Claire McDonald

Single centre experience of ivabradine in postural orthostatic tachycardia syndrome

AIMS Postural orthostatic tachycardia syndrome (POTS) is associated with tachycardia on orthostasis. Patients frequently report palpitations, presyncope, and fatigue. Conventional therapy is effective in less than 60%. Case reports suggest ivabradine (a selective sinus node blocker, with no effect on blood pressure) may alleviate POTS-related symptoms. This is a retrospective case-series. METHODS AND RESULTS Postural orthostatic tachycardia syndrome patients prescribed ivabradine were identified from the pharmacy database. Case notes were reviewed and participants completed a symptom assessment tool. Twenty-two patients were identified. Data were available from 20. Eight patients reported reduced tachycardia and fatigue and four reported only reduced tachycardia. The most common reason for discontinuing ivabradine was lack of efficacy (n = 6). Five patients reported side-effects resulting in two discontinuing treatment. CONCLUSION This retrospective case series indicates that 60% of patients treated with ivabradine report a symptomatic improvement. A randomized controlled trial accessing the efficacy of ivabradine in POTS is indicated, particularly in patients resistant to, or intolerant of, conventional therapy.

Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management

OBJECTIVES To establish the relationship between the functional impairment experienced by Chronic fatigue syndrome (CFS) patients and the symptoms frequently experienced by those with CFS; specifically cognitive impairment, fatigue and orthostatic symptoms. DESIGN Cross sectional questionnaire survey. SETTING Specialist CFS Clinical Service. SUBJECTS Ninety-nine Fukuda diagnosed CFS and 64-matched controls. MAIN OUTCOME MEASURES Symptom and functional assessment tools completed and returned by post included; PROMIS HAQ (Patient-Reported Outcomes Measurement Information System, Health Assessment Questionnaire), CFQ (Cognitive Failures Questionnaire), FIS (Fatigue Impact Scale) and OGS (Orthostatic Grading Scale) assessment tools. RESULTS CFS patients experience greater functional impairment than controls [mean (95% CI) PROMIS HAQ scores CFS 36 (31-42) vs. controls 6 (2-10); P < 0.0001], especially in the functional domains of activities and reach. Poorer functional ability impairment is significantly associated with greater cognitive impairment (P = 0.0002, r = 0.4), fatigue (P < 0.0001, r = 0.5) and orthostatic symptoms (P < 0.0001, r = 0.6). However, only orthostatic symptoms (OGS) independently associated with functional impairment (beta = 0.4, P = 0.01). CONCLUSION Treatment of orthostatic symptoms in CFS has the potential to improve functional capacity and so improve quality of life.

Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms

BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally, we determine the relationship of these indices to the symptoms of PBC. METHODS 16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF). RESULTS PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF. CONCLUSIONS PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).

Orthostatic hypotension and cognitive impairment in Parkinson's disease: Causation or association?

Orthostatic hypotension and cognitive impairment are common in Parkinsons disease (PD) and significantly impair quality of life. Orthostatic hypotension and cognitive impairment appear to be interrelated. Whether the relationship is causative or associative remains unclear. The vascular hypothesis proposes that recurrent episodic hypotension results in cerebral hypoperfusion, in turn causing anoxic damage to vulnerable areas of the brain and impaired cognitive function. Support for this hypothesis has come from brain MRI studies showing an association between white matter hyperintensities and a postural drop in blood pressure among PD patients. Alternatively, the association between orthostatic hypotension and cognitive decline in PD may reflect shared underlying synuclein‐related pathology affecting common neuroanatomical and neurochemical substrates. Cardiac imaging studies demonstrate noradrenergic denervation early in PD, and cardiac denervation has been associated with poorer cognition. Neurogenic orthostatic hypotension occurs as a result of defective norepinephrine release from sympathetic terminals upon standing. Neuropathological studies have also demonstrated Lewy body pathology in the locus coeruleus; the main source of noradrenaline in the brain. Locus coeruleus norepinephrine levels are reduced in PD patients with dementia when compared with PD patients without. In this review, we examine the evidence for an association between orthostatic hypotension and cognitive impairment in PD. We evaluate the literature supporting the hypothesis that progressive noradrenergic denervation underlies both orthostatic hypotension and cognitive impairment, and we examine studies suggesting that recurrent cerebral hypoperfusion results in cognitive decline in PD. Finally, we explore how modulation of blood pressure and the noradrenergic nervous system may improve cognition in PD.

