Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) patients frequently describe sleep problems. The cause remains unclear and treatment is challenging. Restless leg syndrome (RLS) is a common sleep disorder. In this study, we systematically screened PBC patients for the presence of RLS. METHODS: Participants were recruited from our specialist PBC clinical service. Subjects completed the International Restless Leg Syndrome Study Group rating scale (IRLSS) a validated measure of the presence of RLS and its severity. Those fulfilling diagnostic criteria for RLS underwent foot actigraphy (CamNtech Actiwatch) to objectively assess periodic limb movement index (PLMI) (normal <5/h). RESULTS: Restless leg syndrome was assessed in 42 consecutive early stage PBC patients. Twelve (29%) fulfilled the IRLSS criteria for RLS. Scores were significantly higher in PBC compared to controls (P = 0.005). Twenty-four patients were further assessed with foot actigraphy for 3 nights (12 with subjective RLS symptoms and 12 with no RLS symptoms). Thirteen of twenty-four subjects had PLMI >5/h and four had moderate or severe PLMI >15/h. All moderate or severe PLMI subjects had subjective symptoms of moderate or severe RLS. No patients had PLMI >10 in the absence of RLS symptoms. Eleven PBC patients with symptomatic RLS went on to have treatment. Sixty-three per cent had clear benefit in restless leg symptoms and associated symptoms of fatigue. CONCLUSION: Restless leg syndrome symptoms are common and underdiagnosed in PBC patients. RLS represents a potential therapy for PBC patients with daytime sleepiness, fatigue and unpleasant lower limb symptoms and this is worthy of further studies in larger cohorts.

Autonomic symptoms are common and are associated with overall symptom burden and disease activity in primary Sjogren's syndrome.

OBJECTIVES: To determine the prevalence of autonomic dysfunction (dysautonomia) among patients with primary Sjögren's syndrome (PSS) and the relationships between dysautonomia and other clinical features of PSS. METHODS: Multicentre, prospective, cross-sectional study of a UK cohort of 317 patients with clinically well-characterised PSS. Symptoms of autonomic dysfunction were assessed using a validated instrument, the Composite Autonomic Symptom Scale (COMPASS). The data were compared with an age- and sex-matched cohort of 317 community controls. The relationships between symptoms of dysautonomia and various clinical features of PSS were analysed using regression analysis. RESULTS: COMPASS scores were significantly higher in patients with PSS than in age- and sex-matched community controls (median (IQR) 35.5 (20.9-46.0) vs 14.8 (4.4-30.2), p<0.0001). Nearly 55% of patients (vs 20% of community controls, p<0.0001) had a COMPASS score >32.5, a cut-off value indicative of autonomic dysfunction. Furthermore, the COMPASS total score correlated independently with EULAR Sjögren's Syndrome Patient Reported Index (a composite measure of the overall burden of symptoms experienced by patients with PSS) (ß=0.38, p<0.001) and disease activity measured using the EULAR Sjögren's Syndrome Disease Activity Index (ß=0.13, p<0.009). CONCLUSIONS: Autonomic symptoms are common among patients with PSS and may contribute to the overall burden of symptoms and link with systemic disease activity.

Falls and fall-related injury are common in older people with chronic liver disease.

BACKGROUND: Improved survival with chronic liver disease (CLD) and increased incidence in the older has led to a rapidly expanding population which faces similar "geriatric syndromes" as the general population. With risk factors such as autonomic dysfunction, cognitive impairment, and muscle abnormalities in CLD it is expected that falls and injury will be common. AIM: To determine prevalence of falls and injury in chronic liver disease and to identify potential modifiable fall associations. METHODS: Falls prevalence was estimated by providing patients aged ≥ 65 years with CLD a falls data collection tool, via the post or in the clinic. A younger CLD cohort and age-matched and sex-matched community controls was used for comparison. A sub-group underwent multidisciplinary falls assessment to identify modifiable fall associations. RESULTS: Falls were significantly more common in older people with CLD (47 % in previous year) than in controls; incidence of injury did not differ. Regression identified orthostatic symptoms, lower-limb strength, and fear of falling as being independently associated with falls in CLD. Those who had fallen had significantly greater difficulty with daily activities. CONCLUSION: Falls are prevalent in older people with CLD, and are potentially preventable with multifactorial intervention. Services must prepare for expansion in the older CLD population; here we demonstrate how this expansion may affect falls services and provide a potential therapeutic target.

Lower ambulatory blood pressure in chronic fatigue syndrome.

