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Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits, disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning light treatment. The aim of the present pilot study was to test the effect of morning light treatment in a group of 13 well-characterized patients with PBC [all females; (mean ± SD) 53 ± 10 years]. Six healthy individuals (4 females, 57 ± 14 years) and 7 patients with cirrhosis (1 female, 57 ± 12 years) served as controls and diseased controls, respectively. At baseline, all participants underwent an assessment of quality of life, diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness, and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day course of morning bright light treatment, immediately after getting up (light box, 10,000 lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline, both patients with PBC and patients with cirrhosis had significantly worse subjective sleep quality compared to controls. In patients with PBC, light treatment resulted in an improvement in subjective sleep quality and a reduction in daytime sleepiness. In addition, both their sleep onset and get-up time were significantly advanced. Finally, the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after light administration but post-hoc comparisons were not significant in any of the groups. In conclusion, a brief course of morning bright light treatment had positive effects on subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This unobtrusive, side-effect free, non-pharmacological treatment is worthy of further study.

BACKGROUND & AIMS Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. METHODS Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail-making test A (TMT-A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). RESULTS Both patients with and without OHE history improved in TMT-A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT-A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. CONCLUSIONS HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well-characterized group of patients with cirrhosis.

Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation.

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.

UNLABELLED Hyperammonaemia/mild hepatic encephalopathy (HE) can be simulated by the oral administration of a so-called amino acid challenge (AAC). This study sought to assess the effects of the AAC alone and in combination with either ammonia-lowering [L-ornithine-L-aspartate (LOLA)] or vigilance-enhancing medication (caffeine). Six patients with cirrhosis (5 males; 61.3 ± 9.2 years; 5 Child A, 1 Child B) and six healthy volunteers (5 males; 49.8 ± 10.6 years) were studied between 08:00 and 19:00 on Monday of three consecutive weeks. The following indices were obtained: hourly capillary ammonia, hourly subjective sleepiness, paper & pencil/computerized psychometry and wake electroencephalography (EEG) at 12:00, i.e. at the time of the maximum expected effect of the AAC. RESULTS On average, patients had worse neuropsychological performance and slower EEG than healthy volunteers in all conditions but differences did not reach significance. In healthy volunteers, the post-AAC increase in capillary ammonia levels was contained by both the administration of LOLA and of caffeine (significant differences between 10:00 and 14:00 h). The administration of caffeine also resulted in a reduction in subjective sleepiness and in the amplitude of the EEG on several frontal/temporal-occipital sites (p

Background Since direct-acting antivirals (DAAs) have been approved for the treatment of hepatitis C virus (HCV) infection, a small series of patients with new-onset neuropsychiatric alterations have been referred to us. We therefore set out to study neuropsychiatric function in relation to DAAs prospectively. Methods Ten patients with cirrhosis and 12 post-liver transplant (post-LT) patients were enrolled. All underwent wake electroencephalography (EEG) and a neuropsychological evaluation (paper and pencil battery, simple/choice reaction times, working memory task) at baseline, at the end of treatment with DAAs and after 6 months. At the same time points, full blood count, liver/kidney function tests, quantitative HCV RNA, ammonia and immunosuppressant drug levels were obtained, as appropriate. Results Patients with cirrhosis were significantly older than post-LT patients (65±12 vs 55±7 years; P

Background Providing structured information for the understanding of hepatic encephalopathy (HE) might be relevant to the prevention and management of the syndrome. The aim of our study was to design a brief, structured educational intervention and evaluate its usefulness in preventing HE-related hospitalisation over time. Methods Thirty-nine cirrhotic outpatients with a history of HE were enrolled and randomly assigned to an intervention (group A; n=20) or control group (group B; n=19). All of them underwent evaluation of HE (clinical and quantitative neuropsychiatric assessment) and completed the Questionnaire on the Awareness of Encephalopathy. A 15 min educational session was then provided to patients in group A, including basic information on the pathophysiology, hygienic and medical management of HE. Results No demographic/clinical differences were observed at baseline between the two groups. Similarly, there were no significant differences in HE-related information available at baseline between the two groups; knowledge of HE was limited in both. The intervention was highly effective in increasing patients’ understanding of treatment of the condition (from 5% to 80%). The educational intervention also reduced the risk of developing an episode of HE over a period of 12 months. Conclusion The educational intervention confirmed the poor knowledge of patients with previous HE about their condition, served as a tool to increase patients’ awareness, and minimised HE-related readmission rates over a period of 1 year.

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.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.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.In conclusion, an MMSE 26 identifies older patients with cirrhosis who are more prone to manifest HE signs.

Despite the impact of hepatic encephalopathy on quality of life and prognosis, easily administered tests for its diagnosis are still lacking.To assess the usefulness of the Scan package, a three-level-difficulty computerised reaction time test, to diagnose varying degrees of hepatic encephalopathy.Sixty-one cirrhotic patients underwent clinical evaluation, paper-and-pencil psychometry and the Scan package; 32 healthy controls served as reference.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, p0.0001; test: F(2,154)=277, p0.0001; group×test: F(6,154)=7, p0.0001], with different parts being more/less sensitive to varying degrees of encephalopathy.The Scan package seems useful for the diagnosis of hepatic encephalopathy and covers a considerable portion of its spectrum of severity.