Lower urinary tract symptoms in Parkinson's disease: Prevalence, aetiology and management

Lower urinary tract symptoms (LUTS) are common in Parkinsons disease (PD), effecting 27-85% of patients with PD. Irritative symptoms predominate and urodynamic studies confirm high prevalence of detrusor overactivity in PD. LUTS are present early in PD and are more common in PD than in age matched controls. The assessment of LUTS in PD is complicated by coexisting bradykinesia and cognitive impairment. Although LUTS become more troublesome as PD progresses it remains unclear if LUTS severity correlates with motor symptoms and/or duration of PD. The underlying cause of LUTS in PD remains to be fully elucidated. Animal and human studies suggest the net effect of the basal ganglia is to supress micturition. Although LUTS are a common in PD, few studies have examined the assessment and management of LUTS specifically in patients with PD. Pilot studies have suggested that bladder training, antimuscarinic drugs and intravesical botulinum toxin maybe helpful but these trials have been small and frequently lacked a suitable control group making them vulnerable to the placebo effect. Furthermore the adverse effects of antimuscarinic drugs on cognitive and gastrointestinal function may limit the use of these drugs in PD. In this review we summarise the literature describing the prevalence of LUTS in PD, discuss the emerging data delineating the underlying pathophysiology of LUTS and examine interventions helpful in the management of LUTS in people with PD.

Blood pressure variability and cognitive decline in older people: a 5-year longitudinal study.

Background: Cognitive impairment is common in later life. Identifying potential modifiable risk factors for cognitive decline may ameliorate the burden of disease. Cross-sectional studies show an association between blood pressure (BP) variability and impaired cognitive function in patients with hypertension and/or dementia. However, research examining the association between BP variability and cognitive function in the general older population is scarce. Objective: In this study, we examined the association between BP variability and cognitive function over 5-year follow-up in an unselected community-dwelling cohort. Methods: Ambulatory BP monitoring was performed in 353 community-dwelling people aged at least 65 years. Cognitive assessment, using the Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG), was performed at baseline and at 5-year follow-up. BP variability was calculated using the coefficient of variation. Cognitive change over 5 years was defined as baseline score minus follow-up score. Results: Increased daytime systolic variability was associated with poorer performance on the CAMCOG total score and subscores. Daytime diastolic variability was associated with poorer performance on total CAMCOG, CAMCOG executive score, and MMSE. These findings were independent of demographic and cardiovascular risk factors. Daytime systolic variability was also independently associated with greater decline in total CAMCOG and MMSE scores over 5-year follow-up. Conclusion: Increased BP variability is associated with poorer cognitive function in older people and may represent a novel modifiable risk factor for cognitive decline.

Postural tachycardia syndrome is associated with significant symptoms and functional impairment predominantly affecting young women: a UK perspective

