Maximilian Mehdorn

Neurostimulation for Parkinson's Disease with Early Motor Complications

BACKGROUND Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinsons disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinsons disease. METHODS In this 2-year trial, we randomly assigned 251 patients with Parkinsons disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinsons Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinsons Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS Subthalamic stimulation was superior to medical therapy in patients with Parkinsons disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality

PURPOSE NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Camptocormia in idiopathic Parkinson's disease: A focal myopathy of the paravertebral muscles†

The objective of our study was to describe the clinical features of camptocormia, an involuntary, marked flexion of the thoracolumbar spine in idiopathic Parkinsons disease (PD) and to understand its etiology. In a prospective, cross‐sectional study, we examined 15 patients with PD and camptocormia using laboratory parameters, EMG, muscle magnetic resonance imaging, and biopsy of the paravertebral muscles. The clinical data were compared with a matched control group of PD patients without camptocormia, and the biopsies were compared with muscles from age‐matched autopsies. Almost all the patients (median age, 68.0 years; 7 women) with camptocormia suffered from advanced PD. Camptocormia occurred at a median of 9.0 years after the PD diagnosis. Compared with our clinical control group, back pain was more frequent and less dopa‐sensitive in the patients with camptocormia who suffered more often from additional diseases of the back. On EMG, we found mainly a myopathic pattern. The MRI of the paravertebral muscles showed localized changes ranging from edema with contrast enhancement, which are considered to be early signs, to atrophy and/or fatty degeneration, interpreted as late degenerative changes. Early signs were seen mainly during the first year and degenerative changes after 1.5 years. Biopsies revealed consistently myopathic changes and in some cases fatty degeneration. Clinical or electromyographic features favoring dystonia were absent. Camptocormia is a major disabling, non‐fluctuating and levodopa‐resistant complication of advanced PD. The cause of camptocormia in idiopathic PD is a focal myopathy. Our findings suggest that the myopathy has a progressive course, which finally leads to degeneration of the paravertebral muscles.

A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma

PURPOSE A randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma. PATIENTS AND METHODS 149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400mg weekly added to standard radiochemotherapy followed by 400mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points. RESULTS 142 patients were evaluated for efficacy (per protocol cohort). 12 moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n=81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55-1.37), for patients without residual tumour (n=61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57-1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52-1.57; P=0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41-1.44; P=0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35-1.67; P=0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27-1.64; P=0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated. CONCLUSION This study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

PURPOSE In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Navigational place learning in children and young adults as assessed with a standardized locomotor search task

Spatial behaviour was investigated using a spatial learning task based on the Radial Arm Maze, the Morris Water Maze, and open-field search-task procedures. Ninety-six healthy children from six age groups (3, 4, 5, 7, 10 and 12 years) with no history of CNS disorders were studied with respect to the emergence of position-, cue- and place responses. Participants were to detect x out of n hidden locations, frames of reference could be varied systematically, and three spatial memory errors and speed of navigation were recorded automatically. Task difficulties were equivalent for each age group. Results showed that navigational place learning was fully developed by the age of 10, whereas participants relied on cue orientation up to age 7. Even in the youngest group, the task could be achieved without relying on egocentric orientation, provided that proximal cues were presented. Most of the errors were of the reference memory type, whereas working memory errors were extremely rare. Speed of navigation markedly improved between age 5 and 7. An additional experiment showed that navigational place-learning behaviour was clearly dependent on distal cues. A third study showed that in young adults, learning of the spatial layout improved, but performance on the place task did not improve any further. No sex differences were observed.

Recovery of spatial memory and persistence of spatial orientation deficits after traumatic brain injury during childhood.

The present study set out to examine the recovery of spatial learning and cognitive mapping skills after severe TBI in childhood. A prospective investigation was carried out with repeated measures. Children with TBI (n = 18) and healthy matched controls (n = 18) were investigated while the children with TBI stayed in a rehabilitation facility (t0) and 4 years later (t1). Children were assessed with the Kiel Locomotor Maze, where they had to remember defined locations in an experimental chamber with completely controlled intra- and extra-maze cues until the learning criterion was reached. During probe trials, cognitive mapping strategies were assessed. Results showed (i) that spatial learning is functionally restituted 4 years post-trauma and (ii) that cognitive mapping skills are still impaired 4 years post-trauma. It was concluded that cognitive performance of children who survived a severe TBI may be overestimated, having far reaching consequences for the children.

Uncoupling of dopaminergic and subthalamic stimulation: Life-threatening DBS withdrawal syndrome.

Deep brain stimulation (DBS) in therapy for advanced Parkinsons disease (PD) is an accepted treatment. Infections of the system and other complications occasionally result in hardware removal and subsequent medical treatment alone for months.

Children's Spatial Behavior is Differentially Affected After Traumatic Brain Injury

Spatial behavior in 20 children with severe traumatic brain injury (TBI) and 20 healthy controls was investigated using the Kiel Locomotor Maze. Children had to remember defined locations in an experimental chamber with completely controlled intra- and extra-maze cues until learning criterion was reached. In a second experiment, spatial orientation strategies were assessed. Children with TBI were shown to be impaired in spatial learning and spatial memory. Spatial orientation was found to be deficient even in cases where spatial learning and memory proved to be unimpaired, especially in tasks that demanded the use of relational place strategies. Children who suffered a TBI at an early age proved to be more severely impaired in spatial learning and orientation than older children.