The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis.

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.

Evaluation of individual cognitive remediation therapy (CRT) for the treatment of young people with anorexia nervosa.

PURPOSE: Research suggests that there are cognitive inefficiencies underlying Anorexia Nervosa (AN), with CRT showing promise in improving these inefficiencies in adults. This area has yet to be explored in a younger population. The aim of this study was to evaluate the use of CRT for young people. METHODS: A within-subjects design was used to compare the performance of children and adolescents with AN on several neuropsychological measures administered before and after a course of CRT. RESULTS: Ninety-two female participants diagnosed with AN aged between 11 and 17 (M = 14.8, SD = 1.6), all receiving treatment at a specialist inpatient unit. The assessment consisted of the Rey-Osterrieth Complex Figure test (ROCFT), the Behaviour Rating Inventory of Executive Function-Self-Report (BRIEF-SR), and the D-KEFS Colour-Word Interference Test (CWT). Repeated-measures t tests were used to analyse the ROCFT and BRIEF-SR data. There was a significant improvement in Central Coherence Index (p < .001), Immediate Recall (p < .001), Shift (p < .001) Cognitive Shift (p = 002), Behavioural shift (p < .001), Emotional Control (p < .001), Working Memory (p = .001), Plan/Organize (p < .001), Monitor (p = .001) BRI (p < .001), MI (p = .001), and GEC (p < .001). On the D-KEFS CWT, a repeated-measure Wilcoxon signed-rank test revealed a significant improvement in Error Rate (p = .019) and a repeated-measures t test revealed a significant improvement in time taken (p < .001). CONCLUSIONS: Results suggest that CRT for children and adolescents with AN could strengthen specific cognitive domains.

Vigilance and wake EEG architecture in simulated hyperammonaemia: a pilot study on the effects of L-Ornithine-L-Aspartate (LOLA) and caffeine.

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 < 0.05; paired t-test). Changes in ammonia levels, subjective sleepiness and the EEG in the three conditions were less obvious in patients. In conclusion, both LOLA and caffeine contained the AAC-induced increase in capillary ammonia, especially in healthy volunteers. Caffeine also counteracted the AAC effects on sleepiness/EEG amplitude. The association of ammonia-lowering and vigilance-enhancing medication in the management of HE is worthy of further study.

Sleep-wake abnormalities in patients with cirrhosis.

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.

Effect of Morning Light Glasses and Night Short-Wavelength Filter Glasses on Sleep-Wake Rhythmicity in Medical Inpatients.

Sleep and circadian rhythm disorders are common amongst medical inpatients. They are caused by a mixture of factors, including noise, loss of habitual daily routines, and abnormal exposure to light, which tends to be insufficient in the day and too high at night. The aim of the present study was to test the efficacy of morning light therapy plus night short-wavelength filter glasses on sleep quality/timing, and sleepiness/mood over the daytime hours, in a group of well-characterized medical inpatients. Thirty-three inpatients were enrolled and randomized (2:1) to either treatment (n = 22; 13 males, 48.3 ± 13.3 years) or standard of care (n = 11; 8 males, 56.9 ± 12.9 years). On admission, all underwent a baseline assessment of sleep quality/timing and diurnal preference. During hospitalization they underwent monitoring of sleep quality/timing (sleep diaries and actigraphy), plus hourly assessment of sleepiness/mood during the daytime hours on one, standard day of hospitalization. Patients in the treatment arm were administered bright light through glasses immediately after awakening, and wore short-wavelength filter glasses in the evening hours. Treated and untreated patients were comparable in terms of demographics, disease severity/comorbidity, diurnal preference and pre-admission sleep quality/timing. During hospitalization, sleep diaries documented a trend for a lower number of night awakenings in treated compared to untreated patients (1.6 ± 0.8 vs. 2.4 ± 1.3, p = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 ± 00:35 vs. 07:44 ± 00:40, p = 0.008). Sleepiness during a standard day of hospitalization, recorded between 09:30 and 21:30, showed physiological variation in treated compared to untreated patients, who exhibited a more blunted profile. The level of sleepiness reported by treated patients was lower over the 09:30-14:30 interval, i.e., soon after light administration (interaction effect: F = 2.661; p = 0.026). Mood levels were generally higher in treated patients, with statistically significant differences over the 09:30-14:30 time interval, i.e., soon after light administration (treatment: F = 5.692, p = 0.026). In conclusion, treatment with morning bright light and short-wavelength filter glasses in the evening, which was well tolerated, showed positive results in terms of sleepiness/mood over the morning hours and a trend for decreased night awakenings.

Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study.

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.

Changes in Accident & Emergency Visits and Return Visits in Relation to the Enforcement of Daylight Saving Time and Photoperiod.

