Jeroen P. P. van Vugt

Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial

BACKGROUNDnPatients with advanced Parkinsons disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS.nnnMETHODSnWe recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinsons disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074.nnnFINDINGSnBetween Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinsons disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups.nnnINTERPRETATIONnAlthough there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinsons disease.nnnFUNDINGnStichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging.

Ambulatory Monitoring of Activities and Motor Symptoms in Parkinson's Disease

Ambulatory monitoring of motor symptoms in Parkinsons disease (PD) can improve our therapeutic strategies, especially in patients with motor fluctuations. Previously published monitors usually assess only one or a few basic aspects of the cardinal motor symptoms in a laboratory setting. We developed a novel ambulatory monitoring system that provides a complete motor assessment by simultaneously analyzing current motor activity of the patient (e.g., sitting, walking, etc.) and the severity of many aspects related to tremor, bradykinesia, and hypokinesia. The monitor consists of a set of four inertial sensors. Validity of our monitor was established in seven healthy controls and six PD patients treated with deep brain stimulation (DBS) of the subthalamic nucleus. The patients were tested at three different levels of DBS treatment. Subjects were monitored while performing different tasks, including motor tests of the Unified PD Rating Scale (UPDRS). Output of the monitor was compared to simultaneously recorded videos. The monitor proved very accurate in discriminating between several motor activities. Monitor output correlated well with blinded UPDRS ratings during different DBS levels. The combined analysis of motor activity and symptom severity by our PD monitor brings true ambulatory monitoring of a wide variety of motor symptoms one step closer.

Pharmacogenetics of antiparkinsonian drug treatment: a systematic review

Pharmacotherapy is the mainstay in the treatment of Parkinsons disease and the armamentarium of drugs available for the therapy of this disease is still expanding. Anti-Parkinsons disease drugs are effective in reducing the physical symptoms, such as hypokinesia, bradykinesia, rigidity and tremor. However, there is a large interindividual variability in response to anti-Parkinsons disease drugs with respect to both drug efficacy and toxicity. It is thought that genetic variability in genes encoding drug-metabolizing enzymes, drug receptors and proteins involved in pathway signaling is an important factor in determining interindividual variability in drug response. Pharmacogenetics aims at identifying genetic markers associated with drug response. Ideally, knowledge of these genetic markers will enable us to predict an individuals drug response in terms of both efficacy and toxicity. The role of pharmacogenetics in the treatment of Parkinsons disease is relatively unexplored. Therefore, we aim to present a systematic review of the published pharmacogenetic studies in Parkinsons disease and to describe polymorphic genes of interest for future research.

Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson’s disease

ObjectiveTo identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson’s disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis.MethodsPatients included were first-time users of the non-ergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180xa0days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment.ResultsThe study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85–21.2]. Daily levodopa dosages between 500 and 1000xa0mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08–4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07–0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship.ConclusionThis study identified apomorphine use and levodopa dosages between 500 and 1000xa0mg as non-genetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings.

Feasibility of external rhythmic cueing with the Google Glass for improving gait in people with Parkinson’s disease

New mobile technologies like smartglasses can deliver external cues that may improve gait in people with Parkinson’s disease in their natural environment. However, the potential of these devices must first be assessed in controlled experiments. Therefore, we evaluated rhythmic visual and auditory cueing in a laboratory setting with a custom-made application for the Google Glass. Twelve participants (mean agexa0=xa066.8; mean disease durationxa0=xa013.6xa0years) were tested at end of dose. We compared several key gait parameters (walking speed, cadence, stride length, and stride length variability) and freezing of gait for three types of external cues (metronome, flashing light, and optic flow) and a control condition (no-cue). For all cueing conditions, the subjects completed several walking tasks of varying complexity. Seven inertial sensors attached to the feet, legs and pelvis captured motion data for gait analysis. Two experienced raters scored the presence and severity of freezing of gait using video recordings. User experience was evaluated through a semi-open interview. During cueing, a more stable gait pattern emerged, particularly on complicated walking courses; however, freezing of gait did not significantly decrease. The metronome was more effective than rhythmic visual cues and most preferred by the participants. Participants were overall positive about the usability of the Google Glass and willing to use it at home. Thus, smartglasses like the Google Glass could be used to provide personalized mobile cueing to support gait; however, in its current form, auditory cues seemed more effective than rhythmic visual cues.

Discontinuation of ropinirole and pramipexole in patients with Parkinson's disease: clinical practice versus clinical trials

ObjectiveTo compare characteristics and incidence of discontinuation of Parkinson’s disease (PD) patients starting ropinirole or pramipexole in clinical practice with data from randomised controlled clinical trials (RCTs).MethodsIncluded in the retrospective clinical-practice cohort were first-time users of ropinirole or pramipexole diagnosed with PD before 2005. Baseline characteristics and incidence of discontinuation were compared between the clinical-practice cohort and RCTs. Treatment discontinuation was defined as more than 180xa0days between two refills of ropinirole or pramipexole. The incidence of discontinuation in RCTs was based on the reported rate of discontinuation for any cause.ResultsIncluded were 45 patients who started with ropinirole and 59 patients who started with pramipexole. Treatment was discontinued within 3xa0years in 51% (ropinirole) and 60% (pramipexole) of the patients. Ten RCTs with ropinirole and 12 with pramipexole were identified. Baseline characteristics did not differ between the clinical-practice cohort and RCTs. RCTs reported discontinuation rates comparable with those at the same timepoint in the clinical practice until 1xa0year of follow-up.ConclusionThis study shows that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. However for the long term, discontinuation in practice is possibly higher.

