Evolution of hepatic encephalopathy over time: ecological data from a tertiary referral centre for hepatology.

OBJECTIVES: Few data on hepatic encephalopathy (HE) over time are available, thus our aim was to study its evolution in patients with varying degree of HE on first assessment. METHODS: Eighty-six patients with cirrhosis (age = 58 ± 11 years; males = 72) were evaluated 2-10 times for liver transplantation selection purposes, differential diagnosis or treatment optimization. The presence/severity of HE was assessed by clinical and neuropsychiatric indices [ Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalography (EEG)] and the severity of liver disease by the Model for End-Stage Liver Disease (MELD) score. Treatment was instituted/modified after each evaluation. RESULTS: Amongst 23 unimpaired patients, 56/6% remained unimpaired, 35/3% developed covert HE, 9/0% developed overt HE on second/third evaluation. Amongst 32 patients with covert HE, 25/10% became unimpaired, 44/19% remained covert, 31/13% developed overt HE. Finally, amongst 32 patients with overt HE, 19/16% became unimpaired, 25/13 % became covert and 56/25% remained overt. PHES results improved in patients with overt HE and EEG worsened over time (despite remaining normal) in unimpaired patients. In patients with multiple evaluations, HE evolution was manifold and difficult to predict. CONCLUSIONS: HE evolution over time is variable and largely dependent on HE history/management. These data support the concept that HE is an essentially reversible condition.

Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3.

PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER3 4, PER3 5; rs228697 SNP: PER3 C, PER3 G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER3 4 /PER3 4 and PER3 5 /PER3 5 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19 PER3 4 /PER3 4 and 11 PER3 5 /PER3 5 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3 G variant and morningness (OR = 2.10), and between the PER3 G-PER3 4 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms between PER3 5 /PER3 5 and PER3 4 /PER3 4 subjects at baseline. After light administration, PER3 4 /PER3 4 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

Recent developments in the diagnosis and treatment of covert/minimal hepatic encephalopathy.

The terms minimal hepatic encephalopathy and covert hepatic encephalopathy are defined. Clinical assessment is unreliable and both require the use of diagnostic tools. Of these, psychometric tests are the most widely used. They require proper standardization and may be biased by patient cooperation or lack thereof. The measure of the critical flicker frequency and of the electroencephalogram, possibly quantified, are also useful. The alteration of any of them is not strictly parallel in size and may vary from patient to patient. When possible, the use of multiple measures might increase diagnostic reliability. These functional measures should be interpreted within the clinical/biochemical profile of the patient to exclude other disorders. A flow chart for treatment is proposed on the basis of current knowledge.

The self-morningness/eveningness (Self-ME): An extremely concise and totally subjective assessment of diurnal preference.

The assessment of diurnal preference, or the preferred timing of sleep and activity, is generally based on comprehensive questionnaires such as the Horne-Östberg (HÖ). The aim of the present study was to assess the reliability of a subject's self-classification as extremely morning (Self-MM), more morning than evening (Self-M), more evening than morning (Self-E) or extremely evening (Self-EE) type, based on the last question of the HÖ (Self-ME). A convenience sample of 461 subjects [23.8 ± 4.7 years; 322 females] completed a full sleep-wake assessment, including diurnal preference (HÖ), night sleep quality (Pittsburgh Sleep Quality Index, PSQI), daytime sleepiness (Karolinska Sleepiness Scale, KSS), and habitual sleep-wake timing (12 d sleep diaries; n = 296). Significant differences in HÖ total score were observed between Self-ME classes, with each class being significantly different from neighboring classes (p < 0.0001). Significant differences in sleep-wake timing (bed time, try to sleep and sleep onset, wake up, and get up time) were observed between Self-ME classes. Such differences were maintained when sleep-wake habits were analysed separately on work and free days, and also in a smaller group of 67 subjects who completed the Self-ME as a stand-alone rather than as part of the original questionnaire. Significant differences were observed in the time-course of subjective sleepiness by Self-ME class in both the large and the small group, with Self-MM and Self-M subjects being significantly more alert in the morning and sleepier in the evening hours compared with their Self-E and Self-EE counterparts. Finally, significant differences were observed in night sleep quality between Self-ME classes, with Self-EE/Self-E subjects sleeping worse than their Self-MM/Self-M counterparts, and averaging just over the abnormality PSQI threshold of 5. In conclusion, young, healthy adults can define their diurnal preference based on a single question (Self-ME) in a way that reflects their sleep-wake timing, their sleepiness levels over the daytime hours, and their night sleep quality. Validation of the Self-ME across the decades and in diseased populations seems worthy.

