liver Diseases.)

The relationship between hepatic encephalopathy (HE) and the sleep-wake disturbances exhibited by patients with cirrhosis remains debated. The aim of this study was to examine the usefulness of sleep-wake interview within the context of HE assessment. One-hundred-and-six cirrhotic patients were asked three yes/no questions investigating the presence of difficulty falling asleep, night awakenings and daytime sleepiness. All underwent formal HE assessment, quantitative electroencephalography and standardised psychometry. Fifty-eight were monitored for 8 ± 6 months in relation to the occurrence of HE. Patients complaining of daytime sleepiness (n = 75, 71 %) had slower EEGs than those who did not report it (relative alpha power: 37 ± 19 vs. 48 ± 17 %, p < 0.05). In addition, daytime sleepiness was associated with the presence of portal-systemic shunt (79 vs. 57 %, p < 0.05) and HE history (72 vs. 45 %, p < 0.05). Finally, the absence of excessive daytime sleepiness had a Negative Predictive Value of 92 % (64-100) in relation to the development of HE during the follow-up period. These data support the appropriateness of adding a yes/no question on the presence of excessive daytime sleepiness to routine assessment of patients with cirrhosis, to help identify those who do not need further, formal HE screening.

Background: Impaired sleep quality and daytime sleepiness have been described in patients with primary biliary cirrhosis (PBC). However, no information is available on their sleep timing/diurnal preference., Aims: To evaluate such variables and determine their relationship with sleep quality, fatigue, pruritus and quality of life., Methods: Seventy-four patients with PBC (58 ± 12 years), 79 healthy volunteers (56 ± 8 years) and 60 patients with cirrhosis (58 ± 12 years) underwent formal assessment of sleep quality/timing, diurnal preference and daytime sleepiness. Patients with PBC also underwent assessment of fatigue, quality of life and the daytime course of sleepiness/pruritus., Results: Sleep timing was significantly delayed in both patients with PBC and with cirrhosis, compared to healthy volunteers (sleep onset time: 23:18 ± 01:00 vs. 23:30 ± 01:00 vs. 22:54 ± 00:54 hours, respectively; P < 0.05). In patients with PBC, delayed sleep timing was associated with impaired sleep quality (P < 0.05). Sleepiness showed a physiological daily rhythm, with early afternoon/evening peaks. Pruritus was absent in the morning and increased over the afternoon/evening hours. Both the daytime course of pruritus and sleepiness changed in relation to diurnal preference. Patients with PBC and significant pruritus (upper quartile) had prolonged sleep latency (39 ± 37 vs. 21 ± 23 min, P = 0.05) and earlier wake-up times (5.9 ± 0.8 vs. 6.7 ± 0.9 min, P < 0.05). Significant correlations were observed between sleep timing and quality of life., Conclusions: Patients with PBC exhibited a delay in sleep timing that was associated with impaired sleep quality/quality of life. In addition, an interplay was observed between diurnal preference and the daytime course of pruritus/sleepiness., (© 2012 John Wiley & Sons A/S.)

Patients suffering from prodromal (i.e., amnestic mild cognitive impairment, aMCI) and overt Alzheimer's disease (AD) show abnormal cortical sources of resting state electroencephalographic (EEG) rhythms. Here we tested the hypothesis that these sources show extensive abnormalities in liver cirrhosis (LC) patients with a cognitive impairment due to covert and diffuse hepatic encephalopathy (CHE). EEG activity was recorded in 64 LC (including 21 CHE), 21 aMCI, 21 AD, and 21 cognitively intact (Nold) subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. Widespread sources of theta (all but frontal), alpha 1 (all but occipital), and alpha 2 (parietal, temporal) rhythms were higher in amplitude in all LC patients than in the Nold subjects. In these LC patients, the activity of central, parietal, and temporal theta sources correlated negatively, and parietal and temporal alpha 2 sources correlated positively with an index of global cognitive status. Finally, widespread theta (all but frontal) and alpha 1 (all but occipital) sources showed higher activity in the sub-group of LC patients with CHE than in the patients with aMCI or AD. These results unveiled the larger spatial-frequency abnormalities of the resting state EEG sources in the CHE compared to the AD condition.