Objective To examine a large UK cohort of patients with postural tachycardia syndrome (PoTS), to compare demographic characteristics, symptoms and treatment of PoTS at one centre compared to the largest patient group PoTS UK and to verify if their functional limitation is similar to patients with chronic fatigue syndrome (CFS). Design A cross-sectional study assessed the frequency of symptoms and their associated variables. Patients and setting Two PoTS cohorts were: (1) recruited via PoTS UK, (2) diagnosed at Newcastle Hospitals National Health Service (NHS) Foundation Trust 2009–2012. Patients with PoTS were then compared to a matched cohort with CFS. Main outcome measures Patients’ detailed demographics, time to diagnosis, education, disability, medications, comorbidity and precipitants. Symptom assessment tools captured, Fatigue Impact Scale, Epworth Sleepiness Scale, Orthostatic Grading Scale (OGS), Hospital Anxiety and Depression Scale, Health Assessment Questionnaire, Cognitive Failures Questionnaire. Results 136 patients with PoTS participated (84 members of PoTS UK (170 cohort; 50% return) and 52 (87 cohort; 60%) from Newcastle Clinics). The PoTS UK population was significantly younger than the clinic patients, with significantly fewer men (p=0.005). Over 60% had a university or postgraduate degree. Significantly more of the PoTS UK cohort were working, with hours worked being significantly higher (p=0.001). Time to diagnosis was significantly longer in the PoTS UK cohort (p=0.04). Symptom severity was comparable between cohorts. The PoTS total group was compared with a matched CFS cohort; despite comparable levels of fatigue and sleepiness, autonomic symptom burden (OGS) was statistically significantly higher. The most common treatment regime included β-blockers. Overall, 21 treatment combinations were described. Up to 1/3 were taking no treatment. Conclusions Patients with PoTS are predominantly women, young, well educated and have significant and debilitating symptoms that impact significantly on quality of life. Despite this, there is no consistent treatment.

Ambulatory Blood Pressure Variability Increases Over a 10-Year Follow-Up in Community-Dwelling Older People

BACKGROUND Greater ambulatory blood pressure variability (ABPV) is associated with end-organ damage and increased mortality. Age-related changes in the cardiovascular and autonomic nervous systems make age-associated increases in ABPV likely. Cross-sectional studies support this hypothesis, showing greater ABPV among older compared to younger adults. The only longitudinal study to examine changes in ABPV, however, found ABPV decreased over 5 years follow-up. This unexpected observation probably reflected the highly selected nature of the study participants. METHODS In this longitudinal study, we assessed changes in ABPV over 10 years in a community-cohort of older people. In addition, we examined the extent to which ABPV was predicted by demographics, cardiovascular risk factors, and medication. Clinical examination and 24-hour ambulatory blood pressure monitoring were carried out at baseline and at 10 years follow-up in 83 people, median age 70 years. ABPV was calculated using SD and coefficient of variation (Cv). Three time periods were examined: daytime, nighttime, and 24 hours. RESULTS Daytime and 24-hour, systolic and diastolic, SD, and Cv were significantly greater at follow-up than at baseline (P < 0.001 in all cases). Mean BP did not change. CONCLUSIONS Multilevel modeling showed follow-up interval had a significant, positive effect on SD and Cv (P < 0.004), independent of age, sex, and medication.ABPV increased over a 10-year follow-up despite stable mean BP. ABPV may therefore be an additional target for treatment in older people. Future studies should examine what degree of ABPV is harmful and if control of ABPV reduces adverse outcome.

Poor Sleep Quality and Progression of Gait Impairment in an Incident Parkinson’s Disease Cohort

Abnormal sleep may associate with cognitive decline in Parkinsons disease (PD). Furthermore, sleep dysfunction may associate with worse motor outcome. We hypothesised that PD patients with poor quality sleep would have greater progression in gait dysfunction, due to structural and functional overlap in networks subserving sleep and gait regulation. 12 PD patients and 12 age-matched controls completed longitudinal follow-up over 36 months. Poor sleep efficiency and greater sleep fragmentation correlated significantly with progression of step-width variability, a gait characteristic mediated by postural control, providing evidence that poor sleep in PD is associated with a more rapid deterioration in gait.

The Pattern of Hospital Admissions Prior to Care Home Placement in People With Parkinson’s Disease: Evidence of a Period of Crisis for Patients and Carers

Objectives: We hypothesized that the number and length of hospital admissions in people with Parkinson’s disease (PD) would increase immediately prior to admission to a care home relative to those who were able to continue living at home or who died. Method: PD patients at Hoehn and Yahr Stages III to V were followed-up over two and a half years with deaths and care home placements recorded. Hospital admissions data were collected over this period. Results: Of 286 patients included in the study, 7.3% entered a care home and 28.3% died. In the final 120 days prior to the study exit point (care home placement, death, or continued living at home), longer hospital stay was significantly associated with care home placement, after adjusting for the competing risk of death. Conclusion: Our data provide evidence that, for many people with PD, a period of crisis is reached immediately prior to care home placement.