OBJECTIVE: To examine blood pressure circadian rhythm in subjects with chronic fatigue syndrome (CFS) and appropriate normal and fatigued controls to correlate parameters of blood pressure regulation with perception of fatigue in an observational cohort study. The cause of CFS remains unknown and there are no effective treatments. METHODS: To address whether inactivity was a confounder, we performed a 24-hour ambulatory blood pressure monitoring in the following three subject groups: 1) CFS patients (Fukuda Diagnostic criteria) (n = 38); 2) normal controls (n = 120); and 3) a fatigue comparison group (n = 47) with the autoimmune liver disease primary biliary cirrhosis (PBC). All patients completed a measure of fatigue severity (Fatigue Impact Scale). In view of the different demographics between the patient groups, patients were age- and sex-matched on a case-by-case basis to normal controls and blood pressure parameters were compared. RESULTS: Compared with the control population, the CFS group had significantly lower systolic blood pressure (p < .0001) and mean arterial blood pressure (p = .0002) and exaggerated diurnal variation (p = .009). There was a significant inverse relationship between increasing fatigue and diurnal variation of blood pressure in both the CFS and PBC groups (p < .05). CONCLUSION: Lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with CFS. We would suggest the need for a randomized, placebo-controlled trial of agents to increase blood pressure such as midodrine in CFS patients with an autonomic phenotype.

Impedance cardiography: a role in vasovagal syncope diagnosis?

BACKGROUND: vasovagal syncope is the most common cause of syncope in all age groups, with diagnosis usually based on history, examination and basic investigations to exclude alternative causes of syncope. Where doubt exists, the head-up tilt (HUT) test is used for diagnosis but is time consuming and lacks a gold standard to accurately assess sensitivity and specificity. Alternative methods of diagnosing vasovagal syncope would thus be useful. OBJECTIVE: to investigate the potential for impedance cardiography (ICG)-derived haemodynamic measures to predict HUT test outcome in unexplained syncope. DESIGN: prospective controlled study. SUBJECTS: eighty-six patients with unexplained syncope and 43 non-syncopal controls. METHODS: all subjects underwent continuous heart rate, blood pressure and ICG measurements during 10 min supine rest and during HUT. Vasovagal syncope was diagnosed when patients experienced symptom reproduction with concomitant haemodynamic derangements. RESULTS: during rest prior to HUT, the syncopal group had higher mean heart rate (P = 0.0008) and lower baroreceptor effectiveness index (P < 0.0001) compared to non-syncopal controls. On comparing patients who presented with unexplained syncope who subsequently had a positive HUT (therefore a diagnosis of vasovagal syncope 55 [64%]; mean age 47 years, range 17-85) to those having a negative tilt test (n = 31; mean age 47 years, range 17-88), there were no significant differences found in cardiovascular or autonomic parameters prior to HUT. A predictive ROC curve model at a 85% threshold allowed using cardiac index (CI), end-diastolic index (EDI) and left ventricular work index (LVWI) would identify those who would have a positive HUT from baseline cardiovascular measurements (CI >3.5, EDI > 77, LVWI >4.7) with 93% sensitivity and 17% specificity. CONCLUSION: supine haemodynamic measures derived from transthoracic ICG can simply, non-invasively and sensitively differentiate HUT-positive patients from those with negative tilt tests. Further work is needed, particularly in older patients, before this technique can be used in clinical practice.

Fatigue and autonomic dysfunction in non-alcoholic fatty liver disease.

BACKGROUND: Fatigue is a significant symptom in nonalcoholic fatty liver disease (NAFLD) that impacts upon quality of life and is unrelated to liver disease severity. We examined the relationship between parameters of blood pressure regulation with perception of fatigue in NAFLD. METHODS: Thirty-four non-diabetic subjects with histologically proven, non-cirrhotic NAFLD (26 [77%] males and 8 [23%] females) (mean +/- SD age 54 +/- 11) and 34 age, sex and BMI matched non-diabetic controls underwent subjective and objective evaluation of cardiovascular autonomic function (24 h blood pressure and head up tilt testing). All subjects completed the fatigue impact scale. RESULTS: The NAFLD group had significantly higher autonomic symptom burden assessed using the orthostatic grading scale (OGS) compared to controls (4 +/- 4 vs. 1 +/- 2; p = 0.0003). Increasing orthostatic symptoms correlated with increasing fatigue (p = 0.006; r(2) = 0.3). Fatigue in NAFLD correlated inversely with 24 h measurement of systolic, diastolic and mean blood pressures (all p < 0.03; r(2) = 0.2). This relationship was predominantly related to lower blood pressure at night (p < 0.003; r(2) = 0.3). On head up tilt testing 57% of the NAFLD group had neurally-mediated hypotension (vasovagal syncope and/or orthostatic hypotension) (p = 0.006 compared to controls). The degree of blood pressure drop in response to standing correlated with fatigue severity (p = 0.008; r(2) = 0.3) and the autonomic symptom burden (OGS) (p = 0.03; r(2) = 0.2). CONCLUSION: Autonomic symptoms are prevalent in NAFLD and associate with objective measures of autonomic dysfunction. Fatigue in NAFLD is associated with lower blood pressure and autonomic dysfunction. Studies are needed to determine whether this is a potential therapeutic target for fatigue in NAFLD.

