Opicapone in UK clinical practice: effectiveness, safety and cost analysis in patients with Parkinson's disease.

Aim: This subanalysis of the OPTIPARK study aimed to confirm the effectiveness and safety of opicapone in patients with Parkinson's disease and motor fluctuations in clinical practice specifically in the UK and to assess the impact of opicapone on treatment costs. Methods: Patients received opicapone added to levodopa for 6 months. Clinical outcomes were assessed at 3 and 6 months and treatment costs at 6 months. Results: Most patients' general condition improved at 3 months, with sustained improvements reported at 6 months. Opicapone improved motor and non-motor symptoms at both timepoints, was generally well tolerated and reduced total treatment costs by GBP 3719. Conclusion: Opicapone added to levodopa resulted in clinical improvements and reduced treatment costs across UK clinical practice.

Patients with Parkinson's disease (PD) often experience motor fluctuations (reduced and variable response to medication) following prolonged treatment with levodopa, which is currently the most effective treatment for the symptoms of PD. Opicapone has been developed for use in combination with levodopa to reduce the occurrence of motor fluctuations and was shown to be effective in two large clinical trials. This study describes the effectiveness, safety and cost-saving impact of opicapone when used to treat patients with PD and motor fluctuations across everyday clinical practice in the UK. Six months' treatment with opicapone was generally well tolerated, resulted in an improvement of the patients' overall PD condition and reduced treatment costs. Clinical trial registration: Registered in July 2016 at NCT02847442 (ClinicalTrial.gov).

The effect of directional social cues on saccadic eye movements in Parkinson's disease.

There is growing interest in how social processes and behaviour might be affected in Parkinson's disease. A task which has been widely used to assess how people orient attention in response to social cues is the spatial cueing task. Socially relevant directional cues, such as a picture of someone gazing or pointing to the left or the right have been shown to cause orienting of visual attention in the cued direction. The basal ganglia may play a role in responding to such directional cues, but no studies to date have examined whether similar social cueing effects are seen in people with Parkinson's disease. In this study, patients and healthy controls completed a prosaccade (Experiment 1) and an antisaccade task (Experiment 2) in which the target was preceded by arrow, eye gaze or pointing finger cues. Patients showed increased errors and response times for antisaccades but not prosaccades. Healthy participants made most anticipatory errors on pointing finger cue trials, but Parkinson's patients were equally affected by arrow, eye gaze and pointing cues. It is concluded that Parkinson's patients have a reduced ability to suppress responding to directional cues, but this effect is not specific to social cues.

Weight in Parkinson's Disease: Phenotypical Significance.

Body weight in Parkinson's disease (PD) is a significant nonmotor feature. Weight homeostasis is a complex physiological process and gets deranged in PD patients leading to changes in weight. While both the low and high body weight have been reported as risk factors for PD, the majority of PD patients have a lower weight and a subset of patients lose weight during the course of the disease, while a small proportion gain weight. A number of clinical parameters such as older age, impaired cognition, severity of disease, and an imbalance of food intake determined by satiety and hunger hormones have been reported to be associated with but not the cause of weight change. Low body weight and weight loss have a negative impact on disease severity, dyskinesia quality of life, and mortality indicative of disease progression. An early assessment of olfactory impairment seems to identify patients at risk of weight loss, the patients with more severe olfactory loss-anosmic group, lose weight as compared to the patients with some preservation of olfaction, the hyposmic group. Higher levodopa dose per kilogram body weight increases the risk of dyskinesia, higher body weight seems to be protective against this complication. The identification of PD patients according to the nonmotor phenotype of "Park-olfaction-weight-phenotype" and the "olfaction-weight-dyskinesia" triad should help to develop strategies to prevent weight reduction and improve general health and complications of PD patients. The phenotype seems to reflect a differential prodromal pathology and influence clinical disease. Higher body weight patients would benefit from life style changes to achieve a healthy profile. Weight monitoring and weight orientated approach to management of PD patients should help to improve their outcome. Body weight change might be a surrogate to disease progression and may be used to investigate neuroprotection strategies.

A prospective observational study of outcomes from rehabilitation of elderly patients with moderate to severe cognitive impairment.

