Harald Treuer

The nucleus accumbens: A target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders

We considered clinical observations in patients with obsessive-compulsive- and anxiety-disorders, who underwent bilateral anterior capsulotomy, as well as anatomical and pathophysiological findings. Based on these considerations, we choose the shell region of the right nucleus accumbens as target for deep brain stimulation (DBS) in a pilot-series of four patients with severe obsessive-compulsive- and anxiety-disorders. Significant reduction in severity of symptoms has been achieved in three of four patients treated. Clinical results as well as a 15-O-H(2)O-PET study, perfomed in one patient during stimulation, speak in favour of the following hypothesis. As a central relay-structure between amygdala, basal ganglia, mesolimbic dopaminergic areas, mediodorsal thalamus and prefrontal cortex, the accumbens nucleus seems to play a modulatory role in information flow from the amygdaloid complex to the latter areas. If disturbed, imbalanced information flow from the amygdaloid complex could yield obsessive-compulsive- and anxiety-disorders, which can be counteracted by blocking the information flow within the shell region of the accumbens nucleus by deep brain stimulation.

Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus

The occurrence of radiation-induced apoptosis in normal brain was investigated using an animal model of radiosurgery. Adult male Fischer rats aged 3 to 4 months were subjected to single dose convergent beam irradiation (10 Gy). Apoptotic cell death was determined by in situ labeling of DNA nick ends (TUNEL) and light microscopic evaluation of cell morphology. Five hours after irradiation, a highly significant increase of apoptotic cells in the subgranular zone of the dentate gyrus was paralleled by a corresponding significant decrease of cells immunoreactive for the proliferation marker Ki-67. Morphology, location and distribution of cells affected by radiation-induced apoptosis in the dentate gyrus subgranular zone, together with NeuN-immunohistochemistry, support the contention that these cells belong to the immature progenitor population responsible for neurogenesis in the adult rat hippocampus.

Risk analysis of linear accelerator radiosurgery.

PURPOSE To evaluate the toxicity of stereotactic single-dose irradiation and to compare the own results with already existing risk prediction models. METHODS AND MATERIALS Computed tomography (CT) or magnetic-resonance (MR) images, and clinical data of 133 consecutive patients treated with linear accelerator radiosurgery were analyzed retrospectively. Using the Cox proportional hazards model the relevance of treatment parameters and dose-volume relationships on the occurrence of radiation-induced tissue changes (edema, localized blood-brain barrier breakdown) were assessed. RESULTS Sixty-two intraparenchymal lesions (arteriovenous malformation (AVM): 56 patients, meningioma: 6 patients) and 73 skull base tumors were selected for analysis. The median follow-up was 28.1 months (range: 9.0-58.9 months). Radiation-induced tissue changes (32 out of 135, 23.7%) were documented on CT or MR images 3.6-58.7 months after radiosurgery (median time: 17.8 months). The actuarial risk at 2 years for the development of neuroradiological changes was 25.8% for all evaluated patients, 38.4% for intraparenchymal lesions, and 14.6% for skull base tumors. The coefficient: total volume recieving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model calculated for all patients, intraparenchymal lesions, and AVMs. In skull base tumors, the volume of normal brain tissue covered by the 10 Gy isodose line (VBRAIN10) was the only significant variable. CONCLUSIONS These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.

Cystic craniopharyngioma: long-term results after intracavitary irradiation with stereotactically applied colloidal beta-emitting radioactive sources.

OBJECTIVE Long-term follow-up data were analyzed to assess the value of intracavitary irradiation with stereotactically applied beta-emitting radioisotopes for the treatment of craniopharyngioma cysts. METHODS Sixty-two of 70 consecutive patients with predominantly cystic craniopharyngiomas were selected for retrospective analysis. Beta-Emitting isotopes were injected intracystically using a computed tomography-guided and computer-assisted three-dimensional stereotactic treatment planning and application system (cumulative dose to the inner surface of the cyst wall, 200 Gy). RESULTS The tumor response rate gained with yttrium-90-labeled silicate (66 of 78 cysts) or phosphorous-32-labeled chromic phosphate (8 of 78 cysts) was 79.5%. Four cysts treated with rhenium-186-labeled sulfate did not respond. Mean survival after intracavitary irradiation was 9.0 +/- 0.9 years (median follow-up, 11.9 yr). In patients with solitary cysts, the mean survival was 12.5 +/- 1.4 years (actuarial 5- and 10-yr survival rates, 80 and 64%, respectively). Six months postoperatively, visual deficits (38 of 62 patients) had improved in 23 patients and were stable in 15 patients. The side effects that occurred 6 to 12 months after treatment with yttrium-90 were complete blindness (three patients), worsening of visual field cuts (one patient), third nerve palsy (one patient), and diabetes insipidus and/or panhypopituitarism (three patients). CONCLUSIONS Intracavitary irradiation using yttrium-90 or phosphorous-32 is highly effective in the treatment of cystic craniopharyngiomas. If applied as initial treatment in patients with solitary cysts, it is the only required therapy over a long period.