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) β1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.

Background: Despite the impact of hepatic encephalopathy on quality of life and prognosis, easily administered tests for its diagnosis are still lacking., Aim: To assess the usefulness of the Scan package, a three-level-difficulty computerised reaction time test, to diagnose varying degrees of hepatic encephalopathy., Methods: Sixty-one cirrhotic patients underwent clinical evaluation, paper-and-pencil psychometry and the Scan package; 32 healthy controls served as reference., Results: Twenty-nine patients were classified as unimpaired, 15 as having minimal and 17 as having overt hepatic encephalopathy. All healthy controls were able to complete the Scan package; in contrast, the number of patients who were able to complete three/two/one part decreased in parallel with the degree of encephalopathy (χ(2)=17, p=0.01). Reaction times in all three parts increased significantly with the severity of encephalopathy. However, the profile of increase was different [group: F(3,77)=26, p<0.0001; test: F(2,154)=277, p<0.0001; group×test: F(6,154)=7, p<0.0001], with different parts being more/less sensitive to varying degrees of encephalopathy., Conclusions: The Scan package seems useful for the diagnosis of hepatic encephalopathy and covers a considerable portion of its spectrum of severity., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Gamma-hydroxybutyrate (GHB) is currently authorized by the European Medicines Agency (EMA) to treat narcolepsy with cataplexy in adults, and by the Food and Drug Administration (FDA) to treat cataplexy in patients with narcolepsy, with an expanded indication for the treatment of excessive daytime sleepiness. This study meta-analyses and reviews the effectiveness of GHB on the clinical features of narcolepsy and its neurophysiological correlates., Methods: A systematic review of the literature using Medline, Embase, Web of Science, Cochrane reviews, clinical-trials.gov, Scopus, Scirus, and a subsequent meta-analysis were performed. Considered outcomes were: cataplexy attacks, subjective daytime sleepiness, sleep attacks, clinical global impression change (CGI-c), quality of life (QoL), hypnagogic hallucinations, sleep paralysis, mean sleep latencies on the multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT), nocturnal polysomnographic data., Results: Nine randomized controlled trials reporting data on the effectiveness of GHB on narcolepsy were identified, for a total of 1,154 patients (771 patients in the GHB-treated group and 383 in the placebo group). The meta-analysis showed that GHB reduced cataplexy attacks both on a daily (weighted mean difference (WMD) -1.10; 95% confidence interval (CI) -1.29/-0.90, p < 0.00001) and a weekly basis (WMD -7.04; 95% CI -12.45/-1.63, p = 0.01), subjective nocturnal awakenings (WMD -1.33; 95% CI -1.78/-0.88, p < 0.00001), daytime sleep attacks on a weekly basis (WMD -9.30; 95% CI -15.92/-2.68, p = 0.006), subjective daytime sleepiness (WMD -2.81; 95% CI -4.13/-1.49, p < 0.0001) and sleep stage shifts (WMD -9.69; 95% CI -17.14/-2.24, p = 0.01). GHB increased sleep stages 3 + 4 (WMD 4.11; 95% CI 0.07/8.16, p = 0.05) and improved the CGI-c score (odds ratio (OR) 3.45; 95% CI 2.47/4.80, p < 0.00001). No significant changes were observed in night sleep latency, total sleep time, rapid-eye movement (REM) sleep and sleep stages 1 and 2., Conclusions: This meta-analysis demonstrates the effectiveness of GHB in treating major, clinically relevant narcolepsy symptoms and sleep architecture abnormalities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Unlabelled: In patients with cirrhosis, hyperammonemia and hepatic encephalopathy are common after gastrointestinal bleeding and can be simulated by an amino acid challenge (AAC), or the administration of a mixture of amino acids mimicking the composition of hemoglobin. The aim of this study was to investigate the clinical, psychometric, and wake-/sleep-electroencephalogram (EEG) correlates of induced hyperammonemia. Ten patients with cirrhosis and 10 matched healthy volunteers underwent: (1) 8-day sleep quality/timing monitoring; (2) neuropsychiatric assessment at baseline/after AAC; (3) hourly ammonia/subjective sleepiness assessment for 8 hours after AAC; (4) sleep EEG recordings (nap opportunity: 17:00-19:00) at baseline/after AAC. Neuropsychiatric performance was scored according to age-/education-adjusted Italian norms. Sleep stages were scored visually for 20-second epochs; power density spectra were calculated for consecutive 20-second epochs and average spectra determined for consolidated episodes of non-rapid eye movement (non-REM) sleep of minimal common length. The AAC resulted in: (i) an increase in ammonia concentrations/subjective sleepiness in both patients and healthy volunteers; (ii) a worsening of neuropsychiatric performance (wake EEG slowing) in two (20%) patients and none of the healthy volunteers; (iii) an increase in the length of non-REM sleep in healthy volunteers [49.3 (26.6) versus 30.4 (15.6) min; P = 0.08]; (iv) a decrease in the sleep EEG beta power (fast activity) in the healthy volunteers; (v) a decrease in the sleep EEG delta power in patients., Conclusion: AAC led to a significant increase in daytime subjective sleepiness and changes in the EEG architecture of a subsequent sleep episode in patients with cirrhosis, pointing to a reduced ability to produce restorative sleep., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background & Aims: Electroencephalography has not been completely quantified in patients with cirrhosis. We investigated the electroencephalogram (EEG) dynamics in patients with cirrhosis., Methods: We performed closed-eye EEGs on 175 patients with cirrhosis (age, 55 ± 11 years; 24% Child-Pugh class A, 48% class B, and 285 class C), conducted clinical and psychometric assessments for hepatic encephalopathy (HE), and followed the patients for 1 year. EEG characteristics were assessed in the frequency domain, in the frontal (F3-F4) and parietal (P3-P4) derivations. Intrahemispheric (frontoparietal, right, and left) and interhemispheric (F3-F4 and P3-P4) coherence were computed. The EEGs of 50 healthy volunteers (age, 56 ± 17 