Subthalamic oscillatory activity during normal and impaired speech.

OBJECTIVE: We studied the relationship between oscillatory activity in the subthalamic nucleus (STN) and speech production in order to better understand the functional role of the STN. METHODS: We simultaneously recorded subthalamic local field potentials and audio recordings from 5 patients with Parkinson's disease while they performed verbal fluency tasks. We then analyzed the oscillatory signals present in the subthalamic nucleus during these tasks. RESULTS: We report that normal speech leads to a suppression of subthalamic alpha and beta power. Contrarily, a patient with motor blocks during speech initiation showed a low beta power increase. We also report an increase in error rates in the phonemic non-alternating verbal fluency task during deep brain stimulation (DBS). CONCLUSIONS: We confirm previous findings that intact speech leads to desynchronization in the beta range in the STN. The speech related narrowband beta power increase in a patient with speech problems suggests that exaggerated synchronization in this frequency band is associated with motor blocks during speech initiation. The increased number of errors in verbal fluency tasks during DBS might be caused by an impairment of the response inhibition network caused by stimulation of the STN. SIGNIFICANCE: We suggest that the inability to attenuate beta activity during motor processes is associated with motor freezing across motor behaviours such as speech and gait, as previously shown for freezing of gait.

Peaks in the beta band of the human subthalamic nucleus: a case for low beta and high beta activity.

OBJECTIVE: Peaks in the beta band of local field potentials (LFPs) may serve as a biological feedback signal for closed-loop deep brain stimulation (DBS) in Parkinson's disease (PD). However, the specific frequency of such peaks and their response to DBS and to different types of movement remains uncertain. In the present study, the authors examined the abundance of discernible peaks in the beta band and the effect of different types of movement and DBS on these peaks. METHODS: Subthalamic nucleus LFPs were analyzed from 38 patients with PD in a frequency range between 10 and 35 Hz, as well as the impact of movement (gait, hand movements) and electrical stimulation on these peaks. The position of the electrode segments from which LFPs were recorded was computed. RESULTS: The authors found a bimodal distribution of peaks in the beta band with discernible high- (27 Hz) and low-frequency (15 Hz) peaks. Movement of either hand had no significant effect on these peaks, whereas walking significantly reduced high-frequency beta peaks but not the peaks in the low beta band. Stimulation caused an amplitude-dependent suppression of both peaks. CONCLUSIONS: DBS suppresses LFP beta peaks of different frequencies, whereas beta suppression caused by movement is dependent on the type of movement and frequency of the peak. These results will support the investigation of distinct LFP spectra for the application of closed-loop DBS.

Bilateral double beta peaks in a PD patient with STN electrodes.

Subthalamic local field potentials in the beta band are considered as potential biomarkers for closed-loop deep brain stimulation. To investigate the subthalamic beta band peak amplitudes in a Parkinson's disease patient over an extended period of time by using a novel and commercially available neurostimulator with permanent sensing capability. We recorded local field potentials of the subthalamic nucleus using the Medtronic Percept™ implantable neurostimulator at rest and during physical activity (gait) with and in response to deep brain stimulation. We found a double-peaked beta activity on both sides. Increasing stimulation and physical activity resulted in a decreased beta band amplitude, but was accompanied by the appearance of a second, and previously unrecognized peak at 13 Hz in the right hemisphere. Our results will support the investigation of distinct different peaks in the beta band and their relevance and usefulness as closed-loop biomarkers.

Establishment of a Visual Analog Scale for DBS Programming (VISUAL-STIM Trial).

Background: Deep brain stimulation (DBS) has become a standard treatment for advanced stages of Parkinson's disease, essential tremor, and dystonia. In addition to the correct surgical device implantation, effective programming is regarded to be the most important factor for clinical outcome. Despite established strategies for adjusting neurostimulation, DBS programming remains time- and resource-consuming. Although kinematic and neuronal biosignals have recently been examined as potential feedback for closed-loop DBS (CL-DBS), there is an ongoing need for programming strategies to adapt the stimulation parameters and electrode configurations accurately and effectively. Methods: Here, we tested the usefulness of a patient-rated visual analog scale (VAS) for real-time adjustment of DBS parameters. The stimulation parameters (contact and amplitude) in Parkinson's patients with STN-DBS (n = 17) were optimized based on the patient's subjective VAS rating. A Minkowski distance (Md) was calculated to compare the individual combination of contact selection and amplitude to the stimulation parameters that resulted from classical programming based on clinical signs and symptoms. Results: We found no statistically significant difference between VAS-based and classical programming in regard to the specific contact or amplitude used or in regard to the clinical disease severity (UPDRS). Conclusions: Our data suggest that VAS-based and classical programming strategies both lead to similar short-term results. Although further research will be required to assess the validity of VAS-based DBS programming, our results support the investigation of the patient's subjective rating as an additional and valid feedback signal for individualized DBS adjustment.

