Overestimation of grey matter atrophy in glioblastoma patients following radio(chemo)therapy.

OBJECTIVE: Brain atrophy has the potential to become a biomarker for severity of radiation-induced side-effects. Particularly brain tumour patients can show great MRI signal changes over time caused by e.g. oedema, tumour progress or necrosis. The goal of this study was to investigate if such changes affect the segmentation accuracy of normal appearing brain and thus influence longitudinal volumetric measurements. MATERIALS AND METHODS: T1-weighted MR images of 52 glioblastoma patients with unilateral tumours acquired before and three months after the end of radio(chemo)therapy were analysed. GM and WM volumes in the contralateral hemisphere were compared between segmenting the whole brain (full) and the contralateral hemisphere only (cl) with SPM and FSL. Relative GM and WM volumes were compared using paired t tests and correlated with the corresponding mean dose in GM and WM, respectively. RESULTS: Mean GM atrophy was significantly higher for full segmentation compared to cl segmentation when using SPM (mean ± std: ΔVGM,full = - 3.1% ± 3.7%, ΔVGM,cl = - 1.6% ± 2.7%; p < 0.001, d = 0.62). GM atrophy was significantly correlated with the mean GM dose with the SPM cl segmentation (r = - 0.4, p = 0.004), FSL full segmentation (r = - 0.4, p = 0.004) and FSL cl segmentation (r = -0.35, p = 0.012) but not with the SPM full segmentation (r = - 0.23, p = 0.1). CONCLUSIONS: For accurate normal tissue volume measurements in brain tumour patients using SPM, abnormal tissue needs to be masked prior to segmentation, however, this is not necessary when using FSL.

Delineation of gliomas using radial metabolite indexing.

(1) H MRSI has demonstrated the ability to characterise and delineate brain tumours, but robust data analysis methods are still needed. In this study, we present an objective analysis method for MRSI data to delineate tumour abnormality regions. The presented method is a development of the choline-to-N-acetylaspartate index (CNI), which uses perpendicular distances in a choline versus N-acetylaspartate plot as a measure of abnormality. We propose a radial CNI (rCNI) method that uses the choline to N-acetylaspartate ratio directly as an abnormality measure. To avoid problems with small or zero denominators, we perform an arctangent transformation. CNI abnormality contours were evaluated using a z-score threshold of 2 (CNI2) and 2.5 (CNI2.5) and compared with rCNI2. Simulations modelling low-grade (LGG) and high-grade (HGG) gliomas with different tissue compartments and partial volume effects suggest improved specificity of rCNI2 (LGG 92%/HGG 91%) over CNI2 (LGG 69%/HGG 69%) and CNI2.5 (LGG 74%/HGG 75%), whilst retaining a similar sensitivity to both CNI2 and CNI2.5. Our simulation results also confirm a previously reported increase in specificity of CNI2.5 over CNI2 with little penalty in sensitivity. The analysis of MRSI data acquired from 10 patients with low-grade glioma at 3 T suggests a more robust delineation of the lesions using rCNI with respect to conventional imaging compared with standard CNI. Further analysis of 29 glioma datasets acquired at 1.5 T, together with previously published estimated tumour proportions, suggests that rCNI has higher sensitivity and specificity for the identification of abnormal MRSI voxels.

Classification of single-voxel 1H spectra of brain tumours using LCModel.

This study presents a novel method for the direct classification of (1)H single-voxel MR brain tumour spectra using the widespread analysis tool LCModel. LCModel is designed to estimate individual metabolite proportions by fitting a linear combination of in vitro metabolite spectra to an in vivo MR spectrum. In this study, it is used to fit representations of complete tumour spectra and to perform a classification according to the highest estimated tissue proportion. Each tumour type is represented by two spectra, a mean component and a variability term, as calculated using a principal component analysis of a training dataset. In the same manner, a mean component and a variability term for normal white matter are also added into the analysis to allow a mixed tissue approach. An unbiased evaluation of the method is carried out through the automatic selection of training and test sets using the Kennard and Stone algorithm, and a comparison of LCModel classification results with those of the INTERPRET Decision Support System (IDSS) which incorporates an advanced pattern recognition method. In a test set of 46 spectra comprising glioblastoma multiforme, low-grade gliomas and meningiomas, LCModel gives a classification accuracy of 90% compared with an accuracy of 95% by IDSS.

Time- and dose-dependent volume decreases in subcortical grey matter structures of glioma patients after radio(chemo)therapy.

Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.

Reduced diffusion in white matter after radiotherapy with photons and protons.

