Wolfgang Hamel

Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease

We studied 48 patients after bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) who were evaluated 6 months after the surgical procedure using the Unified Parkinsons Disease Rating Scale (UPDRS) in a standardized levodopa test. Additional follow‐up was available in 32 patients after 12 months and in 20 patients after 24 months. At 6 months follow‐up, STN‐DBS reduced the UPDRS motor score by 50.9% compared to baseline. This improvement remained constant at 12 months with 57.5% and at 24 months with 57.3%. Relevant side effects after STN‐DBS included intraoperative subdural hematoma without neurological sequelae (n = 1), minor intracerebral bleeding with slight transient hemiparesis (n = 1), dislocation of impulse generator (n = 2), transient perioperative confusional symptoms (n = 7), psychotic symptoms (n = 2), depression (n = 5), hypomanic behaviour (n = 2), and transient manic psychosis (n = 1). One patient died because of heart failure during the first postoperative year. The current series demonstrates efficacy and safety of STN‐DBS beyond the first year after surgical procedure. Complications of STN‐DBS comprise a wide range of psychiatric adverse events which, however, were temporary.

Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease

The optimal stimulation site in subthalamic deep brain stimulation (STN‐DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN‐DBS.

Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait

Gait analysis was carried out to assess the effects of l-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold l-dopa dose, were found. Interestingly, stride length was more improved by l-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the “on” period, subthalamic nucleus stimulation failed to reduce this symptom effectively.

A Quick and Universal Method for Stereotactic Visualization of the Subthalamic Nucleus before and after Implantation of Deep Brain Stimulation Electrodes

For deep brain stimulation (DBS) of the subthalamic nucleus (STN), it would be an advantage if the STN could be visualized with fast acquisition of MR images, allowing direct and individual targeting. We present a protocol for T2-weighted, nonvolumetric fast-acquisition MRI, implemented at 8 centers in 6 countries. Acquisition time varied between 3 min 5 s and 7 min 48 s according to the center, and imaging often provided visualization of the STN on axial and coronal scans. Postoperatively, the same imaging protocol permitted visualization of the target area and DBS electrodes with minimum artifacts. This imaging technique may contribute to a decrease in the number of electrode passes at surgery.

Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor.

SummaryBackground. The ventro-lateral thalamus is the stereotactic target of choice for severe intention tremor. Nevertheless, the optimal target area has remained controversial, and targeting of the subthalamic area has been suggested to be superior. Patients and methods. Eleven patients with disabling intention tremor of different etiology (essential tremor (n = 8), multiple sclerosis (n = 2) and one with, spinocerebellar ataxia) were implanted bilaterally with DBS electrodes targeted to the ventro-lateral thalamus using micro-recording and micro-stimulation. Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation. Postoperative tremor suppression elicited by individual electrode contacts was quantified using a lateralised tremor rating scale at least 3 months (in most patients >1 year) after implantation. The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI. Results. In all patients, DBS suppressed intention tremor markedly. On average, tremor on the left and right side of the body was improved by 68% (±19; standard deviation) and 73% (±21), respectively. In most patients, distal electrode contacts located in the subthalamic area proved to be more effective than proximal contacts in the ventro-lateral thalamus. In stereotactic coordinates, the optimal site was located 12.7 mm (±1.4; mean ± standard deviation) lateral, 7.0 (±1.6) mm posterior, and 1.5 (±2.0) mm ventral to the mid-commissural point. In general, the best contacts could be selected for permanent stimulation. Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (paraesthesiae, dysarthria, gait ataxia) which were more pronounced with bilateral stimulation resulting in slightly less tremor suppression on the left and right side of body (63 ± 18 and 68 ± 19%, respectively). Conclusion. Direct comparison of different stimulation sites in individual patients revealed that DBS in the subthalamic area is more effective in suppressing pharmacoresistant intention tremor than the ventro-lateral thalamus proper. Anatomical structures possibly involved in tremor suppression include cerebello-thalamic projections, the prelemniscal radiation, and the zona incerta.

Pattern of recurrence following local chemotherapy with biodegradable carmustine (BCNU) implants in patients with glioblastoma

AbstractObjective: Recently a randomized placebo-controlled phase III trial of biodegradable polymers containing carmustine has demonstrated a significant survival benefit for patients treated with local chemotherapy. A local chemotherapy applied directly to the resection cavity may act directly on residual tumor cells in adjacent brain possibly leading to a local control of the tumor and increased survival. Methods: We have analyzed the pattern of recurrence using serial MRI studies of 24 patients treated with GLIADEL® Wafers or placebo wafers following resection of glioblastomas. Results: Of 24 patients 11 received carmustine wafers and 13 placebo. The age distribution and Karnowsky performance scores of the two populations were not different. However, the median survival (14.7 versus 9.5 months; P = 0.007) and the time to neurological deterioration (12.9 ± 4.85 vs. 9.4 ± 2.73 months; P = 0.035) was significantly longer in the treatment group versus the placebo treated control. Preoperative and follow up MRI studies were evaluated in a blinded fashion. Out of 24 patients that entered the analysis 11 showed clearance of all contrast enhancement following resection of glioblastomas. Seventeen tumors progressed locally and 7 showed different patterns of distant failure. Within the carmustine treated group 8 patients showed a local treatment failure with recurrent tumors immediately adjacent to the resection cavity or progression form a residual tumor. Three patients showed a multifocal distant and local pattern of failure after complete or subtotal removal. In no case the local chemotherapy resulted in a distant recurrence only. However, the time to radiographic progression was 165.1 ± 80.75 days for the GLIADEL® Wafer group and 101.9 ± 43.06 days for the placebo group (P = 0.023). Conclusion: In this subgroup analysis of a phase III trial population both the clinical progression and radiological progression were significantly delayed in patients treated with local chemotherapy, resulting in an increased survival time. Local chemotherapy with carmustine containing wafer implants did not result in an altered pattern of recurrence and did not promote multifocal patterns of recurrence.

