[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is preceded by a premotor phase of unknown duration. Dopaminergic degeneration during this phase may lead to subtle cognitive and behavioural changes, such as decreased novelty seeking. Consequently, premotor subjects might be most comfortable in jobs that do not require optimal dopamine levels, leading to an overrepresentation in structured and predictable occupations, or an underrepresentation in artistic occupations. In a case-control study, 750 men with PD (onset ≥40 years) and 1300 healthy men completed a validated questionnaire about their lifetime occupational status. Occupations were classified using the RIASEC model. Odds ratios (ORs) were calculated for the conventional and artistic categories, both for the most recent occupation before symptom onset, and for the very first occupation. Because farming has been associated with a PD risk, ORs were calculated separately for farming. A reduced risk of PD was found for men with an artistic occupation late in life (OR 0.14, 95 % CI 0.04-0.53), while an artistic first occupation did not prevent PD (OR 0.72, CI 0.32-1.59). Conventional occupations showed no increased risk (recent: OR 1.07, CI 0.70-1.64; first: OR 1.14, CI 0.77-1.71). In support of previous reports, farming was associated with an increased risk of PD (recent: OR 2.6, CI 1.4-4.6; first: OR 2.7, CI 1.6-4.5). PD patients were older than controls, but various statistical corrections for age all lead to similar results. Artistic occupations late in life are associated with a reduced risk of subsequent PD, perhaps because this reflects a better preserved dopaminergic state. No initial occupation predicted PD, suggesting that the premotor phase starts later in life.
Journal of Neurology 07/2015; DOI:10.1007/s00415-015-7828-y · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various ancillary investigations can assist clinicians in the differential diagnosis of patients with parkinsonism. It is unknown which test offers greatest diagnostic value in clinical practice. We included 156 consecutive patients with parkinsonism, but with an initially uncertain diagnosis. At baseline, all patients underwent extensive clinical testing and the following ancillary investigations: brain magnetic resonance imaging (MRI); (123)I-iodobenzamide single photon-emission computed tomography (IBZM-SPECT); analysis of cerebrospinal fluid (CSF); and anal sphincter electromyography (EMG). The final diagnosis was established after 3-year follow-up by two movement disorder specialists, according to international consensus criteria. We determined the diagnostic value by comparing the baseline clinical parameters and ancillary studies with the final diagnosis. Out of a potential 138 parameters, univariate analysis identified 35 parameters that discriminated Parkinson's disease (PD, n = 62) and atypical parkinsonism (AP, n = 94), with AUC of 0.55-0.81. Stepwise logistic regression showed that the combination of tandem gait, axial UPDRS subscore, slow saccadic eye movements and dysphagia yielded an AUC of 0.93, adjusted for optimism. The combination of tandem gait and axial UDPRS subscore yielded an AUC of 0.90. None of the ancillary investigations alone or in combination with clinical testing improved this clinically based diagnostic accuracy, not even in a subgroup of patients with the greatest diagnostic uncertainty at baseline. Our study demonstrates that a comprehensive set of clinical tests provides good accuracy to differentiate PD from AP. Our results also suggest that routine MRI, IBZM-SPECT, CSF analysis and anal sphincter EMG do not improve this diagnostic accuracy. Future work should evaluate the possible diagnostic value of more advanced diagnostic tests.
Journal of Neurology 11/2014; 262(2). DOI:10.1007/s00415-014-7568-4 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders.
Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics.
Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride channelopathy patients and shorter than 30 ms in all of the sodium channelopathy patients. This resulted in a detection rate of over 95%.
Myotonic discharges of a single muscle can be used to better guide towards a molecular diagnosis in non-dystrophic myotonic syndromes.
[Show abstract][Hide abstract] ABSTRACT: The DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results.
We evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2-20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of "positive" (statistically significant at p < 0.05) findings using empirical data of recent meta-analyses with > =3 studies of interventions from the Cochrane Database of Systematic Reviews.
The simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results.
Our simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there are = <5 studies of very unequal sizes.
BMC Medical Research Methodology 02/2014; 14(1):25. DOI:10.1186/1471-2288-14-25 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis.
Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented.
The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented.
We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.
[Show abstract][Hide abstract] ABSTRACT: Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.
Breast Cancer Research and Treatment 10/2013; 141(3). DOI:10.1007/s10549-013-2711-y · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-SN prediction models are frequently used in clinical decision making to identify patients that may not need axillary treatment, but these models still need to be validated by follow-up data. Our purpose was the validation of non-sentinel node (SN) prediction models in predicting regional recurrences in patients without axillary treatment.