years) served as controls., Results: Compared with controls, the EEGs of patients with cirrhosis had a reduced frequency in the posterior derivations (P3/P4 mean dominant frequency, 9.1 ± 1.8 and 8.9 ± 1.7 Hz vs 10.4 ± 1.3 and 10.2 ± 1.3 Hz, respectively; P < .01) and an increase in interhemispheric parietal relative coherence within the theta band (22.3% ± 5.5% vs 18.9% ± 3.5%; P < .01). These features were more prominent in patients with Child class C and in patients with a history of overt HE; they correlated with hyperammonemia and hyponatremia. The decrease in EEG frequency, along with the increase in interhemispheric theta coherence in the posterior derivations, was inversely associated with survival and the occurrence of overt HE during the follow-up period., Conclusions: In patients with cirrhosis, alterations in the EEG were significantly associated with the severity of liver disease and HE; the EEG might be used in determining prognosis., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Portal hypertension is key to the natural history of cirrhosis and the standard way to assess it is the hepatic venous pressure gradient. Hepatic venous pressure gradient is a strong predictor of variceal bleeding/survival and is the only suitable tool to assess the response of portal hypertension to medical treatment. The clinical applications, indications and timing for hepatic venous pressure gradient measurement, together with measurement principles and costs, are reviewed., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: The psychometric hepatic encephalopathy score (PHES), which includes 5 psychometric tests, is a standard for the diagnosis of minimal hepatic encephalopathy (HE). We investigated whether a simplified PHES (SPHES) is as useful as the whole PHES., Methods: The PHES was determined for 79 cirrhotic patients (the training group), who were followed up for the development of overt HE. Backward logistic regression was performed by eliminating stepwise variables--removal did not impair regression. A separate series of 65 patients was used as a validation group., Results: The PHES was abnormal in 45 patients. The SPHES, determined from the digit symbol, serial dotting, and line tracing tests, did not differ significantly from the full PHES; 24 of the 79 patients developed overt HE. The likelihood of developing overt HE was higher among patients with an abnormal PHES (log-rank P = .003) or SPHES (P = .004). By using Cox regression and model for end-stage liver disease scores to analyze data from patients with previous HE and transjugular intrahepatic portosystemic shunts, PHES (relative risk, 4.16; P = .003) and SPHES (relative risk, 3.70; P = .004) were the only variables associated with the development of overt HE. The accuracy of the SPHES was confirmed in the validation group., Conclusions: A simplified PHES is as good as the PHES in diagnosing minimal HE and in predicting the occurrence of overt HE., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)α, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 ± 22 vs 7 ± 6, P < 0.01), IL6 (32 ± 54 vs 12 ± 13, P < 0.05) and TNFα (17 ± 8 vs 11 ± 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 ± 270 vs 258 ± 255, P < 0.01) and ammonia (66 ± 35 vs 45 ± 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFα and IL6; EEG indices with ammonia and IL6. CRP and TNFα concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05)., Conclusion: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Portal hypertension is key to the natural history of cirrhosis. The standard way to assess portal hypertension is the hepatic venous pressure gradient (HVPG). HVPG has been convincingly shown to be a strong predictor of variceal bleeding and survival. In addition, it has been shown to predict other portal hypertension-related clinical events, to include fluid retention and hepatic encephalopathy. Finally, HVPG is the only suitable tool to assess the response of portal hypertension to medical treatment. Thus, although not necessarily easy to measure, HVPG provides the clinician with information which is prognostically crucial and otherwise unobtainable., (Copyright © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Quantification of the number of noninhibited responses (lures) in the inhibitory control task (ICT) has been proposed for the diagnosis of minimal hepatic encephalopathy (MHE). We assessed the efficacy of ICT compared with recommended diagnostic standards., Methods: We studied patients with cirrhosis and healthy individuals (controls) who underwent the ICT at 2 centers (center A: n=51 patients and 41 controls, center B: n=24 patients and 14 controls). Subjects were evaluated for MHE by psychometric hepatic encephalopathy score (PHES). Patients from center B also were assessed for MHE by critical flicker frequency and spectral electroencephalogram analyses., Results: Patients with cirrhosis had higher ICT lures (23.2+/-12.8 vs 12.9+/-5.8, respectively, P<.01) and lower ICT target accuracy (0.88+/-0.17 vs 0.96+/-0.03, respectively, P<.01) compared with controls. However, lures were comparable (25.2+/-12.5 vs 21.4+/-13.9, respectively, P=.32) among patients with/without altered PHES (center A). There was a reverse, U-shaped relationship between ICT lure and target accuracy; a variable adjusting lures was devised based on target accuracy (weighted lures at center B). This variable differed between patients with and without MHE. The variable weighted lures was then validated from data collected at center A by receiver operator characteristic curve analysis; it discriminated between patients with and without PHES alterations (area under the curve=0.71+/-0.07). However, target accuracy alone was as effective as a stand-alone variable (area under the curve=0.81+/-0.06)., Conclusions: The ICT is not useful for the diagnosis of MHE, unless adjusted by target accuracy. Testing inhibition (lures) does not seem to be superior to testing attention (target accuracy) for the detection of MHE., (Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior., Methods: The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries., Results: There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality., Conclusions: Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.