OBJECTIVES: To evaluate rehabilitation outcomes in patients with moderate to severe cognitive impairment. DESIGN: Prospective observational cohort study. SETTING: Rehabilitation unit for older people. SUBJECTS: A total of 116 patients (70F) mean age (SD) 86.3 (6.4). Group 1: 89 patients with moderate cognitive impairment (Mini-Mental State Examination 11-20); and Group 2: 27 patients with severe cognitive impairment (Mini-Mental State Examination 0-10). INTERVENTION: A personalised rehabilitation plan. MAIN MEASURES: Barthel Activity of Daily Living score on admission and discharge, length of stay and discharge destination. RESULTS: Of 116 patients, 64 (55.2%) showed an improvement in Barthel score. Mini-Mental State Examination was significantly higher in those who improved, 15.4 (SD 3.7) vs.13.2 (SD 5.1): p = 0.01. The mean Barthel score improved in both groups; Group 1 - 14.7 (SD 19.1) vs. Group 2 - 9.3 (SD 16.3): p = 0.17. Of 84 home admissions in Group 1, more patients returning home showed improvements of at least 5 points in the Barthel score compared with nursing/residential home discharges (32/37 - 86.5% vs. 10/28 - 35.7%: p = 0.0001). In Group 2 of 17 home admissions, 6/6 (100%) home discharges showed improvement compared with 3/7 (42.8%) discharges to nursing/residential home (p = 0.07). In Group 1, a discharge home was associated with significantly greater improvement in number of Barthel items than a nursing/residential home discharge (3.27 (SD 2.07) vs. 1.86 (SD 2.32): p = 0.007). A similar non-significant pattern was noted for severe cognitive impairment patients (3.5 (3.06) vs. 1.14 (1.06); p = 0.1). CONCLUSION: Patients with moderate to severe cognitive impairment demonstrated significant improvements in Barthel score and Barthel items showing that such patients can and do improve with rehabilitation.

B-type natriuretic peptides help in cardioembolic stroke diagnosis: pooled data meta-analysis.

BACKGROUND AND PURPOSE: Determining the underlying cause of stroke is important to optimize secondary prevention treatment. Increased blood levels of natriuretic peptides (B-type natriuretic peptide/N-terminal pro-BNP [BNP/NT-proBNP]) have been repeatedly associated with cardioembolic stroke. Here, we evaluate their clinical value as pathogenic biomarkers for stroke through a literature systematic review and individual participants' data meta-analysis. METHODS: We searched publications in PubMed database until November 2013 that compared BNP and NT-proBNP circulating levels among stroke causes. Standardized individual participants' data were collected to estimate predictive values of BNP/NT-proBNP for cardioembolic stroke. Dichotomized BNP/NT-proBNP levels were included in logistic regression models together with clinical variables to assess the sensitivity and specificity to identify cardioembolic strokes and the additional value of biomarkers using area under the curve and integrated discrimination improvement index. RESULTS: From 23 selected articles, we collected information of 2834 patients with a defined cause. BNP/NT-proBNP levels were significantly elevated in cardioembolic stroke until 72 hours from symptoms onset. Predictive models showed a sensitivity >90% and specificity >80% when BNP/NT-proBNP were added considering the lowest and the highest quartile, respectively. Both peptides also increased significantly the area under the curve and integrated discrimination improvement index compared with clinical models. Sensitivity, specificity, and precision of the models were validated in 197 patients with initially undetermined stroke with final pathogenic diagnosis after ancillary follow-up. CONCLUSIONS: Natriuretic peptides are strongly increased in cardioembolic strokes. Future multicentre prospective studies comparing BNP and NT-proBNP might aid in finding the optimal biomarker, the best time point, and the optimal cutoff points for cardioembolic stroke identification.

Prognostic significance of weight changes in Parkinson's disease: the Park-weight phenotype.