Deep Brain Stimulation Programming for Movement Disorders: Current Concepts and Evidence-Based Strategies.

Deep brain stimulation (DBS) has become the treatment of choice for advanced stages of Parkinson's disease, medically intractable essential tremor, and complicated segmental and generalized dystonia. In addition to accurate electrode placement in the target area, effective programming of DBS devices is considered the most important factor for the individual outcome after DBS. Programming of the implanted pulse generator (IPG) is the only modifiable factor once DBS leads have been implanted and it becomes even more relevant in cases in which the electrodes are located at the border of the intended target structure and when side effects become challenging. At present, adjusting stimulation parameters depends to a large extent on personal experience. Based on a comprehensive literature search, we here summarize previous studies that examined the significance of distinct stimulation strategies for ameliorating disease signs and symptoms. We assess the effect of adjusting the stimulus amplitude (A), frequency (f), and pulse width (pw) on clinical symptoms and examine more recent techniques for modulating neuronal elements by electrical stimulation, such as interleaving (Medtronic®) or directional current steering (Boston Scientific®, Abbott®). We thus provide an evidence-based strategy for achieving the best clinical effect with different disorders and avoiding adverse effects in DBS of the subthalamic nucleus (STN), the ventro-intermedius nucleus (VIM), and the globus pallidus internus (GPi).

Deep Brain Stimulation Programming 2.0: Future Perspectives for Target Identification and Adaptive Closed Loop Stimulation.

Deep brain stimulation has developed into an established treatment for movement disorders and is being actively investigated for numerous other neurological as well as psychiatric disorders. An accurate electrode placement in the target area and the effective programming of DBS devices are considered the most important factors for the individual outcome. Recent research in humans highlights the relevance of widespread networks connected to specific DBS targets. Improving the targeting of anatomical and functional networks involved in the generation of pathological neural activity will improve the clinical DBS effect and limit side-effects. Here, we offer a comprehensive overview over the latest research on target structures and targeting strategies in DBS. In addition, we provide a detailed synopsis of novel technologies that will support DBS programming and parameter selection in the future, with a particular focus on closed-loop stimulation and associated biofeedback signals.

Subthalamic oscillatory activity and connectivity during gait in Parkinson's disease.

Local field potentials (LFP) of the subthalamic nucleus (STN) recorded during walking may provide clues for determining the function of the STN during gait and also, may be used as biomarker to steer adaptive brain stimulation devices. Here, we present LFP recordings from an implanted sensing neurostimulator (Medtronic Activa PC + S) during walking and rest with and without stimulation in 10 patients with Parkinson's disease and electrodes placed bilaterally in the STN. We also present recordings from two of these patients recorded with externalized leads. We analyzed changes in overall frequency power, bilateral connectivity, high beta frequency oscillatory characteristics and gait-cycle related oscillatory activity. We report that deep brain stimulation improves gait parameters. High beta frequency power (20-30 Hz) and bilateral oscillatory connectivity are reduced during gait, while the attenuation of high beta power is absent during stimulation. Oscillatory characteristics are affected in a similar way. We describe a reduction in overall high beta burst amplitude and burst lifetimes during gait as compared to rest off stimulation. Investigating gait cycle related oscillatory dynamics, we found that alpha, beta and gamma frequency power is modulated in time during gait, locked to the gait cycle. We argue that these changes are related to movement induced artifacts and that these issues have important implications for similar research.

Subthalamic stimulation, oscillatory activity and connectivity reveal functional role of STN and network mechanisms during decision making under conflict.

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards.