An unusual case of inter-haemispheric disconnection syndrome occurring in a patient who had undergone hepatic transplantation is presented. The underlying disorder, at first wrongly interpreted as encephalitis, was found to be severe, diffuse cerebral vasculitis. The hypothesis that treatment with tacrolimus might have caused, or at least favoured the vascular damage is discussed.

Background: Sleep-wake disturbances are common in patients with cirrhosis and are generally attributed to the presence of hepatic encephalopathy., Aim: To determine the relationship between sleep and neuropsychiatric disturbances in patients with cirrhosis., Methods: The study population comprised 87 patients, classified as neuropsychiatrically unimpaired or as having minimal/overt hepatic encephalopathy. Nineteen healthy volunteers served as controls. Validated questionnaires were used to assess sleep quality [Pittsburgh sleep quality index (PSQI)], day-time sleepiness [Epworth sleepiness scale (ESS)] and diurnal preference. Health-related quality of life (H-RQoL) was assessed using the 36-item short form health profile (SF-36v1) and the chronic liver disease questionnaire., Results: Patients slept significantly less well than the healthy volunteers (PSQI score: 8.4 +/- 4.9 vs. 4.6 +/- 2.5, P<0.01) and had more pronounced day-time sleepiness (abnormal ESS: 21 vs. 0%; chi(2)=3.8, P=0.05). No significant relationships were observed between sleep indices and the presence/degree of hepatic encephalopathy. H-RQoL was significantly impaired in the patients (SF-36v1 physical score: 36 +/- 15 vs. 50 +/- 10, P<0.001; SF-36v1 mental score: 46 +/- 11 vs. 50 +/- 10, P<0.01); night-time sleep disturbance was an independent predictor of poor H-RQoL (P<0.01)., Conclusions: Sleep-wake abnormalities are common in patients with cirrhosis; they significantly affect H-RQoL but are not related to the presence of hepatic encephalopathy.