Neurodegenerative Parkinson's disease (PD) is associated with a changing profile of weight as the disease advances. Whilst some patients gain weight, a significant proportion of patients lose weight. PD patients have a lower body weight as compared with non-PD controls. Weight loss is not a benign phenomenon. Patients with lower initial body weight and weight losers have a higher risk of developing dyskinesia. There is a relationship between body weight and levodopa dose, patients with higher levodopa dose per kilogram are at a higher risk of dyskinesia, the risk escalates above 6 mg per kilogram. Lower weight patients have risk of undernutrition and the associated disease pathology due to frailty. Weight losers are at risk of higher mortality and poor quality of life. PD patients should be assessed for body weight and the dose of levodopa be adjusted according to periodic weight changes, supplemented by other dopaminergic medications. Patients at risk of weight loss may be identified by their severe loss of olfaction since there seems to exist the olfaction-weight-dyskinesia phenotype. Measures should be taken to prevent weight loss in at-risk patients to prevent low-weight-related adverse outcomes in PD patients. These measures may protect PD patients from motor and non-motor adverse effects as the disease advances.

Non-motor symptoms profile and burden in drug naïve versus long-term Parkinson's disease patients.

BACKGROUND: Recent studies have demonstrated that, contrary to common perception non-motor symptoms (NMS) occur and may dominate early and untreated stage of Parkinson's disease (PD). OBJECTIVE: The aim of this ongoing study was to describe the overall NMS profile and burden in drug naïve PD patients (DNPD) compared to a group of long-term PD patients (LTPD, disease duration ≥15 years). METHODS: Cross sectional UK data from a multicenter (16 sites) collaboration were obtained and specifically NMS dataset from validated scales were analysed in DNPD and LTPD patients. The NMS scale (NMSS) was used as the primary outcome variable. RESULTS: Out of a current database of 468 PD patients, 57 were DNPD (58% males, mean age 64.8 years, median Hoehn and Yahr stage 1) and 25 were LTPD (44%, mean age 67.6 years, median Hoehn and Yahr stage 3). DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1-150) compared to the LTPD patients (mean 74.0, range 6-155), but 26.3% had severe and 19.3% had very severe burden of NMSS using NMSS cutoff scores. In comparison, 20.0% of the LTPD patients had severe and 60.0% very severe burden of NMS (p = 0.003). CONCLUSIONS: NMS are common in DNPD patients and over 45% may have severe to very severe burden of NMS, which is a key determinant of quality of life. In LTPD patients not only the burden of "very severe" NMS is significantly higher, but there are also differences in the profile of expression of NMS.

B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis.

OBJECTIVE: To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information. METHODS: Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes. RESULTS: Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10-406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32-4.01 for BNP; and odds ratio 2.63, 95% CI 1.75-3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality. CONCLUSION: BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.

Olfactory loss as a supporting feature in the diagnosis of Parkinson's disease: a pragmatic approach.

There is ample evidence from a large number of clinical and pathological studies of an early involvement of olfactory bulbs and cortex in the Lewy body pathology in idiopathic Parkinson's disease (iPD), the olfactory system being one of the first targets of degeneration in this condition. The olfactory dysfunction may be measurably present at the time of initial presentation and progresses in a proportion of patients as the disease advances. Patients with iPD have a more severe olfactory loss as compared to multisystem atrophy whereas the syndromes of corticobasal degeneration and progressive supranuclear palsy have no olfactory loss. A proportion of drug induced parkinsonism may have olfactory loss indicative of primary pathology of dopaminergic degeneration in these patients. Unlike single photon emission tomography, formal measurement of olfaction would provide a supportive role in diagnosing or excluding iPD depending on the duration of an individual patient's parkinsonian symptoms. Whilst olfaction may be only minimally impaired in early stages and may thus not help to differentiate from other syndromes, an intact olfaction in patients with parkinsonism of few years' duration would indicate a non-iPD pathology. Olfactory measurement is easy, cheap and now easily available in a number of tests, and olfactory assessment at different stages of parkinsonism should be used as a diagnostic aid for idiopathic PD and would enhance the diagnostic accuracy of iPD when used in conjunction with the UK Parkinson's disease society Brain Bank supportive criteria for diagnosis of idiopathic Parkinson's disease.

Olfaction, dyskinesia and profile of weight change in Parkinson's disease: identifying neurodegenerative phenotypes.

