Vincent J.J. Odekerken

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.

GPi vs STN deep brain stimulation for Parkinson disease: Three-year follow-up

Objective: To compare motor symptoms, cognition, mood, and behavior 3 years after deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) in advanced Parkinson disease (PD). Methods: Patients with PD eligible for DBS were randomized to bilateral GPi DBS and bilateral STN DBS (1:1). The primary outcome measures were (1) improvement in motor symptoms in off-drug phase measured with the Unified Parkinson Disease Rating Scale (UPDRS) and (2) a composite score for cognitive, mood, and behavioral effects, and inability to complete follow-up at 36 months after surgery. Results: Of the 128 patients enrolled, 90 were able to complete the 3-year follow-up. We found significantly more improvement of motor symptoms after STN DBS (median [interquartile range (IQR)] at 3 years, GPi 33 [23–41], STN 28 [20–36], p = 0.04). No between-group differences were observed on the composite score (GPi 83%, STN 86%). Secondary outcomes showed larger improvement in off-drug functioning in the AMC Linear Disability Scale score after STN DBS (mean ± SD, GPi 65.2 ± 20.1, STN 72.6 ± 18.0, p = 0.05). Medication was reduced more after STN DBS (median levodopa equivalent dose [IQR] at 3 years, GPi 1,060 [657–1,860], STN 605 [411–875], p < 0.001). No differences in adverse effects were recorded, apart from more reoperations to a different target after GPi DBS (GPi n = 8, STN n = 1). Conclusions: Off-drug phase motor symptoms and functioning improve more after STN DBS than after GPi DBS. No between-group differences were observed on a composite score for cognition, mood, and behavior, and the inability to participate in follow-up. Classification of evidence: This study provides Class II evidence that STN DBS provides more off-phase motor improvement than GPi DBS, but with a similar risk for cognitive, mood, and behavioral complications.

Thalamic deep brain stimulation for orthostatic tremor: Clinical and neurophysiological correlates

Orthostatic tremor (OT) is characterized by progressive unsteadiness during stance, due to fine-amplitude leg tremor with a 13e18 Hz frequency, leading to limited ability to stand or walk and impaired functioning. Medication is often ineffective. Bilateral deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius medialis (Vim) has been reported in only five patients so far [1e5]. A 70-years-old lady complained of progressive bilateral postural hand tremor and unsteadiness during stance and walking since 20 years. She could stand without support only for a few seconds, could not walk longer than 10 min and had difficulties in many activities including writing and cooking. Clonazepam (6 mg/day) and other benzodiazepines, gabapentin, and pramipexole were ineffective. Her medical history included Menieres disease, vitrectomy for macula pucker, and gynecological surgeries. Neurological and surface EMG evaluations revealed a 16 Hz leg tremor, which appeared immediately after the patient stood and necessitated her sitting after about 30 s (Video 1, Fig. 1 panel A). A postural arm tremor, downbeat nystagmus, and brisk stretch reflexes were observed, though neither ataxia nor parkinsonism was. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2015.06.008.

Deep brain stimulation for Parkinson’s disease: meta-analysis of results of randomized trials at varying lengths of follow-up

OBJECTIVE Deep brain stimulation (DBS) is effective in the management of patients with advanced Parkinsons disease (PD). While both the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are accepted targets, their relative efficacy in randomized controlled trials (RCTs) has not been established beyond 12 months. The objective of this study was to conduct a meta-analysis of RCTs to compare outcomes among adults with PD undergoing DBS of GPi or STN at various time points, including 36 months of follow-up. METHODS The MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases were searched. Registries for clinical trials, selected conference proceedings, and the table of contents for selected journals were also searched. Screens were conducted independently and in duplicate. Among the 623 studies initially identified (615 through database search, 7 through manual review of bibliographies, and 1 through a repeat screen of literature prior to submission), 19 underwent full-text review; 13 of these were included in the quantitative meta-analysis. Data were extracted independently and in duplicate. The Cochrane Collaboration tool was used to assess the risk of bias. The GRADE evidence profile tool was used to assess the quality of the evidence. Motor scores, medication dosage reduction, activities of daily living, depression, dyskinesias, and adverse events were compared. The influence of disease duration (a priori) and the proportion of male patients within a study (post hoc) were explored as potential subgroups. RESULTS Thirteen studies (6 original cohorts) were identified. No difference in motor scores or activities of daily living was identified at 36 months. Medications were significantly reduced with STN stimulation (5 studies, weighted mean difference [WMD] -365.46, 95% CI -599.48 to -131.44, p = 0.002). Beck Depression Inventory scores were significantly better with GPi stimulation (3 studies; WMD 2.53, 95% CI 0.99-4.06 p = 0.001). The motor benefits of GPi and STN DBS for PD are similar. CONCLUSIONS The motor benefits achieved with GPi and STN DBS for PD are similar. DBS of STN allows for a greater reduction of medication, but not as significant an advantage as DBS of GPi with respect to mood. This difference is sustained at 36 months. Further long-term studies are necessary.