Hypometric anticipatory postural adjustments in dystonia are not affected by deep brain stimulation of globus pallidus internus.

BACKGROUND: Dystonia is a movement disorder with patterned, directional, and often sustained muscle contractions that produce abnormal postures or repetitive movements. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, gait freezing and falls in patients treated with DBS. Because these symptoms may point to deficient gait initiation processes, we systematically assessed the anticipatory postural adjustments (APAs) prior to stepping in dystonia patients with GPi-DBS. METHODS: Thirteen patients with focal/segmental dystonia under GPi-DBS and twelve healthy control subjects were included in the study. Data were collected using pressure sensitive sensors and APAs were studied by centre of pressure measures. We compared APAs of both groups and analysed the influence of GPi-DBS on APAs in patients. RESULTS: Medio-lateral and antero-posterior COP displacements, total COP path, maximal APA velocity and 1st step length were all smaller in patients for both ON (p=0.006, p=0.018, p=0.002, p=0.016, p=0.04) and OFF (p=0.001, p=0.01, p=0.001, p=0.03, p=0.024) condition compared to healthy subjects. GPi-DBS did not change APA parameters in patients. CONCLUSIONS: Observations that APAs are impaired in dystonia and are at the same time not affected by the stimulation current are compatible with the assumption that APAs and dystonic symptoms may rely on distinct networks, possibly within the same cortical and basal ganglia structures. With no effect of stimulation on APAs it is unlikely that this would be a mechanism of impaired balance in the patients after the surgery.

Deep Brain Stimulation during Pregnancy and Delivery: Experience from a Series of "DBS Babies".

INTRODUCTION: Deep brain stimulation (DBS) is widely used to improve quality of life in movement disorders (MD) and psychiatric diseases. Even though the ability to have children has a big impact on patients' life, only a few studies describe the role of DBS in pregnancy. OBJECTIVE: To describe risks and management of women treated by DBS for disabling MD or psychiatric diseases during pregnancy and delivery. METHODS: We report a retrospective case series of women, followed in two DBS centers, who became pregnant and went on to give birth to a child while suffering from disabling MD or psychiatric diseases [Parkinson's disease, dystonia, Tourette's syndrome (TS), Obsessive Compulsive Disorder (OCD)] treated by DBS. Clinical status, complications and management before, during, and after pregnancy are reported. Two illustrative cases are described in greater detail. RESULTS: DBS improved motor and behavioral disorders in all patients and allowed reduction in, or even total interruption of disease-specific medication during pregnancy. With the exception of the spontaneous early abortion of one fetus in a twin pregnancy, all pregnancies were uneventful in terms of obstetric and pediatric management. DBS parameters were adjusted in five patients in order to limit clinical worsening during pregnancy. Implanted material limited breast-feeding in one patient because of local pain at submammal stimulator site and led to local discomfort related to stretching of the cable with increasing belly size in another patient whose stimulator was implanted in the abdominal wall. CONCLUSION: Not only is it safe for young women with MD, TS and OCD who have a DBS-System implanted to become pregnant and give birth to a baby but DBS seems to be the key to becoming pregnant, having children, and thus greatly improves quality of life.

Postural stability under globus pallidus internus stimulation for dystonia.

OBJECTIVE: Deep brain stimulation of the globus pallidus internus (GPi-DBS) is an efficient and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, falls and bradykinesia in patients after the DBS procedure. The aim of this study was to quantify the effect of GPi-DBS on postural performance in patients with cranio-cervical dystonia. METHODS: Thirteen patients with focal/segmental dystonia and GPi-DBS participated in the study. We performed two postural tests (pull test and push and release test) in on- and off-stimulation conditions and recorded the movements of the patients with inertial sensors. RESULTS: Under stimulation patients exhibited a higher number of steps (p=0.015), reduced first step length (p=0.011) and lower stepping velocity (p=0.001), compared to off stimulation. We observed a higher number of steps in the push and release test compared to the pull test (p=0.038). The interaction between stimulation condition and test type was significant (p=0.027). CONCLUSIONS: The velocity and amplitude of postural reactions are compromised by GPi-DBS in patients with cranio-cervical dystonia. SIGNIFICANCE: This information corresponds to patient's reports of falls and postural instability after GPi-DBS. Pre-operatively, patients should be informed about the possibility of the occurrence of such phenomena.