11C-METHIONINE AND 18F-2-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY :A TOOL FOR DIAGNOSIS OF CEREBRAL GLIOMA AND MONITORING AFTER BRACHYTHERAPY WITH 125I SEEDS

Forty-six patients with suspected brain tumors were investigated by positron emission tomography (PET). Using 11C-methionine PET, the spatial extent of increased uptake in gliomas was larger than that of contrast enhancement on CT/MR images in 67% or the same in 33%. Ten of 46 patients treated with brachytherapy for low-grade gliomas were also investigated with 18F-2-fluorodeoxyglucose (FDG)-PET. One year after seed implantation, the glucose metabolism had not changed, but the decline of methionine uptake was significant. In conclusion, 11C-methionine PET may improve tumor delineation and, following brachytherapy, provides more information on the therapeutic effects than FDG.

CT-Guided and Computer Assisted Stereotactic Biopsy Technique, Results, Indications

SummaryOn the base of a stereotactic device originally described by Riechert and Mundinger a three-dimensional localization and treatment planning system for CT-guided computer assisted stereotactic procedures has been developed. The experience with 338 patients, in which image guided stereotaxy has been used for the assessment of various intracerebral lesions, is presented. In 54 of these patients the cannula was introduced with a 20 MHz Doppler-probe positioned at the tip of the needle. A comparison of tissue specimens taken stereotactically with tissue material after tumour resection and/or autopsy was performed in 35 patients. The accuracy of the histological diagnosis was 88%. Bleeding as a complication due to the stereotactic intervention occurred in 8 patients (2.4%). Two of these patients had a fatal outcome (mortality: 0.6%). The morbidity (transient and permanent deterioration of the clinical status) was 1.2%.

Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases

PURPOSE Solid and necrotic brain tumors respond to radiosurgery, although necrotic lesions often contain a significant proportion of hypoxic cells which cannot become reoxygenated during the short overall treatment time of single dose application. In addition to the direct cytotoxic action, delayed vascular occlusion followed by ischemic tumor cell death could contribute to the effect of radiosurgery. MATERIALS AND METHODS In order to determine the impact of the two possible effects on tumor response, a 3-dimensional computer simulation was developed and fitted to response data obtained from 90 patients who were treated by LINAC radiosurgery for 1-3 brain metastases with median marginal doses of 20 Gy. Complete response rates were as follows: small, solid lesions (diameter 0.4-1 cm), 52% (12/23); large solid lesions (1.1-5.2 cm), 28% (17/60); large necrotic lesions, 12% (6/50). The 3-dimensional computer model simulated the growth of small solid and large, solid or necrotic tumors situated in a vascularized stroma. Oxygen supply, tumor cell division (cell cycle time 5 days), neovascularization, tumor cell kill by single dose irradiation (linear-quadratic model, alpha/beta=10 Gy, oxygen enhancement ratio 3.0) and time-dependent vascular occlusion (alpha/beta=3 Gy) were modeled by Monte-Carlo simulation techniques. RESULTS In the presence of neovascularization, solid tumors with a hypoxic fraction of 1-2% developed. Without neoangiogenesis, central necrosis occurred, and tumors had a hypoxic fraction of 20-25%. Assuming a pure cytotoxic effect of radiosurgery, neither the dose-response relationship for the solid lesions of different size nor that for the large lesions with solid or necrotic appearance could be reproduced for any given level of radiosensitivity. This was only possible by introducing a vascular effect that led to the occlusion of >/=99% of the vessels at the border of the target volume within 1 year after irradiation. In the presence of the vascular effect, the apparent radiosensitivity of the tumor cells was increased by 50-100%. Calculations of the dose-equivalent for the vascular effect show that it contributes 19-33% of the overall effect of single dose radiosurgery. CONCLUSION This simulation study suggests that the therapeutic effect of single radiosurgery in malignant brain tumors cannot be understood without the consideration of vascular effects. The computer model might serve as a basis for exploring new treatment modalities that modify both cytotoxic and vascular effects of radiosurgery.

Linear accelerator radiosurgery for recurrent malignant tumors of the skull base

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

Stereotactic linear accelerater-based radiosurgery for the treatment of patients with glomus jugulare tumors

The optimal treatment for patients with glomus jugulare tumor (GJT) of the skull base remains controversial. Surgical excision is associated with a high incidence of cranial nerve injury, decreased quality of life, and high mortality. Fractionated radiotherapy is used to control the majority of these tumors, but disadvantages are a prolonged therapy interval and exposition of adjacent brain tissue to irradiation. The authors present the results of a study on 12 of 14 consecutively admitted patients who were treated using linear accelerator‐based radiosurgery (LINAC‐RS), an innovative method for the treatment of GJT.

Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor—A unusual clinical benefit

This is a single case report of a patient with spinocerebellar ataxia type 2 (SCA2) and severe tremor. Whereas disease progression with prevailing ataxia and dysmetria was slow over the first symptomatic 6 years, 6 months prior to operation were characterized by the development of a severe, debilitating postural tremor rendering the patient unable to independently sit, stand, speak, or swallow. Deep brain stimulation (DBS) at a subthalamic–thalamic electrode position almost completely arrested her tremor. The patient regained the functional state prior to her rapid disease progression allowing a restricted range of daily activities. Her condition has remained approximately stable over the two postoperative years to date. In addition to the efficacy of DBS on cerebellar tremor, the results illustrate a remarkable improvement of the patients general condition and independence.