OBJECTIVES: To study the relationship between olfaction and body weight profile in Parkinson's disease. METHODS: Prospective assessment of 99 PD patients for clinical parameters, olfaction using UPSIT and current and previous body weight. Patients were categorised as weight losers (WL) and non-weight losers (NWL) depending on change of weight from previous years. Olfaction was categorised into two groups at the cut-off of the median level of UPSIT scores. Data was analysed to study the relationship of olfaction on weight change. RESULTS: Thirty-nine were weight losers (WL) and 60 non-weight losers (NWL). WL were significantly older (p = 0.02), females (p = 0.03) and had more severe impairment of olfaction, UPSIT 15 ± 4 vs 19 ± 5; p < 0.004. Patients with more severe olfaction (anosmic) impairment were older (p = 0.001) and had significantly lower weight, 75 vs 83 kg, p = 0.01. There was no difference in the proportion of smokers, medication usage, difficult swallowing or calorie consumption in any group. Weight losers and severe olfaction loss were associated with more severe H&Y stage. Patients below the median-UPSIT (anosmic) had lost weight during the previous years whereas those above the median (hyposmic) had gained weight. Regression analysis revealed UPSIT at the median level to be the most significant variable (p < 0.001) for weight loss. There was continuous loss of olfaction with increasing disease severity. Higher olfactory loss was associated with higher risk of dyskinesia. CONCLUSION: Early assessment of olfaction may identify patients of different phenotypes for weight change and risk of dyskinesia during the course of the disease.

Antiplatelets in secondary stroke prevention: should clopidogrel be the first choice?

Antiplatelet therapy has proven efficacy in the secondary prevention of recurrent non-cardioembolic ischaemic stroke. Recent evidence suggests clopidogrel is as effective as combined therapy with aspirin and extended-release dipyridamole for the prevention of recurrent stroke. As cerebrovascular and ischaemic heart disease are closely related, it would be sensible to use a drug shown to prevent vascular events in both territories. Clopidogrel meets these criteria, is superior to aspirin monotherapy, and has fewer side effects compared with extended-release dipyridamole. While there is no direct evidence supporting the use of clopidogrel in transient ischaemic attacks, it is likely that clopidogrel is effective because transient ischaemic attacks and stroke are part of the same disease spectrum. Clopidogrel could thus be useful as first line secondary prevention therapy in all non-cardioembolic stroke subtypes and transient ischaemic attacks, to prevent recurrent ischaemic events in all vascular territories.

Is investigating for carotid artery disease warranted in non-cortical lacunar infarction?

Carotid intervention in severe carotid stenosis after an anterior circulation ischemic event reduces the risk of further infarcts if the surgery is performed soon after the incident event. At present, there is no recommendation to differentiate among subtypes of anterior circulation infarcts or transient ischemic events. However, evidence is mounting that demonstrates a difference in pathophysiology of lacunar and nonlacunar (large artery) infarcts. The natural history of lacunar strokes is different from large artery infarcts for recurrence and mortality. Stroke is a heterogenous disease and consideration needs to be directed to manage different stroke subtypes differently. Lacunar infarcts mostly do not arise from large artery atheromatous disease or by cardioembolic phenomena, and there is a negative predictive value for severe carotid stenosis in lacunar strokes. Thus, current evidence suggests that lacunar strokes may not warrant investigation for carotid stenosis.

Fall risk factors in elderly patients with cognitive impairment on rehabilitation wards.

BACKGROUND: Confusion and cognitive impairment, are risk factors for falls in hospital. Evidence for reducing falls in cognitively-impaired patients is limited and to date no intervention has consistently been shown to reduce falls in this group of patients. We explored characteristics associated with falls in cognitively-impaired patients in a rehabilitation setting. METHODS: In a prospective observational study, 825 consecutive patients were studied. Patient characteristics were assessed on admission. Factors predisposing to falls in cognitively-impaired patients were identified. RESULTS: Cognitively-impaired patients were more likely to be fallers or recurrent fallers and more likely to sustain an injury than cognitively intact patients. They had a higher incidence of nursing home discharges and a significantly higher mortality. Logistic regression analysis showed that an unsafe gait (P < 0.001; 95% confidence interval, 0.13-0.57) was the only independent risk factor for falls in this group of patients. There was a cumulative higher risk of falling associated with an unsafe gait demonstrable throughout the patients' stay. CONCLUSION: Unsafe gait was the only significant independent risk factor for falls among cognitively-impaired patients in a rehabilitation environment. Interventions that improve gait patterns or that enhance safety for patients with abnormal gait are required if fall reduction in this group of patients is to be achieved.