Effect of micro lesions of the basal ganglia on ballistic movements in patients with deep brain stimulation.

Bradykinesia and hypokinesia are the prominent symptoms of substantia nigra degeneration in Parkinson's disease (PD). In segmental dystonia, movements of not affected limbs are not impaired. Here we studied the impact of the mere implantation of stimulation electrodes on the performance of fast movements in these two groups. We investigated 9 PD patients with subthalamic electrodes and 9 patients with segmental dystonia with electrodes in the globus pallidus internum. Patients were studied on the first postoperative day without electrical stimulation of the electrodes. Subjects had to perform boxing movements with either touching the target or stopping the fist in front of the target. PD subjects performed significantly faster movements in the touch-task only as compared to dystonic patients. No difference was seen in the stopping task. In conclusion, our findings suggest that a small subthalamic lesion in individuals with PD specifically reverses bradykinesia during simple ballistic movements (touch) but not during complex ones requiring more pre-programming (no-touch paradigm).

Pattern of local field potential activity in the globus pallidus internum of dystonic patients during walking on a treadmill.

The basal ganglia (BG) are involved in gait. This notion is exemplified by observations that gait is disturbed by most diseases that affect the BG. However, it is unclear in what way the BG are activated during gait. One method to investigate the activity of the BG is to record local field potentials (LFPs) from electrodes placed in the BG for therapeutic purposes. Nowadays, the globus pallidus internum (GPi) represents the target for deep brain stimulation (DBS) in dystonia. LFPs recorded from this area have been shown to delineate activity associated with dystonic cramps but also activity that may be relevant for certain types of movement. In this study we recorded LFPs from DBS electrodes implanted into the GPi of eight patients with dystonia during walking on a treadmill machine and compared these data with data acquired during rest (sitting and standing). There was no difference in the power of frequency bands during the sitting and standing conditions. LFP power in the theta (4-8 Hz), alpha (8-12 Hz) and gamma (60-90 Hz) frequency bands was higher during walking than during the resting conditions. Beta (15-25 Hz) frequencies were the only frequencies that were down-regulated during walking. The amplitude of the theta and alpha frequency bands was modulated during the gait cycle. These data shed light on the function of the BG in patients with dystonia and demonstrate that, during gait, their overall activity increases in a specific way without showing increases of narrow frequency bands.

Alpha frequency modulation in the human basal ganglia is dependent on motor task.

Depth recordings from the basal ganglia of patients suffering from Parkinson's disease (PD) or dystonia have revealed local field potential (LFP) activity in specific frequency bands. Depth recordings also allow us to study LFP power spectra during different types of limb movements, thus helping to elucidate the role of the basal ganglia in specific motor tasks. Accordingly, we recorded bilateral LFP activity from the subthalamic nucleus (STN) of patients with PD (n=9) and from the globus pallidus internum (GPi) of patients with dystonia (n=8). Recordings were taken during the performance of repetitive passive, active and ballistic fast extensions and flexions of the elbow joint and during rest. The first result was that the frequency spectra varied task-specifically in a similar fashion in GPi and STN. The amplitude of the alpha frequency on the contralateral side was significantly higher in ballistic fast movements compared with rest, passive and active performance in both STN and GPi. In conclusion, ballistic fast movements cause synchronized basal ganglia activity in the alpha range. Because this was seen in both patient groups (PD and dystonia) we consider this activity as task-specific rather than disease-related.

Trigeminal neuralgia due to neurovascular compression: high-spatial-resolution diffusion-tensor imaging reveals microstructural neural changes.