BACKGROUND AND PURPOSE: Radio(chemo)therapy is standard in the adjuvant treatment of glioblastoma. Inevitably, brain tissue surrounding the target volume is also irradiated, potentially causing acute and late side-effects. Diffusion imaging has been shown to be a sensitive method to detect early changes in the cerebral white matter (WM) after radiation. The aim of this work was to assess possible changes in the mean diffusivity (MD) of WM after radio(chemo)therapy using Diffusion-weighted imaging (DWI) and to compare these effects between patients treated with proton and photon irradiation. MATERIALS AND METHODS: 70 patients with glioblastoma underwent adjuvant radio(chemo)therapy with protons (n = 20) or photons (n = 50) at the University Hospital Dresden. MRI follow-ups were performed at three-monthly intervals and in this study were evaluated until 33 months after the end of therapy. Relative white matter MD changes between baseline and all follow-up visits were calculated in different dose regions. RESULTS: We observed a significant decrease of MD (p < 0.05) in WM regions receiving more than 20 Gy. MD reduction was progressive with dose and time after radio(chemo)therapy (maximum: -7.9 ± 1.2% after 24 months, ≥50 Gy). In patients treated with photons, significant reductions of MD in the entire WM (p < 0.05) were seen at all time points. Conversely, in proton patients, whole brain MD did not change significantly. CONCLUSIONS: Irradiation leads to measurable MD reduction in white matter, progressing with both increasing dose and time. Treatment with protons reduces this effect most likely due to a lower total dose in the surrounding white matter. Further investigations are needed to assess whether those MD changes correlate with known radiation induced side-effects.

Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy.

BACKGROUND AND PURPOSE: Standard treatment of high grade gliomas includes gross tumour resection followed by radio(chemo)therapy. Radiotherapy inevitably leads to irradiation of normal brain tissue. The goal of this prospective, longitudinal study was to use MRI to quantify normal appearing white and grey matter changes following radiation treatment as a function of dose and time after radiotherapy. MATERIALS AND METHODS: Pre-radiotherapy (proton or photon therapy) MRI and follow-up MRIs collected in 3 monthly intervals thereafter were analysed for 22 glioma patients and included diffusion tensor imaging, quantitative T1, T2* and proton density mapping. Abnormal tissue was excluded from analysis. MR signal changes were quantified within different dose bin regions for grey and white matter and subsequently for whole brain white matter. RESULTS: We found significant reductions in mean diffusivity, radial diffusivity, axial diffusivity and T2* in normal appearing white matter regions receiving a radiation dose as low as 10-20 Gy within the observational period of up to 18 months. The magnitude of these changes increased with the received radiation dose and progressed with time after radiotherapy. Whole brain white matter also showed a significant reduction in radial diffusivity as a function of radiation dose and time after radiotherapy. No significant changes were observed in grey matter. CONCLUSION: Diffusion tensor imaging and T2* imaging revealed normal appearing white matter changes following radiation treatment. The changes were dose dependant and progressed over time. Further work is needed to understand the underlying tissue changes and to correlate the observed diffusion changes with late brain malfunctions.

Measuring Cerebral and Cerebellar Glutathione in Children Using 1H MEGA-PRESS MRS.

BACKGROUND AND PURPOSE: Glutathione is an important antioxidant in the human brain and therefore of interest in neurodegenerative disorders. The purpose of this study was to investigate the feasibility of measuring glutathione in healthy nonsedated children by using the 1H Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence at 3T and to compare glutathione levels between the medial parietal gray matter and the cerebellum. MATERIALS AND METHODS: Glutathione was measured using MEGA-PRESS MRS (TR = 1.8 seconds, TE = 131 ms) in the parietal gray matter (35 × 25 × 20 mm3) of 6 healthy children (10.0 ± 2.4 years of age; range, 7-14 years; 3 males) and in the cerebellum of 11 healthy children (12.0 ± 2.7 years of age; range, 7-16 years; 6 males). A postprocessing pipeline was developed to account for frequency and phase variations in the edited ON and nonedited OFF spectra. Metabolites were quantified with LCModel and reported both as ratios and water-scaled values. Glutathione was quantified in the ON-OFF spectra, whereas total NAA, total Cho, total Cr, mIns, Glx, and taurine were quantified in the OFF spectra. RESULTS: We found significantly higher glutathione, total Cho, total Cr, mIns, and taurine in the cerebellum (P < .01). Glx and total NAA were significantly higher in the parietal gray matter (P < .01). There was no significant difference in glutathione/total Cr (P = .93) between parietal gray matter and cerebellum. CONCLUSIONS: We demonstrated that glutathione measurement in nonsedated children is feasible. We found significantly higher glutathione in the cerebellum compared with the parietal gray matter. Metabolite differences between the parietal gray matter and cerebellum agree with published MRS data in adults.