Sleep and circadian rhythms in hospitalized patients with decompensated cirrhosis: effect of light therapy.

Patients with liver cirrhosis often exhibit sleep-wake abnormalities, which are, at least to some extent, circadian in origin. A relatively novel non-pharmacological approach to circadian disruption is appropriately timed bright light therapy. The aims of this pilot study were to investigate sleep-wake characteristics of a well-characterized population of inpatients with cirrhosis, and to evaluate the efficacy of bright light therapy in the hospital setting. Twelve consecutive inpatients with cirrhosis underwent complete sleep-wake assessment, to include qualitative and semi-quantitative (actigraphic) indices of night-time sleep quality, daytime sleepiness, diurnal preference, habitual sleep timing, quality of life, mood and circadian rhythmicity [i.e. urine collections for measurement of the melatonin metabolite 6-sulphatoxymelatonin (aMT6s)]. Patients showed extremely impaired night sleep quality (Pittsburg Sleep Quality Index global score: 16.3 ± 2.1) and daytime sleepiness was common (Epworth Sleepiness Scale: 8.3 ± 3.2). Five patients were randomly assigned to a single room in which lighting was controlled in relation to timing, spectral composition and intensity (lights on at 06:30 and off at 22:30, blue-enriched, more intense light in the morning, red-enriched, less intense light in the afternoon/evening); the others stayed in identical rooms with standard lighting. Sleep diaries revealed poor sleep quality, prolonged sleep latency (67 ± 138 min) and a reduced sleep efficiency (69 ± 21%). These features were confirmed by actigraphy (sleep efficiency: 71 ± 13%; fragmentation index: 55 ± 15%). Quality of life was globally impaired, and mood moderately depressed (Beck Depression Inventory: 19.4 ± 7.9). Seven patients underwent serial urine collections: no circadian aMT6s rhythm was detected in any of them, neither at baseline, nor during the course of hospitalization in either room (n = 4). In conclusion, sleep and circadian rhythms in hospitalized, decompensated patients with cirrhosis are extremely compromised. Treatment with bright light therapy did not show obvious, beneficial effects, most likely in relation to the severity of disturbance at baseline.

Acute hyperammonaemia induces a sustained decrease in vigilance, which is modulated by caffeine.

UNLABELLED: Hyperammonaemia is observed after prolonged, intense exercise, or in patients with hepatic failure. In the latter, it is associated with a set of neurological and psychiatric abnormalities termed hepatic encephalopathy. THE AIMS OF OUR STUDY WERE: 1. to measure vigilance in a condition of induced hyperammonaemia; 2. to assess whether caffeine modulates the effects of hyperammonaemia on vigilance, if any. Ten healthy volunteers (28.5 ± 5 years; 5 males) underwent three experimental sessions consisting of two-hourly measurements of capillary ammonia, subjective sleepiness (Karolinska Sleepiness Scale) and vigilance (Psychomotor Vigilance Task, PVT), in relation to the intake of breakfast (+/-coffee), an amino acid mixture which induces hyperammonaemia (amino acid challenge; AAC), and AAC+coffee (only for participants who had coffee with their standard breakfast). The AAC resulted in: 1. the expected increase in capillary ammonia levels, with highest values at approximately 4 h after the administration; 2. a significant increase in subjective sleepiness ratings; 3. a sustained increase in PVT-based reaction times. When caffeine was administered after the AAC, both subjective sleepiness and the slowing in RTs were significantly milder than in the AAC-only condition. In conclusion, acute hyperammonaemia induces an increase in subjective sleepiness and a sustained decrease in vigilance, which are attenuated by the administration of a single espresso coffee.

Insight into the relationship between brain/behavioral speed and variability in patients with minimal hepatic encephalopathy.