We followed a cohort of 486 women with favorable primary tumor characteristics and pN0(i+)(sn) or pN1mi(sn) for median 4.5 years. None of the patients underwent axillary treatment. Based on four published non-SN prediction models, the threshold allowing separation into low versus high-risk on non-SN involvement was set at 10%.
Overall 5-year regional recurrence rate was 3.0% (SE, ±0.1%). Using the Tenon scoring system, 438 low-risk patients had a 5-year regional recurrence rate of 2.3% (±0.8%), and 48 high-risk patients a recurrence rate of 10.1% (±0.4%). The MSKCC nomogram identified 300 low-risk patients with a recurrence rate of 2.8% (±1.1%), versus 166 high-risk patients with a rate of 3.4% (±0.5%) (20 patients not assessable). The Stanford nomogram identified 21 high-risk patients without recurrence, and 465 low-risk patients with a 3.2% (±0.9%) recurrence rate. A Dutch model discriminated between 384 low-risk patients with a recurrence rate of 2.2% (±0.8%) and 102 high-risk patients with a rate of 6.3% (±2.9%).
The Tenon scoring system outperformed the other models as it identified the largest subgroup of patients with low recurrence rate. In patients resembling our cohort we would recommend axillary treatment if they had a Tenon score above 3.5.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 10/2013; 39(12). DOI:10.1016/j.ejso.2013.09.006 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care. METHODS: We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehorigen-kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791. FINDINGS: We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1.3 points, 95% CI -2.1 to 2.8; corresponding raw logit score difference 0.1, 95% CI 0.003 to 0.2) as was the average PDQL score (difference 3.0 points, 0.4 to 5.6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0.9 points, 95% CI -0.6 to 2.4; corresponding raw logit score difference 0.1, -0.02 to 0.3) or PDQL (difference 1.7 points, -1.2 to 4.6). Secondary outcomes did not differ between groups (UPDRS III score difference 0.6 points, 95% CI -1.4 to 2.6; BELA-A-k score difference 0.8 points, -0.2 to 1.8; cost difference euro742, -euro489 to euro1950). INTERPRETATION: This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits. FUNDING: NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation.
The Lancet Neurology 10/2013; 12(10-10):947-56. DOI:10.1016/S1474-4422(13)70196-0 · 21.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients.
Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100mg/m(2)) or six cycles of TAC (75/50/500mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast.
In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%).
With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.
European journal of cancer (Oxford, England: 1990) 07/2013; 49(15). DOI:10.1016/j.ejca.2013.06.012 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postural instability, recurrent falls and fear of falling are common in advanced Parkinson's disease (PD). We examined the impact of fall frequency, fear of falling, balance confidence and objectively measured balance impairment (using Tinetti's Mobility Index) on health-related quality of life (HrQoL) in PD. In 74 subjects HrQoL was assessed using the 39-item Parkinson's disease Quality of Life Questionnaire [PDQ-39]. Patients were interviewed using a validated falls questionnaire, addressing fall history, consequences of falls and fear of falling. Neurological examination included Hoehn and Yahr scale, the Unified Parkinson's disease Rating Scale and Tinetti's Mobility Index. Disease severity, age and gender explained 43% of the differences in HrQoL across patients (R2 = 0.43). The combination of these factors and each of the factors fear of falling, balance confidence and falls frequency lead to 55%, 50% and 45% of explained variation, respectively. The standardised regression coefficients of these risk factors were 0.34 (fear of falling), 0.28 (balance confidence) and 0.13 (fall frequency). This suggests that fear of falling is a more important determinant of HrQoL than actual falling. These results emphasise the importance of addressing fear of falling in the clinical management of PD, and the need for development of strategies to reduce fear of falling in intervention programs.
[Show abstract][Hide abstract] ABSTRACT: PURPOSEEarly breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. PATIENTS AND METHODS
In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm.ResultsAfter inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). CONCLUSION
In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.
