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In this randomized trial comparing neurostimulation of the subthalamic nucleus with medical management alone in 156 patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. In patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. Parkinson's disease is one of the most disabling chronic neurologic diseases and leads to a significant loss of quality of life. 1 , 2 Several drugs are available that can effectively treat the symptoms of the disease, but long-term medical management is often complicated by the appearance of levodopa-induced motor complications, leading to rapid changes between periods of severe akinesia and periods of mobility that may be accompanied by troublesome hyperkinesias. 3 Dopamine agonists, amantadine, catechol O -methyltransferase (COMT) inhibitors, 3 and other drugs can effectively improve mobility and reduce dyskinesias initially but typically fail after several years. 4 The administration of high-frequency continuous electrical . . .

Background The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare. Methods We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m 2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model. Results The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off). Conclusion In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.

Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke–Fahn–Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to −20·8 points (SD 17·1; −47·9%; n=40) at 6 months; −26·5 points (19·7; −61·1%; n=31) at 3 years; and −25·1 points (21·3; −57·8%; n=32). The improvement from 6 months to 3 years (–5·7 points [SD 8·4]; −34%) was significant and sustained at the 5-year follow-up (–4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. Medtronic.

In this sham-controlled trial of neurostimulation of the internal globus pallidus for primary dystonia, neurostimulation improved movement, disability, and quality-of-life scores. Adverse events were common; 18% of patients had infections at the stimulator site, seroma, or lead breakage or dislodgment, and 12% had dysarthria. In patients with primary dystonia, neurostimulation of the internal globus pallidus improved movement, disability, and quality-of-life scores. Adverse events were common. Primary dystonia comprises a group of idiopathic, incurable movement disorders that vary with respect to age at onset, body distribution, and genetic association. 1 All these disorders are characterized by twisting, repetitive movements or abnormal postures caused by involuntary muscle contractions. 2 The mainstay of treatment for focal or segmental dystonia is the injection of botulinum toxin to denervate the affected muscles. 3 When this approach fails (because too many muscles are involved, the movement pattern is too complex, or neutralizing antibodies develop 4 ), the management of dystonia becomes difficult. Drug therapy is often unsatisfactory, 5 which leaves many patients with a profound incapacity . . .

In this study, we assessed the outcomes of patients with dystonia who underwent surgery treatment following the same algorithm. Eighty consecutive patients with dystonia were submitted to neurosurgical management by means of intrathecal pump implantation, pallidotomy or deep brain stimulation (GPi or VIM). These patients included 48 patients with primary dystonia and 32 patients with secondary dystonia. Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) was used to access pre- and post-operative outcomes. Patients were followed from 12 to 114 months. Mean improvement in BFMDRS score among patients with PrD was 87.54% and 42.21% for SeD. Hemidystonic patients in both groups (PrD, SeD) showed a mean improvement in BFMDRS of 71.05% with GPiDBS. Patients with SeD due to previous perinatal insults showed a mean improvement in BFMDRS of 41.9%, with better results in purely dyskinetic patients (mean improvement of 61.2%). Use of the proposed algorithm facilitated surgical decision planning, which translated in improved diagnostic rates, earlier interventions, appropriate management plans, and outcomes for both groups (PrD, SeD). Therefore, neuroimaging findings had a positive prognostic significance in the response to treatment in patients with primary dystonia compared with patients with secondary dystonia or distortion of basal ganglia anatomy. However, further studies in this line are warranted.

Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (–363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change −0·65 points [SE 0·15]) and did not change with medical therapy alone (–0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change −1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (  = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (  = 63) and 53 ± 31% at 5 years (  = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (  = 9) correlated significantly with improvement after 3 years, but not 5 years. Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. ClinicalTrials.gov NCT00142259.