Arousals and aircraft noise - environmental disorders of sleep and health in terms of sleep medicine.

World wide rules for sleep staging originate to 1967. Since then many investigations aimed to give numbers for the degree of sleep disturbances due to air traffic noise. But the variables used, such as the amount of relative sleep stages, total sleep time, or sleep efficiency, could not explain impairment in health and performance sufficiently. The beginning of the eighties has given new insight into the restorative functions of sleep, according to sleep fragmentation by micro-arousals. These are originating in autonomous dysfunctions during sleep, leading to non-restorative sleep. Environmentally related sleep disturbances are described, EEG and vegetative (micro)-arousals, and the actual knowledge in sleep medicine is given in terms of the international classification of sleep disorders (ICSD). The effects on health, and disturbed performance capacity during the day are shown by self ratings of 160 patients. Elevated metabolic rate caused by micro-arousal and/or insomnia, may play an additional role in health impairment.

[Dynamics of pressure and flow curves of various expiratory pressure valves]. / Dynamik von Druck- und Flusskurven verschiedener Auslassventile.

BACKGROUND: Flow dynamics of exhalation valves in home care ventilators (CPAP-, BiLevel-, and autoadjust machines) are determined by their physical properties. The flow characteristic implies distinct curves leading to expiratory increase and inspiratory decay of pressure depending on flow rate. MATERIAL AND METHODS: For examination of pressure/flow characteristic we examined several valves (one and two circular holes, Sullivan-, Whisper-Swivel-, Silence-valve). Expiratory peak and inspiratory trough assessed at constant pressure (10 mbar) were measured with varying flow rates. RESULTS: Valves differ with their pressure characteristics up to 1.2 mbar for inspiratory and 1.0 mbar for expiratory flow at 2.0 1/s. CONCLUSION: The specific characteristic for each valve is part of the total efficiency of a home care ventilator. Their pressure flow relationship has to be taken into account for titration process and for exchange between different machines and accessories.

[Cost-benefit analysis in patients with sleep-related breathing disorders - diagnosis and ncpap therapy during medical rehabilitation]. / Kosten-Nutzen-Analyse bei Patienten mit schlafbezogenen Atmungsstörungen. Schlafmedizinische Diagnostik und nCPAP-Therapie während der Mmedizinischen Rehabilitation.

In a multi-centre study, 745 patients undergoing internal medical rehabilitation (for hypertension, coronary heart disease, gastrointestinal and respiratory diseases) were investigated. The health economic benefit was evaluated during the 3 weeks of medical rehabilitation, during which a sleep-medical diagnostic work-up and treatment were applied. Ambulatory screening for sleep-related breathing disorders was carried out in all patients. In positive cases (Apnoea-Hypopnoea Index > or = 10) transfer to our sleep lab was recommended. 103 patients were found to be positive, of whom 47 attended the lab; 23 of these accepted nCPAP therapy, while 24 did not. The costs of the additional diagnosis and treatment were considered incremental costs--and the benefit identified as the decrease in days off work as revealed by a comparison of the year before with the year after rehabilitation. Days off work decreased by 38.4 days in the treated group, and increased by 25.4 days in the untreated group. The results were extrapolated to all patients in internal medical rehabilitation in Germany, and a cost-benefit analysis showed that the benefit of expanding the additional investigation to cover all patients would far exceed the incremental costs in the first year after rehabilitation by 58.26 Mio [symbol: see text] and in the second year by 81.15 Mio. [symbol: see text].

[Chronobiological viewpoints of respiratory regulation]. / Chronobiologische Gesichtspunkte der Atmungsregulation.

Control of breathing is ruled by autonomous and behavioural necessities as well. These adaptive functions are realized by temporally structured processes, which are described, analyzed, and functionally estimated by means of the methods of chronobiology. Chronobiological labels like circadian/ultradian, internal clock, Zeitgeber, coordination, entrainment, and resetting are given as examples from sleep, wake, physical strain, and pathophysiology. They are compared to their corresponding functions in respiratory control. Disturbances in chronobiological indicators reveal functional and sleep regulating disorders.

Economic and medical significance of sleep-related breathing disorders.

