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Background: Spontaneous portosystemic shunts (SPSS) are common in cirrhosis. Their characterization and clinical implications remain unclear., Aims: To devise a system of assessment of these shunts, and assess their clinical implications METHODS: We retrospectively studied patients with cirrhosis who underwent imaging in a liver transplant program. A novel index was computed to assess total SPSS -the diameter of a circle having an area equivalent to the sum of the areas of all the existing shunts. This 'SPSS equivalent diameter' was compared with the clinical variables., Results: Among 127 patients, 70% (CI 95% 62-77) had SPSS, and 57% (CI 95% 62-77) had multiple SPSS. The risk for SPSS was related to the severity of cirrhosis (Child-Pugh B/C vs. A: OR 2.4 CI 95% 1.1-5.4) and alcoholic aetiology (OR 2.9 CI 95% 1.2-7.1). The SPSS equivalent diameter was related to a history of HE, cognitive impairment (EEG/PHES) and ammonia(p<0.05). The diameter of the inferior cava vein >19.5 mm was a predictor of large SPSS (AUC 0.77, CI 95% :0.68-0.87, p ≤ 0.001)., Conclusions: The SPSS equivalent diameter, a comprehensive assessment of portosystemic shunting, was associated with severity of liver disease, hyperammonemia, and cognitive dysfunction. The diameter of the inferior vena cava was a good predictor of SPSS., Competing Interests: Declaration of Competing Interest In the name of all the authors, I undersigned Piero Amodio, declares that no Author has any conflict of interest with the paper., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort., Method: Four hundred and sixty-one patients with cirrhosis (59 ± 10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124., Results: Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk., Conclusions: In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT 1 ) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT 1 . Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT 1 was influenced by limited education (<8 years) and advanced age (>80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT 1 (S-ANT 1 ) was obtained. An S-ANT 1 of <10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≥grade 2, and 126 as having MHE/grade 1 HE. This group had lower S-ANT 1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P < 0.001) and higher S-ANT 1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S-ANT 1 was lower than in MHE. Following receiver operating characteristic analysis (Youden's index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three-level score (0 for S-ANT 1 ≥15, 1 for 10 ≤ S-ANT 1 < 15, 2 for S-ANT 1 <10) was obtained. This score was correlated both to the psychometric HE score (P < 0.0001) and to electroencephalography (P = 0.007). By sample random split validation, both S-ANT 1 and its three-level score showed prognostic value regarding the 1-year risk of overt HE and death. No inflammatory bowel disease control had S-ANT <15., Conclusion: The S-ANT 1 is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017;66:198-208)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background & Aims: Chronic alcohol misuse, HCV infection and cirrhosis may cause cognitive alterations. The aim of the present study was to assess the influence of alcohol misuse, HCV infection and cirrhosis per se on the neuropsychological and electroencephalogram (EEG) profile and to evaluate the role of alcohol misuse and HCV infections as potential confounding factors in the detection of minimal hepatic encephalopathy., Methods: A comprehensive neuropsychological profile and EEG spectral parameters were obtained in six age-matched groups of 30 subjects each: (i) HCV-related hepatitis without cirrhosis, (ii) chronic alcohol abusers, (iii) patients with HCV-related cirrhosis, (iv) alcohol-related cirrhosis, (v) cirrhosis not related to alcohol or HCV and (vi) healthy subjects. Cirrhotic patients were matched for MELD score., Results: The factor 'cirrhosis' was associated with low Phonemic Verbal Fluency (PVF) and Difference between Trail Making Test B and A (TMT) (B-A) (P < 0.001). Chronic alcohol misuse was associated with low PVF, TMT (B-A), Memory with Interference Task at 10 (ITM 10) and 30 s (ITM 30) (all P < 0.05). An interaction was found between the factors 'cirrhosis', 'alcohol misuse' and tests (P < 0.01). HCV hepatitis reduced ITM 10 (P < 0.05), but no interaction was found between 'cirrhosis', 'HCV infection' and tests (P = 0.14). The EEG parameters were mainly influenced by 'cirrhosis' (P < 0.05), and EEG alterations were more pronounced in patients with alcoholic cirrhosis (P = 0.04)., Conclusions: Cirrhosis per se, chronic alcohol misuse and HCV infection were found to be associated with cognitive dysfunction. In patients with cirrhosis, the interaction with alcohol misuse further impinged on brain dysfunction., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: A slowed electroencephalogram (EEG) is indicative of the presence of hepatic encephalopathy (HE). Since HE is not reflected in the MELD score and is an important prognostic parameter, we assess the prognostic benefit of the addition of an EEG-based HE index to the MELD., Methods: Three hundred and ninety-two patients with cirrhosis underwent EEG and automated determination of its mean dominant frequency (MDF). MELD was calculated at the time of EEG recording. Patients were monitored for up to 18 months in relation to the occurrence of death/transplantation. The prognostic value of the stand-alone/combined MELD and MDF was calculated using standard survival analysis techniques. Patients transplanted for hepatic decompensation were considered dead on the day of transplantation, those transplanted for hepatocellular carcinoma were censored. The findings were validated using a split-sample technique (reference group: n = 256; test group: n = 136). During the follow-up period, 107 patients died/were transplanted for hepatic decompensation., Results: Both MELD and MDF predicted mortality on Kaplan-Meier analysis, and both were independent predictors of mortality on a Cox model. Based on Cox regression parameters, a novel prognostic index was devised, as follows: MELD-EEG = 0.087*MELD-0.306*MDF. On ROC curve analysis, MELD-EEG had higher prognostic accuracy in predicting 12- and 18-month mortality compared to MELD (P = 0.016 and P = 0.018, respectively). In addition, it had better sensitivity and reduced the misclassification rate for given levels of specificity. On validation, no significant differences were observed between the reference/test groups., Conclusions: The addition of an automatically obtained EEG-based index improves the prognostic accuracy of the MELD score., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE)., Methods: One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations., Results: On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohen's κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The prevalence of EEG abnormalities was significantly higher in patients with a history of HE. During follow-up, 10 patients died, 10 were transplanted and 29 had HE-related hospitalisations. Grade I HE (P = 0.004), abnormal EEG (P = 0.008) and abnormal PHES (P = 0.04) at baseline all predicted the subsequent occurrence of HE; CFF did not., Conclusion: CHE diagnosis probably requires a combination of clinical, neurophysiological and neuropsychological indices.