OBJECTIVE: Intra-individual variability (IIV) of response reaction times (RTs) and psychomotor slowing were proposed as markers of brain dysfunction in patients with minimal hepatic encephalopathy (MHE), a subclinical disorder of the central nervous system frequently detectable in patients with liver cirrhosis. However, behavioral measures alone do not enable investigations into the neural correlates of these phenomena. The aim of this study was to investigate the electrophysiological correlates of psychomotor slowing and increased IIV of RTs in patients with MHE. METHODS: Event-related potentials (ERPs), evoked by a stimulus-response (S-R) conflict task, were recorded from a sample of patients with liver cirrhosis, with and without MHE, and a group of healthy controls. A recently presented Bayesian approach was used to estimate single-trial P300 parameters. RESULTS: Patients with MHE, with both psychomotor slowing and higher IIV of RTs, showed higher P300 latency jittering and lower single-trial P300 amplitude compared to healthy controls. In healthy controls, distribution analysis revealed that single-trial P300 latency increased and amplitude decreased as RTs became longer; however, in patients with MHE the linkage between P300 and RTs was weaker or even absent. CONCLUSIONS: These findings suggest that in patients with MHE, the loss of the relationship between P300 parameters and RTs is related to both higher IIV of RTs and psychomotor slowing. SIGNIFICANCE: This study highlights the utility of investigating the relationship between single-trial ERPs parameters along with RT distributions to explore brain functioning in normal or pathological conditions.

Ammonia-related changes in cerebral electrogenesis in healthy subjects and patients with cirrhosis.

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.

A patients' and caregivers' perspective on hepatic encephalopathy.

Awareness of previous hepatic encephalopathy (HE) and compliance with treatment can probably reduce HE recurrence. The aim of this study was to assess the degree of awareness of previous HE and its treatment in a group of cirrhotic patients and their caregivers. Thirty-five cirrhotic patients with a history of HE and their caregivers (n = 31) were enrolled. Patients underwent evaluation of HE (clinical, psychometry and electroencephalography), quality of life (SF36 questionnaire), and awareness of HE/treatment on an ad hoc questionnaire (QAE). Caregivers underwent the QAE plus the Caregiver Burden Inventory. On the day of study, 7 patients were unimpaired, 8 had minimal and 20 low-grade overt HE. Of the patients, 37 % were aware of previous HE, 6 % of being on treatment and 6 % understood treatment effects. Of the caregivers, 48 % were aware of previous HE, 6 % of their relative being on treatment and 6 % understood treatment effects. Significant correlations were observed between neuropsychiatric status/linear HE indices and both the patients' quality of life and the caregivers' burden. In conclusion, HE awareness was poor in both patients and caregivers, most likely in relation to insufficient/inadequate provision of information.

Neuropsychological tools in hepatology: a survival guide for the clinician.

Neuropsychological assessment has three main applications in clinical hepatology: (i) to detect, grade and monitor liver failure-related cognitive alterations in end-stage liver disease (hepatic encephalopathy), (ii) to substantiate complaints of attention or concentration difficulties in patients with non-cirrhotic chronic hepatitis C viral infection, and (iii) to screen patients who are being considered for liver transplantation for early signs of dementia. However, there is limited agreement on how cognitive assessment should be conducted in these patients, and how results should be interpreted and used to implement clinical decisions. In this review, we summarize the available literature on neuropsychological dysfunction in patients with cirrhosis and with chronic hepatitis C viral infection and provide some guidance on how to utilize neuropsychological assessment in practice.

Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence.

The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.

Neurological complications after orthotopic liver transplantation.

BACKGROUND: The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. AIM: To review present knowledge on the neurological complications of orthotopic liver transplantation. METHODS: The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. RESULTS AND CONCLUSIONS: The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation.

Analysis of EEG tracings in frequency and time domain in hepatic encephalopathy.

Spectral EEG analysis in hepatic encephalopathy (HE) is usually performed disregarding the effect of epoch length, statistical errors and equipment noise. A study on these items was carried out. In addition, spectral analysis and a new analysis, performed in time domain, were compared in the assessment of HE. The EEG tracings of 73 cirrhotic patients with HE were analyzed. Artifact-free periods of about 1 min were selected. Equipment noise was measured by short-circuiting all the electrodes. The equipment noise was notable below 1.5 Hz; the best epoch length was 4s and the statistical errors were minimal for the band with the highest relative power. Nineteen per cent of the tracings were unstable. The spectral values were found to be related to liver function and to the degree of HE, whereas the relationship with psychometric variables was poor. The indexes computed by time-domain analysis were found to be better related to psychometric findings. We have provided information on the optimisation of spectral EEG analysis and presented a time-domain analysis giving results related to psychometric tests and liver function.

Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic patients.

Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 +/- 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test-Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child-Pugh score: 18% of patients were Child-Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child-Pugh score. Psychometric performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.