A predictive model for fatigue and its etiologic associations in primary biliary cirrhosis.

BACKGROUND & AIMS: Excessive day-time somnolence and autonomic dysfunction are biological processes prevalent in Primary Biliary Cirrhosis (PBC) that associate with fatigue. Here we explore how these biological associates inter-relate, and their cumulative impact upon typical clinical cohorts. METHODS: A predictive model for daytime hypersomnolence (Epworth Sleepiness Scale (ESS)) and autonomic dysfunction (Orthostatic Grading Scale (OGS)) was developed in a derivation cohort (n=124) and subsequently validated in a second cohort (n=114). Subjects also completed the disease specific quality of life tool, the PBC-40. RESULTS: A composite predictive criterion (presence of either ESS > or =10 or OGS > or =4) for the presence of fatigue in PBC patients had a sensitivity of 0.71 (95% confidence intervals 0.59-0.81) and specificity 0.8 (0.67-0.9) (positive predictive value (PV); 0.84 (0.72-0.92), negative PV; 0.66 (0.53-0.78) for moderate or severe fatigue). Ninety-seven percent of severely fatigued patients (0% of non-fatigued) met the aetiology predictive criterion (chi(2) 49.6, P<.0001). Expression of both significant daytime somnolence and autonomic dysfunction was not associated with more severe fatigue, suggesting that there is a threshold effect for fatigue in PBC. When applied to a second independent cohort, the composite criterion retained strongly significant predictive value for fatigue. CONCLUSIONS: A significant proportion of fatigue in PBC associates with one or both of autonomic dysfunction (OGS > or =4) and sleep disturbance (ESS > or =10). Those meeting both ESS and OGS criteria were not more severe fatigued than those meeting the diagnostic criterion for either OGS or ESS alone. A threshold effect for fatigue has implications for potential therapeutic interventions.

An integrated care pathway improves quality of life in Primary Biliary Cirrhosis.

BACKGROUND: Clinical management of the chronic autoimmune liver disease, Primary Biliary Cirrhosis (PBC) involves addressing the underlying liver disease and a range of symptoms independent of liver disease severity. We have formally explored how these two perspectives of chronic disease management can be combined into a clinic consultation and impact upon quality of life (QOL) in PBC. AIMS: To develop and implement the first Integrated Care Pathway (ICP) for the management of liver disease progression and symptom management in PBC. METHODS: Process mapping of current practice by a multidisciplinary group developed a flowchart of care from which the clinical record evolved. Symptom assessment is incorporated into the PBC ICP (QOL; PBC-40, autonomic symptoms; Orthostatic Grading Scale, daytime sleepiness; Epworth Sleepiness Scale). All patients were considered who attended clinic between July 2005 and June 2006. Symptom assessment was repeated after 1 year in those participating in the initial clinic cohort. RESULTS: The PBC ICP was successfully introduced into our clinical environment with high levels of patient satisfaction. A total of 225 PBC patients attended over 12 months. Initial QOL assessments were in 195 (87%). Five patients died (3%). Repeat assessment 1 year later occurred in 149 subjects (149/190; 78%). All symptom domains improved after ICP implementation with significant improvements in those with moderate and severe symptoms in all PBC-40 symptom domains (P < 0.02). In those with severe fatigue (n = 38) symptom improvement was even more dramatic (P = 0.002). CONCLUSION: ICP implementation delivers evidence-based care, leads to improvements in QOL coupled with high levels of patient satisfaction.

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence.

A significant proportion of patients with primary biliary cirrhosis (PBC) suffer from severe fatigue. The aim of this study was to characterize patterns of daytime sleep in patients with PBC (using both objective and subjective assessment approaches) and to study the association between sleep abnormality and fatigue severity. Fatigue severity was assessed in 48 female subjects with PBC (using a disease-specific quality of life instrument (the PBC-40) and a generic fatigue measure (Fatigue Impact Scale [FIS]) as well as 48 case-matched normal controls. All participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS, which assesses daytime hypersomnolence). Objective sleep assessment was performed using accelerometry over 7 days. Global sleep quality assessed by the PSQI was significantly lower in the PBC group compared to controls (P < .0001). ESS scores were significantly higher in patients with PBC than controls (P = .0001), suggesting significantly greater daytime somnolence in the patients with PBC. Objective sleep assessment confirmed that subjects with PBC were sleeping on average almost twice as long as controls during the daytime. Both degree of daytime somnolence (ESS) and actual daytime sleep activity (accelerometry) correlated strongly with fatigue severity in the patient group (r2 = 0.5, P < .0001 and r2 = 0.2, P < .01, respectively). In conclusion, Sleep abnormality, in the form of excessive daytime somnolence, is present in a significant proportion of patients with PBC, with the degree of daytime somnolence correlating strongly with the degree of fatigue. Existing agents effective at reducing daytime somnolence (such as modafinil) hold potential for the treatment of fatigue in PBC.