[Show abstract][Hide abstract] ABSTRACT: Reperfusion is mandatory after ischemia, but also triggers ischemia-reperfusion (IR)-injury. Ischemic preconditioning (IPC) can limit endothelial IR-injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Objective. To examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to IR-injury. Methods. We included 15 healthy young (20-25 years) and 15 older men (68-77 years). We examined brachial artery endothelial function using flow mediated dilation (FMD) before and after arm IR (induced by inflation of an upper arm blood pressure cuff for 20 minutes and 15 minutes of reperfusion). In a randomised order, IR was preceded by IPC or a control-intervention consisting of 3 cycles of 5-minute upper arm cuff inflation to 220 or 20 mmHg, respectively. Results. In young men, FMD decreased significantly after IR (6.4±2.7% to 4.4±2.5%). This decrease was not present when IR was preceded by IPC (5.9±2.3 to 5.6±2.5). IPC-induced protection appeared to be significantly reduced in the elderly patients (P=0.04). Although FMD decreased after IR in older men (3.5±1.7 to 2.5±1.0), IPC could not prevent this (3.7±2.1 to 2.2±1.1). Conclusion. This study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after ischaemia-reperfusion in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce IR-injury to clinic.
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether a multifaceted behavioural change programme increases physical activities in patients with Parkinson's disease.
Multicentre randomised controlled trial.
32 community hospitals in the Netherlands, collaborating in a nationwide network (ParkinsonNet).
586 sedentary patients with idiopathic Parkinson's disease aged between 40 and 75 years with mild to moderate disease severity (Hoehn and Yahr stage ≤3).
Patients were randomly assigned to the ParkFit programme or a matched general physiotherapy intervention. ParkFit is a multifaceted behavioural change programme, designed specifically to achieve an enduring increase in the level of physical activity (coaches using motivational strategies; ambulatory feedback).
The primary endpoint was the level of physical activity, measured every six months with a standardised seven day recall (LASA physical activity questionnaire-LAPAQ). Secondary endpoints included two other measures of physical activity (activity diary and ambulatory activity monitor), quality of life (Parkinson's disease questionnaire-PDQ-39), and fitness (six minute walk test).
540 (92.2%) patients completed the primary outcome. During follow-up, overall time spent on physical activities (LAPAQ) was comparable between the groups (adjusted group difference 7%, 95% confidence interval -3 to 17%; P=0.19). Analyses of three secondary outcomes indicated increased physical activity in ParkFit patients, as suggested by the activity diary (difference 30%; P<0.001), the activity monitor (difference 12%; P<0.001), and the six minute walk test (difference 4.8 m; P=0.05). PDQ-39 did not differ between ParkFit patients and controls (difference -0.9 points; P=0.14). The number of fallers was comparable between ParkFit patients (184/299; 62%) and controls (191/287; 67%).
The ParkFit behavioural change programme did not increase overall physical activity, as measured with the LAPAQ. The analysis of the secondary endpoints justifies further work into the possible merits of behavioural change programmes to increase physical activities in daily life in Parkinson's disease.
Clinical trials NCT00748488.
[Show abstract][Hide abstract] ABSTRACT: Background
Occupational therapists may have an added value in the care of patients with Parkinson’s disease whose daily functioning is compromised, as well as for their immediate caregivers. Evidence for this added value is inconclusive due to a lack of rigorous studies. The aim of this trial is to evaluate the (cost) effectiveness of occupational therapy in improving daily functioning of patients with Parkinson’s disease.
A multicenter, assessor-blinded, two-armed randomized controlled clinical trial will be conducted, with evaluations at three and six months. One hundred ninety-two home-dwelling patients with Parkinson’s disease and with an occupational therapy indication will be assigned to the experimental group or to the control group (2:1). Patients and their caregivers in the experimental group will receive ten weeks of home-based occupational therapy according to recent Dutch guidelines. The intervention will be delivered by occupational therapists who have been specifically trained to treat patients according to these guidelines. Participants in the control group will not receive occupational therapy during the study period. The primary outcome for the patient is self-perceived daily functioning at three months, assessed with the Canadian Occupational Performance Measure. Secondary patient-related outcomes include: objective performance of daily activities, self-perceived satisfaction with performance in daily activities, participation, impact of fatigue, proactive coping skills, health-related quality of life, overall quality of life, health-related costs, and effectiveness at six months. All outcomes at the caregiver level will be secondary and will include self-perceived burden of care, objective burden of care, proactive coping skills, overall quality of life, and care-related costs. Effectiveness will be evaluated using a covariance analysis of the difference in outcome at three months. An economic evaluation from a societal perspective will be conducted, as well as a process evaluation.
This is the first large-scale trial specifically evaluating occupational therapy in Parkinson’s disease. It is expected to generate important new information about the possible added value of occupational therapy on daily functioning of patients with Parkinson’s disease.