Fall risk-assessment tools compared with clinical judgment: an evaluation in a rehabilitation ward.

OBJECTIVES: to compare the use of two falls risk-identification tools (Downton and STRATIFY) with clinical judgment (based upon the observation of wandering behaviour) in predicting falls of medically stable patients in a rehabilitation ward for older people. METHODS: in a prospective observational study, with blinded end-point evaluation, 200 patients admitted to a geriatric rehabilitation hospital had a STRATIFY and Downton Fall Risk assessment and were observed for wandering behaviour. RESULTS: wandering had a predictive accuracy of 78%. A total of 157/200 were identified correctly compared to 100/200 using the Downton score (P < 0.0001 95%, CI 0.18-0.42), or 93/200 using STRATIFY (P < 0.0001; 95% CI 0.15-0.37). The Downton and STRATIFY tools demonstrated predictive accuracies of 50% and 46.5%, respectively, with no statistical significance between the two (P = 0.55; 95% CI 0.77-1.71). Sensitivity for predicting falls using wandering was 43.1% (22/51). This was significantly worse than Downton 92.2% (47/51: P < 0.001) and STRATIFY 82.3% (42/51: P < 0.001). CONCLUSIONS: this study showed that clinical observation had a higher accuracy than two used falls risk-assessment tools. However it was significantly less sensitive implying that fewer patients who fell were correctly identified as being at risk.

Cardio-protection in acute stroke.

BACKGROUND: Measures of damage limitation for acute stroke have not produced substantial benefit to reduce stroke mortality. Search continues for measures to reduce stroke mortality. METHODS: Literature review for influence of cardiovascular factors, specifically the value of NT proBNP (a sensitive index of cardiac impairment) for stroke mortality. RESULTS: Cardiovascular factors, in particular cardiac failure, adversely influence acute stroke mortality. There is evidence of cardiological abnormality in acute strokes as indicated by ECG changes and tachycardia secondary to neurohumoral changes in acute strokes. Patients with ECG abnormality, tachycardia, dysrrhythmia and elevated levels of nor-epinephrine in acute stroke phase have higher mortality. Recent studies reveal that Troponin (measure of cardiac injury) and NT-proBNP (measure of cardiac function impairment) are elevated in acute stroke patients, in response to the activated Renin-Angiotensin-Aldosterone-System and other neurohumoral changes, as a protective mechanism for sympatho-inhibitory activity. Patients with elevated troponin have a higher mortality. Similarly elevated NT-proBNP has been reported to be associated with higher short and long-term mortality. In one study all patients who died at 4 months had NT-proBNP levels above the median, no patient with NT-proBNP below the median value died. Two studies revealed that NT-proBNP is more significant than clinical stroke severity for stroke mortality. Protection of myocardium in stroke patients may be possible by the use of drugs such as beta-blockers and the drugs acting on RAAS. Reduction of mortality in studies of candesartan (ACCESS study) and prior betablockers is one such example. Heart is at risk in acute strokes and protecting heart makes sense to reduce stroke mortality. CONCLUSION: Some stroke patients die due to occult cardiac damage and functional impairment in acute phase due to common risk factors. This relationship between brain and heart needs evaluation. Protection of heart with currently available or new drugs in acute strokes is worth investigating since this intervention could be applied to a large proportion of acute stroke patients over a wide time window.

Cascade of levodopa dose and weight-related dyskinesia in Parkinson's disease (LD-WD-PD cascade).

We have studied a cohort of 220 Parkinson's disease (PD) patients for risk factors of developing new dyskinesia. Twenty-nine patients were noticed to have developed new dyskinesia at the second assessment. The dyskinetic patients received significantly higher maximum level daily dose of levodopa. These patients had lost weight during the course of the disease from 72+/-15 to 66+/-17kg, p=0.002. The dyskinetic patients received significantly higher daily dose of levodopa per kilogram body weight, 8.4+/-3.5mg/kg vs. 6.0+/-3.9mg, p=0.003. Weight-losers PD patients developed significantly more dyskinesia than non-weight losers-p=0.002. Logistic regression analysis revealed weight loss and daily levodopa dose per kilogram body weight to be the only significant factors for dyskinesia in addition to disease duration. There was a "dose response to developing dyskinesia" according to the increasing levodopa dose per kilogram body weight.