Background/aims: Sleep-wake abnormalities are common in patients with cirrhosis but their evaluation is time consuming and laborious. The aim of this study was to assess the validity of a simple Sleep Timing and Sleep Quality Screening questionnaire (STSQS) against an established sleep quality questionnaire and daily sleep diaries., Methods: The study population comprised 87 patients with cirrhosis and 19 healthy volunteers. All participants completed the STSQS (sleep quality score range 1-9) and the Pittsburgh Sleep Quality Index (PSQI; total score range: 0-21; scores >5 identify 'poor' sleepers); a subgroup of 35 patients and 12 healthy volunteers also kept daily sleep diaries for 2 weeks., Results: Patients slept significantly less well than the healthy volunteers (total PSQI score: 8.4+/-4.9 vs. 4.6+/-2.5, p<0.01; STSQS sleep quality score: 4.8+/-2.1 vs. 3.6+/-1.4, p=0.02). Significant correlations were observed between the STSQS sleep quality score and the PSQI total score (healthy volunteers: R=0.75, p<0.01; patients: R=0.74, p<0.01). STSQS sleep quality thresholds were identified, which separated individuals classified as 'poor'/'good' sleepers on the basis of the PSQI (healthy volunteers: STSQS sleep quality >4: sensitivity 75%, specificity 93%; patients: STSQS sleep quality >3: sensitivity 83%, specificity 70%). The STSQS provided estimates of habitual sleep timing variables which did not significantly differ from the average data recorded in the sleep diaries, although more variability was observed in the patients., Conclusions: The STSQS provides acceptable estimates of sleep quality and sleep timing and could be used to identify patients with cirrhosis whose sleep behaviour might require further assessment.

Sleep disturbances are common in patients with cirrhosis but their origins are unknown. The aim of this study was to investigate possible involvement of the circadian system. Sleep was monitored for two weeks, in the home environment, using sleep diaries and actigraphy, in 35 patients with cirrhosis (21 men; mean age [+/- 1SD] 58 +/- 10 yr) and 12 matched healthy controls (eight men; mean age 56 +/- 15 yr); urinary 6-sulphatoxymelatonin (aMT6s), the major metabolite of melatonin, was measured over 56 h, to assess circadian rhythmicity. The patients woke up and got up significantly later than the healthy volunteers and their sleep was significantly more fragmented. Mean 24-hour urinary aMT6s outputs were comparable in the patients and controls (15.5 +/- 13.1 vs. 20.3 +/- 13.8 microg/24 h) but were significantly lower in the decompensated patients (9.8 +/- 11.3 vs. 17.0 +/- 13.3 microg/24 h; p = 0.03). Significant 24-hour urinary aMT6s rhythms were observed in 26 (79%) of the 33 patients with complete urine collections; 20 patients had a normally timed (midnight-06:00) urinary aMT6s peak, while it was delayed (> or = 06:00) in the remainder. Significant correlations were observed between abnormalities in the urinary aMT6s profile (delays and/or lack of a 24-hour rhythm) and indices of sleep timing; parallel delays were observed in sleep habits and urinary aMT6s peaks. The association between delayed circadian rhythms and delayed sleep habits observed in approximately one-third of the patients with cirrhosis is reminiscent of 'delayed sleep phase syndrome'; this condition is managed by attempting to resynchronise the circadian clock by exposure to bright light shortly after morning awakening.

