Rob M. A. de Bie

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

BACKGROUND Patients 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. METHODS We 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. FINDINGS Between 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. INTERPRETATION Although 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. FUNDING Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging.

Genome-wide association study confirms extant PD risk loci among the Dutch.

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinsons disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19).

Prevalence of orthostatic hypotension in Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND Although orthostatic hypotension (OH) is recognized as one of the main non-motor symptoms of Parkinsons disease (PD), there is inconsistent evidence about the prevalence of OH in PD. To estimate the prevalence of OH in PD more precisely we conducted a systematic review of the literature. METHODS From PubMed and Embase searches with predefined inclusion criteria, we identified studies published up till December 2009. Prevalence numbers from studies were pooled using a non-linear random-effects meta-analysis. RESULTS We found 25 studies from which the prevalence of OH could be calculated. The pooled estimate of the point prevalence of OH in PD was 30.1% (95% CI: 22.9% to 38.4%). We found a large statistical heterogeneity between studies which could not be reduced by several subgroup analyses. CONCLUSIONS The estimated prevalence of OH in PD is 30%. However, due to the large heterogeneity between studies this pooled estimate should be interpreted with caution. More data from unselected population-based cohorts are needed.

Unilateral pallidotomy in Parkinson's disease: a randomised, single-blind, multicentre trial

BACKGROUND The results of several cohort studies suggest that patients with advanced Parkinsons disease would benefit from unilateral pallidotomy. We have assessed the efficacy of unilateral pallidotomy in a randomised, single-blind, multicentre trial. METHODS We enrolled 37 patients with advanced Parkinsons disease who had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. Patients were randomly assigned to unilateral pallidotomy within 1 month or to pallidotomy after the primary outcome assessment (6 months later). The primary outcome was the difference between the groups in median changes on the motor examination section of the unified Parkinsons disease rating scale (UPDRS 3) score done in the off phase. Secondary outcome measures included levodopa-induced dyskinesias (dyskinesia rating scale [DRS]) and extent of disability (UPDRS 2). FINDINGS The median UPDRS 3 off score of the pallidotomy patients improved from 47 to 32.5, whereas that of control patients slightly worsened from 52.5 to 56.5 (p<0.001). In the on phase the median DRS score improved 50% in pallidotomy patients compared with no change in controls. The UPDRS 2 off score improved with a median of 7 in the pallidotomy group. Two treated patients had major adverse effects. INTERPRETATION Unilateral pallidotomy is an effective treatment in patients with advanced Parkinsons disease, who have an unsatisfactory response to pharmacological treatment.

Directional steering: A novel approach to deep brain stimulation.

Objective: The aim of this study was to investigate whether directional steering through a novel 32-contact electrode is safe and can modulate the thresholds for beneficial and side effects of stimulation. Methods: The study is a single-center, performance and safety study. Double-blind intraoperative evaluations of the thresholds for therapeutic benefit and for side effects were performed in 8 patients with Parkinson disease while stimulating in randomized order in spherical mode and in 4 different steering modes with the 32-contact electrode, and in monopolar mode with a commercial electrode. In addition, simultaneous recordings of local field potentials through all 32 contacts were performed. Results: There were no adverse events related to the experimental device. For 13 of 15 side effects (87%), the threshold could be increased by ≥1 mA while steering in at least one direction in comparison to conventional spherical stimulation, thereby increasing the therapeutic window by up to 1.5 mA. Recording local field potentials through all 32 electrode contacts yielded spatiotemporal information on pathologic neuronal activity. Conclusions: Controlled steering of current through the brain may improve the effectiveness of deep brain stimulation (DBS), allow for novel applications, and provide a tool to better explore pathophysiologic activity in the brain. Classification of evidence: This study provides Class IV evidence that for patients with Parkinson disease, steering DBS current is well tolerated, increases the threshold for side effects, and may improve the therapeutic window of subthalamic nucleus DBS as compared with current standard spherical stimulation.

Unified Parkinson's disease rating scale motor examination: are ratings of nurses, residents in neurology, and movement disorders specialists interchangeable?

The Unified Parkinsons Disease Rating Scale (UPDRS) is widely used for the clinical evaluation of Parkinsons disease (PD). We assessed the rater variability of the UPDRS Motor examination (UPDRS‐ME) of nurse practitioners, residents in neurology, and a movement disorders specialist (MDS) compared to a senior MDS. We assessed the videotaped UPDRS‐ME of 50 PD patients. Inter‐rater and intra‐rater variability were estimated using weighted kappa (κw) and intraclass correlation coefficients (ICC). Additionally, inter‐rater agreement was quantified by calculation of the mean difference between 2 raters and its 95% limits of agreement. Intra‐rater agreement was also estimated by calculation of a 95% repeatability limits. The κw and ICC statistics indicated good to very good inter‐rater and intra‐rater reliability for the majority of individual UPDRS items and the sum score of the UPDRS‐ME in all raters. However, for inter‐rater agreement, it appeared that both nurses, residents, and the MDS consistently assigned higher scores than the senior MDS. Mean differences ranged between 1.7 and 5.4 (all differences P < 0.05), with rather wide 95% limits of agreement. The intra‐rater 95% repeatability limits were rather wide. We found considerable rater difference for the whole range of UPDRS‐ME scores between a senior MDS and nurse practitioners, residents in neurology, and the MDS. This finding suggests that the amount by which raters may disagree should be quantified before starting longitudinal studies of disease progression or clinical trials. Finally, evaluation of rater agreement should always include the assessment of the extent of bias between different raters.

Apathy in Parkinson's disease: A systematic review and meta-analysis

Apathy is a frequently reported neuropsychiatric symptom in Parkinsons disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta‐analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta‐analysis showed a prevalence of apathy in PD of 39.8% (n = 5,388, 905% CI 34.6‐45.0%). Apathy was associated with higher age (3.3 years, 95% CI = 1.7‐4.9), lower mean Mini‐Mental State Evaluation (MMSE) score (−1.4 points, 95% CI = −2.1 to −0.8), an increased risk of co‐morbid depression (relative risk [RR] = 2.3, 95% CI = 1.9‐2.8), higher Unified Parkinsons Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI = 2.6‐10.3), and more severe disability (Hedges‐G = 0.5, 95% CI = 0.3‐0.6). Half of the patients with apathy had concomitant depression (57.2%, 95% CI = 49.4‐64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI = 42.2%‐62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self‐care, and reduce cognitive impairment by improving executive functioning.

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review

Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Fatal human rabies due to duvenhage virus from a bat in Kenya: failure of treatment with coma-induction, ketamine, and antiviral drugs.

11Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2Department ofNeurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 3Department of Intensive Care, Academic Medical Center, University ofAmsterdam, Amsterdam, The Netherlands, 4Department of Clinical Virology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,5Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands, 6Department of Radiology, Academic Medical Center, University of Amsterdam,Amsterdam, The Netherlands, 7Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 8Centre of Expertise forRabies, Canadian Food Inspection Agency, Ottawa Laboratory (Fallowfield), Ottawa, Ontario, Canada

DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation†

Mutations in THAP1, a gene encoding a nuclear pro‐apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio‐cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult‐onset (≥26 years) dystonia (n = 388) and early‐onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early‐onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult‐onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult‐onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.