Hubertus Maximilian Mehdorn

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.

Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article.

OBJECT Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA-induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery. METHODS Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function. RESULTS More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm(3), p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036). CONCLUSIONS Extended resections performed using a tool such as 5-ALA-derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.

A functional endophenotype for sexual orientation in humans

Sexually arousing visual stimuli activate the human reward system and trigger sexual behavior. Here we performed event-related fMRI during visual processing of sexual core stimuli to pinpoint a neuronal correlate of sexual preference in humans. To dissociate gender of the stimulus from sexual preference, we studied male and female heterosexual and homosexual volunteers while they viewed sexual and nonsexual control stimuli. In contrast to previous work, we used core single-sex stimuli displaying male and female sexually aroused genitals. Since stimuli lacked any additional contextual information, they evoked no activity related to neuronal processing of faces, gestures or social interactions. Our prediction was that the sexual preference of the observer determines the neuronal responsiveness to pure male or female sexual stimuli in the human reward and motor system. Consistent with our prediction, the ventral striatum and the centromedian thalamus, showed a stronger neuronal response to preferred relative to non-preferred stimuli. Likewise, the ventral premotor cortex which is a key structure for imitative (mirror neurons) and tool-related (canonical neurons) actions showed a bilateral sexual preference-specific activation, suggesting that viewing sexually aroused genitals of the preferred sex triggers action representations of sexual behavior. The neuronal response of the ventral striatum, centromedian thalamus and ventral premotor cortex to preferred sexual stimuli was consistent across all groups. We propose that this invariant response pattern in core regions of the human reward and motor system represents a functional endophenotype for sexual orientation independent of the gender of the observer and gender of the stimulus.

Does the cerebellum contribute to specific aspects of attention

We present data on attentional and neuropsychological functions of 16 patients with focal cerebellar lesions (13 tumours, 3 haematomas) compared to normative test data, and to 11 control subjects matched for age, gender, and years of education. Patients showed distinct deficits in qualitative aspects of a divided attention task, and in a working memory task. Performance in selective attention was unimpaired. The results support the concept that the cerebellum plays a role not only in motor, but also in higher cognitive functions. They are discussed on the basis of the idea that prediction and preparation are fundamental functions of the cerebellum. Therefore, the results confirm the idea that cerebellar lesions lead to reduced performance in specific attention tasks.

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.

Induction of Empathy by the Smell of Anxiety

The communication of stress/anxiety between conspecifics through chemosensory signals has been documented in many vertebrates and invertebrates. Here, we investigate how chemosensory anxiety signals conveyed by the sweat of humans (N = 49) awaiting an academic examination are processed by the human brain, as compared to chemosensory control signals obtained from the same sweat donors in a sport condition. The chemosensory stimuli were pooled according to the donation condition and administered to 28 participants (14 males) synchronously to breathing via an olfactometer. The stimuli were perceived with a low intensity and accordingly only about half of the odor presentations were detected by the participants. The fMRI results (event-related design) show that chemosensory anxiety signals activate brain areas involved in the processing of social emotional stimuli (fusiform gyrus), and in the regulation of empathic feelings (insula, precuneus, cingulate cortex). In addition, neuronal activity within attentional (thalamus, dorsomedial prefrontal cortex) and emotional (cerebellum, vermis) control systems were observed. The chemosensory perception of human anxiety seems to automatically recruit empathy-related resources. Even though the participants could not attentively differentiate the chemosensory stimuli, emotional contagion seems to be effectively mediated by the olfactory system.

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.

Expression of VEGF and its receptors in different brain tumors

Abstract Introduction: Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and -2 are considered to play a major in tumor angiogenesis, which is a prerequisite for growth of solid tumors. Glioblastoma multiforme is a prominent example of VEGF-induced tumor vascularization; however, little is known about VEGF and in particular VEGFR expression in other types of brain tumors. Methods: VEGFR mRNA was quantified by real time RT-PCR in 12 different types of brain tumors and compared to VEGF protein content measured by ELISA. VEGF splice variants were determined by an RT-PCR method. Results: VEGF protein was highest in glioblastoma and metastatic kidney tumors. In all types of tumors the diffusible splice forms VEGF121 and VEGF165 were expressed; VEGF189 was minor in a few tumors. Expression of VEGF receptors did not necessarily correlate with VEGF content. Both were highly expressed in glioblastomas, but in meningiomas VEGF was low and VEGFR high, and in metastatic tumors the reverse. With few exceptions, in particular oligodendrogliomas, VEGFR-1 expression was parallel to VEGFR-2 expression. Interestingly, for the astrocytic gliomas, the expression of VEGFR correlated well to the tumor malignancy, even better than VEGF content. Conclusions: These results show that VEGF and VEGFR expression in various types of brain tumors differ and are not necessarily parallel.