Heart rate variability (HRV) is reduced in several clinical settings associated with either systemic inflammation or neuropsychiatric impairment. The possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. HRV is decreased in patients with liver cirrhosis but its relationship to the impairment of neuropsychiatric performance, commonly observed in these patients, is unknown. The aim of this study was to investigate the relationship between HRV, hepatic encephalopathy, and production of inflammatory cytokines in patients with cirrhosis. Eighty patients with cirrhosis [53 men, 27 women; mean (+/-1SD) age 54 +/- 10 yr], classified as neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy, and 11 healthy subjects were studied. HRV was assessed by applying Poincaré plot analysis to the R-R interval series on a 5-min ECG. Inflammatory cytokines (TNF-alpha, IL-6, IL-10, and IL-12) were measured in a subgroup of patients. Long-term R-R variability was significantly decreased in the patients with cirrhosis, in parallel with the degree of neuropsychiatric impairment (P < 0.01) and independently of the degree of hepatic dysfunction (P = 0.011). The relative risk of death increased by 7.7% for every 1-ms drop in this variable. Plasma levels of IL-6 significantly correlated with indexes of both HRV and neuropsychiatric performance. The changes observed in HRV and in neuropsychiatric status in patients with cirrhosis are significantly correlated, most likely reflecting a common pathogenic mechanism mediated by inflammatory cytokines.

Background/aims: Slowing of the electroencephalogram (EEG) is a recognised feature of hepatic encephalopathy but its diagnostic sensitivity is indeterminate. Recent advances in EEG analysis should provide better quantifiable/more informative data. The aim of this study was to isolate and determine the scalp distribution of the posterior basic rhythm, in patients with cirrhosis, using a technique for spatio-temporal decomposition (SEDACA) of the EEG., Methods: One hundred and ten patients with cirrhosis, classified, using clinical and psychometric criteria, as neuropsychiatrically unimpaired or as having minimal/overt hepatic encephalopathy were studied. Eyes-closed, awake EEGs were obtained and subjected to standard spectral analysis and spatio-temporal decomposition. Control data were obtained from 26 reference EEGs., Results: The error in the estimate of the SEDACA-derived mean dominant frequency was lower than for the standard EEG derivation (P<0.00001). The SEDACA-derived spectral estimates correlated better with neuropsychiatric status and allowed differentiation of the patients with minimal hepatic encephalopathy from the reference population. The SEDACA-derived spatial information showed an anteriorization of the posterior basic rhythm, which became more prominent as the degree of neuropsychiatric impairment increased (P=0.00052)., Conclusions: Analysis of the EEG utilising SEDACA provides significantly more diagnostic information on the neuropsychiatric status of patients with cirrhosis than obtained conventionally.

Smooth pursuit eye movements (SPEM) are the conjugate movements used to track the smooth trajectory of small dots. Jerky or 'saccadic' ocular pursuit has been reported in patients with cirrhosis, but no formal assessment of SPEM has ever been undertaken. The aim of this study was to evaluate SPEM in patients with cirrhosis and varying degrees of hepatic encephalopathy. The patient population comprised 56 individuals (31 men, 25 women) of mean age 51.1 (range, 25-70) years, with biopsy-proven cirrhosis, classified, using clinical, electroencephalographic, and psychometric variables, as either neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy; patients were further categorized in relation to their treatment status. The reference population comprised 28 healthy volunteers (12 men, 16 women) of mean age 47.3 (range, 26-65) years. SPEM was assessed using an electro-oculographic technique. Visual inspection of the SPEM recordings showed clear disruption of smooth pursuit in the patients with minimal hepatic encephalopathy, and more pronounced disruption, if not complete loss, of smooth pursuit in patients with overt hepatic encephalopathy. The differences observed in quantifiable SPEM indices between the healthy volunteers/unimpaired patients and those with overt hepatic encephalopathy were significant (P < .05). In conclusion, SPEM performance is impaired in patients with hepatic encephalopathy in parallel with the degree of neuropsychiatric disturbance: the pathophysiology of these changes is unknown, but retinal, extrapyramidal, and attentional abnormalities are likely to play a role. Treatment status confounds the classification of neuropsychiatric status and should be taken into account when categorizing these patients.