Psychiatric and social outcome after deep brain stimulation for advanced Parkinson's disease

The aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinsons disease (PD).

Neuropsychological outcome after deep brain stimulation for Parkinson diseaseAuthor Response

Odekerken et al.1 investigated neuropsychological outcome after deep brain stimulation (DBS) in Parkinson disease (PD). The subthalamic nucleus (STN) is the most common DBS target in PD despite data suggesting that it is not superior to globus pallidus pars interna (GPi). The aggregate data from the 3 large, head-to-head trials suggested that GPi DBS results in equivalent motor benefits based on their primary endpoints.2,–,4 However, Odekerken et al.1 …

Does deep brain stimulation improve lower urinary tract symptoms in Parkinson's disease?

To investigate whether deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or the subthalamic nucleus (STN) improve lower urinary tract symptoms (LUTS) in advanced Parkinsons disease (PD).

Anti-Ma2–associated encephalitis in a patient with testis carcinoma

A 30-year-old man presented with 3 months of alternating hyper- and hypothermia, libido loss, hypersomnia, and headache. Neurologic examination was unremarkable. Laboratory tests revealed low serum testosterone and hypocortisolism. MRI showed hypothalamic T2 hyperintensity and contrast enhancement (figure, A). CSF analysis showed moderate lymphocytosis. Cerebral infections and malignancies were excluded. Methylprednisolone was started based on a working-diagnosis of lymphocytic hypothalamitis. After initial improvement, the patient relapsed, with MRI showing limbic involvement (figure, B). Serum and CSF screening was positive for anti-MA2. Ultrasonography showed microcalcification of the right testicle, which was resected. Histology showed focal germ cell neoplasia.

Subthalamic versus globus pallidus deep brain stimulation: Authors' reply

www.thelancet.com/neurology Vol 12 April 2013 329 Authors’ reply The Netherlands SubThalamic and Pallidal Stimulation (NSTAPS) study was initiated to test the hypothesis that bilateral globus pallidus deep brain stimulation would improve disability to a greater extent than would bilateral subthalamic nucleus deep brain stimulation. By contrast with previous studies that investigated the eff ectiveness of deep brain stimulation, we chose a generic disability scale as the primary outcome measure, which was weighted by time spent in either the on phase or the off phase. Our results did not show a between-group diff erence for this primary outcome. As stipulated in our discussion section and in line with Erwin Montgomery’s remarks, this result could be explained by insuffi cient statistical power raising the probability of a type II error. We are of course aware that the absence of diff erence in our primary outcome does not imply equivalence of the two procedures. However, this idea was not our conclusion, nor was it the rationale of the accompanying Comment. Since the secondary outcome measures show clinically important diff erences, we concluded that our data suggest that the subthalamic nucleus, rather than the globus pallidus, could be the preferred target for deep brain stimulation in Parkinson’s disease, because it leads to more substantial improvement of symptoms and disability in the off phase, needs fewer drugs, and has lower battery consumption.

Deep Brain Stimulation for Essential Tremor: Aligning Thalamic and Posterior Subthalamic Targets in 1 Surgical Trajectory

BACKGROUND Ventral intermediate nucleus (VIM) deep brain stimulation (DBS) and posterior subthalamic area (PSA) DBS suppress tremor in essential tremor (ET) patients, but it is not clear which target is optimal. Aligning both targets in 1 surgical trajectory would facilitate exploring stimulation of either target in a single patient. OBJECTIVE To evaluate aligning VIM and PSA in 1 surgical trajectory for DBS in ET. METHODS Technical aspects of trajectories, intraoperative stimulation findings, final electrode placement, target used for chronic stimulation, and adverse and beneficial effects were evaluated. RESULTS In 17 patients representing 33 trajectories, we successfully aligned VIM and PSA targets in 26 trajectories. Trajectory distance between targets averaged 7.2 (range 6-10) mm. In all but 4 aligned trajectories, optimal intraoperative tremor suppression was obtained in the PSA. During follow-up, active electrode contacts were located in PSA in the majority of cases. Overall, successful tremor control was achieved in 69% of patients. Stimulation-induced dysarthria or gait ataxia occurred in, respectively, 56% and 44% of patients. Neither difference in tremor suppression or side effects was noted between aligned and nonaligned leads nor between the different locations of chronic stimulation. CONCLUSION Alignment of VIM and PSA for DBS in ET is feasible and enables intraoperative exploration of both targets in 1 trajectory. This facilitates positioning of electrode contacts in both areas, where multiple effective points of stimulation can be found. In the majority of aligned leads, optimal intraoperative and chronic stimulation were located in the PSA.