Cognitive and psychiatric outcome 3 years after globus pallidus pars interna or subthalamic nucleus deep brain stimulation for Parkinson's disease

BACKGROUNDnEffects on non-motor symptoms, mainly cognitive and psychiatric side effects, could influence the decision for either globus pallidus pars interna (GPi) or subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinsons disease (PD).nnnOBJECTIVEn1) To compare cognitive and psychiatric outcomes 3 years after GPi DBS versus STN DBS, and 2) to report on occurrence of suicidal ideation, psychiatric diagnoses, social functioning, and marital satisfaction 3 years after DBS.nnnMETHODSnPatients were randomized to receive GPi DBS (nxa0=xa065) or STN DBS (nxa0=xa063). Standardized assessments were performed at baseline, 1 year, and 3 years. We used linear mixed model analyses to investigate between-group differences on the Mattis Dementia Rating Scale (MDRS), neuropsychological tests, and psychiatric questionnaires 3 years after DBS.nnnRESULTSnEighty-seven patients (68%) completed at least one neuropsychological test after 3 years. No significant between-group differences were found on the MDRS (pxa0=xa00.61), neuropsychological tests (p-values between 0.17 and 0.87), and psychiatric questionnaires (p-values between 0.23 and 0.88) 3 years after DBS. The Mini International Neuropsychiatric Interview did not indicate a substantial number of psychiatric diagnoses after 3 years. Social functioning and marital satisfaction were comparable in both groups.nnnCONCLUSIONSnThree years after GPi DBS and STN DBS no pronounced between-group differences on measures of cognitive and psychiatric functioning could be demonstrated. Overall, cognitive and psychiatric outcome 3 years after DBS do not provide a clear direction for clinicians when considering which of these two surgical targets to choose.

Involving Patients in Weighting Benefits and Harms of Treatment in Parkinson's Disease

Introduction Little is known about how patients weigh benefits and harms of available treatments for Parkinson’s Disease (oral medication, deep brain stimulation, infusion therapy). In this study we have (1) elicited patient preferences for benefits, side effects and process characteristics of treatments and (2) measured patients’ preferred and perceived involvement in decision-making about treatment. Methods Preferences were elicited using a best-worst scaling case 2 experiment. Attributes were selected based on 18 patient-interviews: treatment modality, tremor, slowness of movement, posture and balance problems, drowsiness, dizziness, and dyskinesia. Subsequently, a questionnaire was distributed in which patients were asked to indicate the most and least desirable attribute in nine possible treatment scenarios. Conditional logistic analysis and latent class analysis were used to estimate preference weights and identify subgroups. Patients also indicated their preferred and perceived degree of involvement in treatment decision-making (ranging from active to collaborative to passive). Results Two preference patterns were found in the patient sample (N = 192). One class of patients focused largely on optimising the process of care, while the other class focused more on controlling motor-symptoms. Patients who had experienced advanced treatments, had a shorter disease duration, or were still employed were more likely to belong to the latter class. For both classes, the benefits of treatment were more influential than the described side effects. Furthermore, many patients (45%) preferred to take the lead in treatment decisions, however 10.8% perceived a more passive or collaborative role instead. Discussion Patients weighted the benefits and side effects of treatment differently, indicating there is no “one-size-fits-all” approach to choosing treatments. Moreover, many patients preferred an active role in decision-making about treatment. Both results stress the need for physicians to know what is important to patients and to share treatment decisions to ensure that patients receive the treatment that aligns with their preferences.

Intracranial Hypertension in 2 Children With Marfan Syndrome

Two unrelated children with Marfan syndrome presented with recurrent intracranial hypertension. Both children complained of headache, nausea, and vomiting and one of them had papilledema. Both had increased cerebrospinal fluid pressure, and their complaints disappeared after lumbar puncture. Although severe headache has been reported in Marfan syndrome due to intracranial hypotension, this is to our knowledge the first report of intracranial hypertension in Marfan patients.

Reply: long-term retention rate of pramipexole in the treatment of Parkinson's disease

To the editor: n nKeranen and colleagues have investigated the retention rate on pramipexole (PRX) among patients diagnosed with idiopathic Parkinson’s disease (PD) in a University Hospital in Finland. Moreover, they investigated reasons for PRX discontinuation, and they tried to identify determinants for PRX discontinuation. We welcome their study as a first initiative to identify reasons for discontinuation and possible determinants. n nThe authors pointed out that they found a retention rate of PRX in PD patients that was higher (63% at 3xa0years) than we found in our cohort (40% at 3xa0years) [1], despite similarities in patient characteristics. We agree that differences in study methods may have contributed to variation in findings. In our study, we assessed the (dis)continuation of PRX treatment with prescription data from pharmacies whereas Keranen et al. used records of physicians. In our opinion, several factors have to be taken into account. Firstly, it is possible that not all changes in medication (discontinuation, dose changes) are written down in medical records. Therefore, some patients that have discontinued could be missed. Secondly, there remains a possibility that some patients have discontinued their medication without informing their physician. There is evidence for non-adherence in patients with PD measured with a computerised monitoring system [2]. However, studies investigating whether patients actually get their medication from the pharmacy are lacking. Lastly, the number of visits to the treating physician (in the study of Keranen et al.) or to the pharmacy (in our study) could be a factor in the precision of the estimation of discontinuation. The mean length of PRX prescriptions in our study was 47xa0days. This implies that we had an evaluation moment (use or no use) every 47xa0days. We do not know the frequency of visits to the treating physician in the study of Keranen et al. n nKeranen et al. found two non-genetic factors that were associated with PRX discontinuation: orthostatic hypotension and entacapone treatment prior to PRX treatment. These findings are an interesting supplement to our study. We think, however, that genetic factors should also be studied in the future [3].