PURPOSE: To preoperatively detect, by using diffusion-tensor imaging coregistered with anatomic magnetic resonance (MR) imaging, suspected microstructural tissue changes of the trigeminal nerves in patients with trigeminal neuralgia (TN) resulting from neurovascular compression. MATERIALS AND METHODS: The study was approved by the institutional review board, and written informed consent was obtained from all patients. Twenty patients (mean age, 51.3 years) with TN and evidence of neurovascular contact were examined with use of a 3.0-T MR unit combined with an eight-channel head coil before undergoing surgical decompression. A single-shot diffusion-tensor echo-planar sequence was used along 15 different diffusion directions, with a b value of 1000 sec/mm(2) and a section thickness of 2 mm. For anatomic correlation, 0.6-mm isotropic three-dimensional fast imaging employing steady-state images were acquired for coregistration with the functional diffusion-tensor maps. After region of interest placement, mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were calculated for each nerve by using the paired-sample two-tailed t test (with P < .005 indicating significance) and compared with surgical findings. RESULTS: FA was significantly lower (P = .004) on the trigeminal neuralgia-affected side (mean FA, 0.203) than on the contralateral side (mean FA, 0.239). ADCs were nearly identical between the normal and TN-affected nerve tissues. CONCLUSION: These findings suggest that diffusion-tensor imaging enables the identification and quantification of anisotropic changes between normal nerve tissue and TN-affected trigeminal nerves. Coregistration of anatomic three-dimensional fast imaging employing steady-state imaging and diffusion-tensor imaging facilitates excellent delineation of the cisternal segments of the trigeminal nerves.

Novel molecular stereotactic biopsy procedures reveal intratumoral homogeneity of loss of heterozygosity of 1p/19q and TP53 mutations in World Health Organization grade II gliomas.

We report a molecular stereotactic biopsy technique that combines histopathologic diagnosis with small sample size-adjusted molecular genetic analysis of low-grade gliomas that are ineligible for tumor resection. Loss of heterozygosity (LOH) of 1p/19q and TP53 mutations were analyzed in 1-mm tissue samples from 42 World Health Organization grade II gliomas (30 astrocytomas, 8 oligoastrocytomas, 4 oligodendrogliomas) using polymerase chain reaction-based microsatellite and sequence analysis. Alternating histological and molecular genetic evaluation within 1-mm steps at different sites within each tumor was performed to determine reproducibility of the results and the intratumoral distribution of the biomarkers. Multiple serial biopsies (range, 2-5 per tumor) taken from distinct intratumoral areas revealed concordant molecular genetic findings and homogeneous distribution of both biomarkers throughout 41 tumors. Contamination by nonneoplastic tissue could be recognized by corresponding histological evaluation and resulted in discordant LOH findings in 1 tumor. The frequency of LOH 1p/19q and TP53 mutations was consistent with the literature; these genetic alterations were found to be mutually exclusive. There was no biopsy-related morbidity. We conclude that determination of the LOH 1p/19q and TP53 status using this molecular stereotactic biopsy technique is safe and reliable in cases of unresectable gliomas.

FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading.

PURPOSE: Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. METHODS: Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. RESULTS: Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). CONCLUSIONS: Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX.

BACKGROUND AND OBJECTIVE: Limited knowledge of the light and temperature distribution within the target volume in combination with non-selective accumulation of the applied photosensitizers (PS) has hampered the clinical relevance of interstitial photodynamic therapy (iPDT) for treatment of malignant glioma patients. The current pilot study focused on the development and the clinical implementation of an accurate and reproducible irradiation scheme for iPDT using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a selectively working PS. STUDY DESIGN/MATERIALS AND METHODS: Monte Carlo simulations of fluence rate and heat transport simulations were performed using the optical properties of normal brain tissue infiltrated by tumor cells (absorption coefficient micro(a) = 0.2 cm(-1), reduced scattering coefficient: micro'(s) = 20 cm(-1)). A modified 3-D treatment-planning software was used to calculate both, the treatment-volume and the exact position of the light diffusers within the lesion. The feasibility and the risk of iPDT were tested in 10 patients with small and circumscribed recurrent malignant gliomas. RESULTS: The optimum distance between the implanted light diffusers was determined to be 9 mm with regard to both fluence rate and temperature distribution. For this distance a temperature increase above 42 degrees C was not expected to occur. Up to six cylindrical light diffusers were stereotactically implanted to achieve a complete irradiation of the tumor volume, which was possible in every single patient (mean tumor volume: 5.9 cm3). The total applied light fluence was between 4,320 J and 11,520 J. Side effects of iPDT were not observed. Median survival was 15 months. CONCLUSION: 5-ALA iPDT in combination with a 3-D treatment-planning (which was based on optical and thermal simulations) is a safe and feasible treatment modality. The clinical impact of these findings deserves further prospective evaluation.

Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods?

UNLABELLED: The aim of the present study was to evaluate whether extended analyses of O-(2-18F-fluoroethyl)-L-tyrosine (FET) uptake kinetics provide results superior to those of standard tumor-to-background ratios in predicting tumor grade in patients with pretreated gliomas. METHODS: Dynamic 18F-FET PET studies (0-40 min after injection of 180 MBq of 18F-FET) were performed on 45 glioma patients with suspected tumor recurrence after multimodal treatment. For the standard method, tumoral maximal standardized uptake value (SUVmax) and the ratio to the background were derived from a summed image 20-40 min after injection. Dynamic data evaluation comprised several approaches: first, SUV within a 90% isocontour threshold (SUV90) and the respective ratio to the background calculated for each time frame between 5 and 40 min after injection; second, the time to peak analysis; and third, various parameters accounting for the individual time course of 18F-FET uptake. Results were correlated with the histopathologic findings of MRI/PET-guided stereotactic biopsies and were evaluated with respect to their discriminatory power to separate low- from high-grade tumors using receiver-operating characteristic (ROC) analyses. RESULTS: The parameters taking into account the individual time course of 18F-FET uptake were able to differentiate low-grade from high-grade recurrent astrocytomas with high diagnostic accuracy, reaching the best differentiation with a sensitivity and specificity of 92% and an area under the ROC curve (AUC) of 0.94. For the other parameters, the respective values were considerably lower (time to peak: 85% sensitivity and 88% specificity; SUV90-to-background ratio for single-frame evaluation of the early-uptake phase: 100% sensitivity, 62% specificity, and 0.81 AUC). The lowest performance was provided by the standard method (SUVmax: 73% sensitivity, 54% specificity, and 0.60 AUC; SUVmax-to-background ratio: 62% sensitivity, 62% specificity, and 0.59 AUC). Time-activity curves (5-40 min after injection) slightly and steadily increased in tumor-free patients and in low-grade tumors, whereas high-grade tumors showed an early peak around 10-15 min after injection followed by a decrease. CONCLUSION: This study has shown differences in the dynamics of 18F-FET uptake between recurrent low- and high-grade gliomas. Therefore, parameters addressing the different kinetic behaviors allow discrimination with high diagnostic power between these 2 prognostically different groups. Thus, the techniques introduced here are clearly superior to the yet most widely used standard method.

Long term course of WHO grade II astrocytomas of the Insula of Reil after I-125 interstitial irradiation.

OBJECTIVE: To present long-term results after interstitial iodine-125 irradiation of adult patients with de-novo World Health Organization (WHO) Grade II astrocytomas and oligoastrocytomas of the insula of Reil with special respect to the treatment-related risk. METHODS: 55 consecutively treated patients (from 1979 to 1992) with circumscribed tumors with a diameter < 5 cm (astrocytomas: 46 patients, oligoastrocytomas: 9 patients) were included. The reference dose-calculated to the outer boundary of the tumor-was in the range of 60-100 Gy and the dose rate was low (< 10 cGy/h). Progression-free survival, risk of malignant transformation, survival, and the incidence of radiogenic complications were estimated by the Kaplan-Meier method. Prognostic factors were obtained from the Cox-model. RESULTS: Median follow up for the survivors was > 10 years. 5-year (10-year) progression-free survival was 40.7 % (20.2 %), and 5-year (10-year) survival 54.6 % (28.4 %). Malignant transformation occurred in 42.4 % after 5 years. Neither of the Kaplan-Meier curves showed a leveling off over time. Transient (progressive) radiogenic complications were observed in 13 [4] patients (one-year overall complication rate: 18%), and were significantly associated with a tumor diameter >3.5 cm (p<0.001). No long term side-effects were detected and delayed external beam irradiation (in case of tumor progression) did not enhance the risk. Tumor enhancement on CT was the only unfavorable predictor for survival. CONCLUSION: A limited overall prognosis for adult patients with insular WHO grade II astrocytomas and oligoastrocytomas was detected. Interstitial I-125 irradiation offers a minimal-invasive and low-risk treatment option for circumscribed tumors with a diameter < 3.5 cm. Larger tumors require further evaluation for optimal treatment.