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.)

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.

Objective: To study the effect of hyperammonaemia on the wake electroencephalogram (EEG) of patients with cirrhosis and healthy volunteers., Methods: Wake EEGs were recorded prior to and after the induction of controlled hyperammonaemia in 10 patients with cirrhosis and 10 matched healthy volunteers., Results: At baseline, patients had higher ammonaemia than healthy volunteers and their dominant EEG rhythm was slower and of higher amplitude. Induced hyperammonaemia resulted in increased spectral power over most of the scalp in healthy volunteers and decreased frequency along the anterior-posterior midline in patients., Conclusions: These findings suggest different effects of hyperammonaemia on the wake EEG in relation to baseline/peak ammonia levels., Significance: The wake EEG is sensitive to hyperammonaemia and power-based EEG parameters may help in its neurophysiological definition, which, to date, has generally been based on EEG frequency indices., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

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.)

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.)

Details of 2 patients with cirrhosis and hepatic encephalopathy whose hobby or job were possibly responsible for a selectively enhanced performance in 1 neuropsychiatric test are reported. Clinicians should be alert to the fact that personal inclinations and habits may impinge on both neuropsychological and psychophysic performance, thus producing a mismatch between the results of different mental status tests. A prospective study with accurate history taking, use of comprehensive assessment protocols, and modeling/critical interpretation of the test results is required to confirm this hypothesis.

Attentional dysfunction, which influences overall cognitive productivity, is not well characterized in cirrhotic patients. The aim of this study was to clarify the features of covert visual attention orienting in cirrhotics without overt hepatic encephalopathy. One hundred consecutive cirrhotic patients and 40 controls were enrolled. Visual covert attention orienting was assessed by the Posner test, which evaluates the effect of a cue on visual reaction times. Patients were characterized by the number connection test (NCT) and electroencephalographic (EEG) spectral analysis. The severity of liver disease was graded using standard laboratory parameters and the Child-Pugh's classification. Fifty-five psychometric and EEG evaluations were performed in the follow-up of 17 patients to assess the relationship between the variations of psychometric and neurophysiological findings. NCT and quantified-EEG parameters (altered in 19% and 40% of cirrhotic patients, respectively) were linked to each other and to the severity of liver disease. The Posner test showed a delay of visual reaction times in class B-C cirrhotic patients. Reaction times were correlated with ammonia and EEG parameters. The effect of the cue was higher in cirrhotic patients than in controls, particularly in the invalid position. This study suggests that cirrhotic patients have a reduced activity rate and reduced capacity to disengage attention previously focused on a cue. Such alterations are linked to NCT and EEG findings.

The attention system in patients with liver cirrhosis has not yet been fully investigated. We therefore studied visual attention orienting in cirrhotic patients without overt hepatic encephalopathy. Seventy cirrhotic patients without overt hepatic encephalopathy (aged 57 +/- 10 yr., mean +/- s.d.) and 55 controls (aged 49 +/- 12 yr.) were enrolled. Visual attention orienting was evaluated by a computerized neuropsychological test. The Reitan A test, commonly used to detect subclinical hepatic encephalopathy, was used to evaluate mental performance. Psychometric test scores were reduced in cirrhotics compared to controls (attention test: neutral condition = 495 +/- 149 vs. 401 +/- 98 msec; valid condition = 434 +/- 110 vs. 398 +/- 84 msec; invalid condition = 485 +/- 146 vs. 392 +/- 110 msec; p < 0.001; Reitan A test = 52 +/- 20 vs. 35 +/- 11 sec., p < 0.001). The attention effect of the cue was found both in controls and cirrhotics; however, it was significantly higher in cirrhotics than in controls (61 +/- 111 vs. 33 +/- 41 msec; p < 0.002). The attention effect was directly correlated with Reitan A test (r = 0.23, p = 0.05) in cirrhotics. In conclusion, in cirrhotic patients without overt hepatic encephalopathy, visual attention orienting was present and focusing to an indexed location had a higher effect on reaction time compared to controls, possibly because of reduced basal arousal.