Daylight saving time (DST) is a source of circadian disruption impinging on millions of people every year. Our aim was to assess modifications, if any, in the number, type, and outcome of Accident & Emergency (A&E) visits/return visits over the DST months. The study included 366,527 visits and 84,380 return visits to the A&E of Padova hospital (Northern Italy) over 3 periods between the years 2007 and 2016: period 1 (2 weeks prior to DST to 19 weeks after), period 2 (2 weeks prior to the return to "winter time" to 4 weeks after), and period 3 (5 consecutive non-DST weeks). For each A&E visit/return visit, information was obtained on triage severity code, main medical complaint, and outcome. Data were aggregated by day, cumulated over the years, and analyzed by generalized Poisson models. Generalized additive models for Poisson data were then used to include photoperiod as an additional covariate. An increase in A&E visits and return visits (mostly white codes, resulting in discharges) was observed a few weeks after the enforcement of DST and was significant over most weeks of period 1 (increase of ≈30 [2.8%] visits and ≈25 [10%] return visits per week per year). After the return to winter time, a decrease in absolute number of return visits was observed (mostly white codes, resulting in discharges), which was significant at weeks 3 and 4 of period 2 (decrease of ≅25 [10%] return visits per week per year). When photoperiod was taken into account, changes in A&E visits (and related white codes/discharges) were no longer significant, while changes in return visits (and related white codes/discharges) were still significant. In conclusion, changes in A&E visits/return visits were observed in relation to both DST and photoperiod, which are worthy of further study and could lead to modifications in A&E organization/staffing.

The use of cognitive remediation therapy on a child adolescent eating disorder unit: Patients and therapist perspectives.

Cognitive remediation therapy (CRT) is an intervention for anorexia nervosa (AN) that focuses on ameliorating the neuropsychological inefficiencies that underlie the illness. The current literature has reported promising results regarding its efficacy as an intervention for AN. However, there is a scarcity of studies considering the implementation of CRT in a child and adolescent population. This article describes an individual CRT therapy programme for children and adolescents with AN delivered on an inpatient unit for eating disorders. It considers the therapeutic process including the differing viewpoints of the patients and the therapists. The article concludes that CRT can be viewed as an engaging therapeutic intervention that could be useful as an additional treatment for AN.

An educational tool for the prophylaxis of hepatic encephalopathy.

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.

Sleep-Wake Profile in Dementia with Lewy Bodies, Alzheimer's Disease, and Normal Aging.

BACKGROUND: Alterations of the sleep-wake cycle are common features of neurodegenerative dementia. OBJECTIVES: To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls. METHODS: 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries. RESULTS: Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p < 0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score = RBD+: 5.2±3.7; RBD-: 2.1±3.2, p = 0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls. DISCUSSION: RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

Neuropsychiatric performance and treatment of hepatitis C with direct-acting antivirals: a prospective study.

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<0.05). Neuropsychological performance and wake EEG were comparable in the two groups at baseline. At the end of a course of treatment with DAAs, a significant slowing in choice reaction times and in the EEG (increased relative delta power) was observed in patients with cirrhosis, which resolved after 6 months. In contrast, no significant changes over time were observed in the neuropsychiatric performance of post-LT patients. No significant associations were observed between neuropsychiatric performance and stand-alone/combined laboratory variables. CONCLUSION: Some degree of neuropsychiatric impairment was observed in relation to treatment with DAAs in patients with cirrhosis, but not in post-LT patients, suggesting that the former may be sensitive to mild DAA neurotoxicity.

Hepatic encephalopathy and sleepiness: an interesting connection?

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.

The influence of environmental factors on sleep quality in hospitalized medical patients.

INTRODUCTION: Sleep-wake disturbances are common in hospitalized patients but few studies have assessed them systematically. The aim of the present study was to assess sleep quality in a group of medical inpatients, in relation to environmental factors, and the switch to daylight-saving time. METHODS: Between March and April 2013, 118 consecutive inpatients were screened and 99 (76 ± 11 years; hospitalization: 8 ± 7 days) enrolled. They slept in double or quadruple rooms, facing South/South-East, and were qualified as sleeping near/far from the window. They underwent daily sleep assessment by standard questionnaires/diaries. Illuminance was measured by a luxmeter at each patient's eye-level, four times per day. Noise was measured at the same times by a phonometer. Information was recorded on room lighting, position of the rolling shutters and number/type of extra people in the room. RESULTS: Compliance with sleep-wake assessment was poor, with a range of completion of 2-59%, depending on the questionnaires. Reported sleep quality was sufficient and sleep timing dictated by hospital routine; 33% of the patients reported one/more sleepless nights. Illuminance was generally low, and rolling shutters half-way down for most of the 24 h. Patients who slept near the window were exposed to more light in the morning (i.e., 222 ± 72 vs. 174 ± 85 lux, p < 0.05 before the switch; 198 ± 72 vs. 141 ± 137 lux, p < 0.01 after the switch) and tended to sleep better (7.3 ± 1.8 vs. 5.8 ± 2.4 on a 1-10 scale, before the switch, p < 0.05; 7.7 ± 2.3 vs. 6.6 ± 1.8, n.s. after the switch). Noise levels were higher than recommended for care units but substantially comparable across times/room types. No significant differences were observed in sleep parameters before/after the switch. CONCLUSION: Medical wards appear to be noisy environments, in which limited attention is paid to light/dark hygiene. An association was observed between sleep quality and bed position/light exposure, which is worthy of further study.

Covert hepatic encephalopathy: does the mini-mental state examination help?

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.

Simple tools for complex syndromes: a three-level difficulty test for hepatic encephalopathy.

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.