Trk A, B, and C are commonly expressed in human astrocytes and astrocytic gliomas but not by human oligodendrocytes and oligodendroglioma

Abstract Neurotrophins regulate the proliferation and differentiation of neurons in the central nervous system via a family of specialized receptors, including TrkA, TrkB, and TrkC. As little is known about their expression or potential role in human glial tissues and glial tumors, we undertook an immunohistochemical analysis of human glia, glioma tissues and cell cultures of glial tumors to characterize the expression of Trk family members (full-length TrkA, TrkB, the truncated form of TrkB, and TrkC). In normal human brain Trk A, B, and C immunoreactivity was found in neurons and some weak staining was also seen astrocytes. No Trk expression was seen on oligodendrocytes. Strong reactivity was seen in reactive astrocytes in a glial scar. In a total of 34 glioma tissue specimens, which included 16 astrocytic tumors (4 low-grade astrocytomas and 12 glioblastomas multiforme) and 15 oligodendrogliomas (8 low-grade and 7 anaplastic) as well as 3 oligoastrocytomas (WHO grade II), TrkA, B, and C immunoreactivity was observed exclusively in specimens from astrocytic gliomas (16/16), but not in any of the oligodendrocytic gliomas (0/15). In the oligoastrocytomas, staining was restricted to the astrocytic component. In the astrocytoma and oligodendroglioma specimens, Trk A, B, and C immunoreactivity was also seen in the surrounding reactive astrocytes. Trk expression was independent of age, sex or histological grade of the investigated tumors. In six primary cell cultures, one derived from human astrocytes and five established from malignant astrocytomas, only TrkA immunoreactivity could be detected, while TrkB (both full-length and truncated isoforms) and TrkC were absent. The TrkA expression in primary cell cultures decreased with continuous cell passaging, and no Trk could be detected in established cell lines derived from glioblastoma. In conclusion, our data suggest that in human glial tissues Trk A, B, and C may be expressed in a lineage-restricted manner, thereby distinguishing between astrocytes and oligodendrocytes in a marker-like fashion. Trk expression, like GFAP expression appears to be increased in activated (reactive)/ neoplastic astrocytes.

Magnetic Resonance Imaging-Based Morphometry and Landmark Correlation of Basal Ganglia Nuclei

Summary. The two principle targets for deep brain stimulation or lesioning in patients with Parkinsons disease, the subthalamic nucleus (STN) and the globus pallidus internus (GPi), reveal a high degree of individual variability which is relevant to the planning of stereotactic operations. Both nuclei can clearly be delineated in T2WI spin echo MRI which was acquired under stereotactic conditions in general anesthesia before surgery. Such images of 35 patients served for retrospective morphometric analysis of different basal ganglia nuclei (STN, GP, red nucleus, and substantia nigra) and several anatomical landmarks (anterior and posterior commissure, maximum width of third ventricle, brain length and width). The average AC-PC distance was 25.74 mm (range 21 to 29 mm) and is in agreement with previous studies. On average, the center of the STN was located 12.65 mm (±1.3) lateral from the midline as determined 3 mm ventral to the intercommissural plane. The average width of the third ventricle was 7.05 mm (±2.41). The width of the third ventricle correlated with the laterality of the STN (rright=.78; rleft=.83) and GP (rright=.76; rleft=.68). Although to a lesser extent, significant correlations were also observed between the laterality of the STN and brain width, improving prediction of STN laterality by multiple linear regression analysis (rright=.82; rleft=.87). Similarly, the laterality of GP correlated with brain width. In addition, gender-specific differences were detected. The STN and GP was located farther lateral in males which may be due to overall brain anatomy as gender-specific differences were also observed for brain width and length and AC-PC distance. MRI-based in vivo-localization of different basal ganglia nuclei extend statistical information from common histological brain atlases which are based on a limited number of brains. The correlations observed between different basal ganglia nuclei, i.e. the STN and GPi, and anatomical landmarks may be useful for surgical planning.

Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease.

Parkinsons disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinsons Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Subthalamic nucleus stimulation for Parkinson's disease preferentially improves akinesia of proximal arm movements compared to finger movements

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) reduces akinesia in Parkinsons disease but its impact on fine motor functions was unknown. We assessed the effects of DBS and a levodopa (L‐dopa) test on the timing of the precision grip in 18 patients. Improvement on UPDRS‐items reflecting hand functions and the shortening of the first phases of the precision grip were more distinct in the L‐dopa test than in the pure STN‐DBS condition. Other akinesia items and the time for build‐up of lifting force were equally improved in both conditions. This suggests that routine STN‐DBS might not be equally effective on all aspects of fine motor functions.