There is no "gold standard" for diagnosing hepatic encephalopathy in patients with cirrhosis. In consequence, the presence of this condition, unless floridly overt, is often missed. As a result, the majority of patients are denied the benefits of treatment. There are a number of individual techniques, which access different aspects of cerebral function that can be used, singly or in combination, to provide diagnostic information in this condition, including mental state assessment, psychometric testing, electroencephalography, sensory and cognitive evoked potentials, and neuroimaging. These have been variously applied to the study of hepatic encephalopathy but fundamental differences in the essential aims of the studies, as well as differences in the patient populations and the acquisition and analysis of the data, have made comparisons difficult. Thus, there is no clear consensus as to the sensitivity, specificity, or validity of these tests when used alone or in combination. There are, however, a number of additional methods that could be used to analyze the electrophysiological data, and a number of alternative evoked potentials that could be measured to provide better diagnostic information. In addition, there are a number of techniques, such as critical flicker frequency and smooth pursuit eye movements, which have not yet been applied systematically in this condition and which may provide useful diagnostic information. Clearly the methods for assessing hepatic encephalopathy need to be reviewed, newer methods for analyzing the electrophysiological data and newer techniques for assessing alternative aspects of cerebral function need to be explored for their diagnostic utility. This process should aim at developing a multidimensional diagnostic tool.

The term minimal hepatic encephalopathy refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy. Use of this term emphasizes the fact that the entity of hepatic encephalopathy is a single syndrome with quantitatively distinct features relating to severity. The absence of clinical evidence of hepatic encephalopathy is key to the diagnosis and can only be determined by a detailed assessment of the patients' history and a comprehensive neurological assessment of consciousness, cognitive, and motor function. The neuropsychological features of minimal hepatic encephalopathy point to a disorder of executive functioning, particularly selective attention and psychomotor speed, but other abnormalities may be observed. Alterations in electrophysiological variables have been described; endogenous evoked potentials are, in principle, more likely to reflect the presence of minimal hepatic encephalopathy, since they reflect cognitive phenomena rather than mere stimulus conduction but the specificity of the changes observed is unclear at present. Changes have also been described in the execution of diadochokinetic movements and in the capacity to discriminate flickering light, both of which may have diagnostic potential. The changes observed in cerebral blood flow and metabolism in SPET, PET, and 1H and 31P MRS studies reflect the pathogenic process that underlies the condition rather than providing diagnostic information. Similarly, the morphological brain abnormalities identified in this population, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei observed in cerebral MR studies, and the central and cortical atrophy observed in neural imaging studies, are unlikely to have diagnostic utility. The presence of minimal hepatic encephalopathy is not without clinical consequence; it has a detrimental effect on health-related quality of life, the ability to perform complex tasks such as driving, and on outcome.

Background and Aims: The influence of sociobiological variables and aging on the variability of the Trail Making Tests (TMT), the Symbol Digit Substituting Test (SDT), and the Line Trait Test (LTT) in the general healthy populations are not well known. Even less is known about the reliability at re-testing. This study aimed at determining the reference range of these tests, taking into account sociobiological variables and age, and the re-testing effect., Methods: We studied 300 healthy subjects from 20 to 80 years of age. The sample was derived by the pooling of two samples stratified by age and sex: a randomized sample of 161 subjects collected from the city registers of Padova, and a convenience sample of 139 subjects collected in 20 towns (mainly rural) of Northern Italy. After normalization, data were assayed for the influence of age, education, job, and gender., Results: Age was found to be a significant independent predictor for all the tests, education for all but the LTT, job only for the TMT-B and a geometrical version of the same test (TMT-G) which was proved to be highly correlated with the TMT-B (r=0.80, p<0.01). Job and the interaction age x education level influenced the difference TMT-B minus TMT-A. From the predicting equations, the normative data and the formulas to obtain Z scores for each test were derived. Reliability was lowest for LTT errors (CV=67%), highest for the SDT (13%), whereas the TMT obtained intermediate values (22-33%, depending on the test)., Conclusions: This study provides the most reliable normative data range for the TMT, SDT and LTT to date because it considers important demographic variables such as age, education and job.