The improvement in outpatient sleep medical care in the Federal Republic of Germany over the last 10 years has been associated with an increase in the costs for diagnosis and therapy of sleep-related breathing disorders. The medical importance of these sleep-related problems consists in their high prevalence, especially in middle-aged men and risk groups, e.g. in patients with cardiovascular conditions. The effect on the performability of patients, which is manifested in the excessive daytime sleepiness at the workplace and in everyday life, are likewise significant. For social insurance agencies, immense costs arise from the sequelae and concomitant illnesses of untreated sleep-related breathing disorders. A comparison of the costs and the benefits of diagnosis, therapy and follow-up of patients with sleep-related breathing disorders over a period of 10 years shows that a mean annual monetary net benefit of DEM 2.3 billion in the Federal Republic of Germany can be assumed. The health economics analysis shows that an appropriate provision of sleep-medical care for the population is of great benefit for the health of the nation and thus for the entire economy.

[Current concepts and techniques in home ventilation therapy]. / Aktuelle Konzepte und Verfahren der Heimbeatmungstherapie.

Home ventilation of spontaneous breathing during wake and chiefly during sleep has gained great importance in the last 10 years by means of noninvasive nasal pressure support ventilation (PSV). Intensive care and weaning has been complemented, or even replaced by this method. Self-adaptive machines are already available for about 2 years. Historical development is outlined, contrasted by the actual procedures, their advantages and disadvantages. Long term therapy implies functional and probably even morphological adaptation of spontaneous control of breathing which is briefly touched, according to recent investigations.

[North Rhine-Westphalia Scientific Rehabilitation Group--"future strategies for rehabilitation"]. / Nordrhein-Westfälischer Forschungsverbund Rehabilitationswissenschaften--"Zukunftsstrategien für die Rehabilitation".

This Northrine-Westfalian integrated research system in rehabilitation aims at the development of future strategies for medical rehabilitation. The well known deficits of rehabilitation have led to different complementary projects. These comprise research on the lack of evidence in efficacy, predictors for outcomes, international cooperation, university related curricula in training, implementation of health economics and disease management, and finally the need for an actual adaptation of social legislation. The research topics have been transformed into key themes which will be coherently integrated by additional external expert knowledge acquired in workshops organized by a task force group for the development of future strategies.

[Glucose tolerance, insulin resistance and arterial hypertension in patients with obstructive sleep apnea syndrome]. / Glukosetoleranz, Insulinresistenz und arterielle Hypertonie bei Patienten mit obstruktivem Schlafapnoe-Syndrom.

Each of 51 patients (42 male, 9 female) examined by polysomnography for suspected obstructive sleep apnea syndrome (OSAS) was subjected to a glucose load test with 75 g glucose and determination of blood sugar and blood insulin levels (at 0, 30, 60, 120 and 180 min). The patients were divided into 4 groups; with and without excess weight (Broca index < or = > 110%), and with and without pathological apnea index (< or = > 10). There was no significant difference between the groups with respect to age. The corresponding groups did not show any significant differences with regard to Broca index or apnea index. However, the patient group with a Broca index > or = 110% and a pathological apnea index > or = 10 was significantly different to all other groups with regard to glucose and insulin level after 60 min. This group was also significantly different to all other groups with regard to systolic and diastolic blood pressure. The reduced glucose tolerance and increased insulin resistance in combination with arterial hypertension in this patient group is indicative that a combination of adiposity and OSAS represents a particularly high risk factor for the development of arterial hypertension even though the pathological mechanism responsible for the development of arterial hypertension is also present in members of both the normal weight OSAS group and the overweight group without OSAS who exhibit a metabolic predisposition for the development of hypertension. A synergetic interaction of both pathomechanisms favors the development of arterial hypertension. Overweight patients with OSAS thus constitute a high-risk group for the development of cardiovascular diseases.

[Comparison of CPAP and BiPAP equipment with reference to work of breathing, pressure and flow constancy]. / Gerätevergleich für CPAP- und BiPAP-Geräte hinsichtlich Atemarbeit, Druck- und Flusskonstanz.

We have investigated mask pressure curves and nasal flow during nasal C- and BiPAP ventilation in the recumbent position. Nasal spontaneous breathing, C- and BiPAP-applications of 10 and 10/7 cmH2O have been investigated in 7 patients and 4 controls. With aid of an automatic computerised analysis each in- and expiratory phase has been normalized by time and plotted as pressure-volume-loop from pooled data. The ventilators showed significant intra- and inter-machine differences. The investigations are considered as approach to real assessment of patient's work of breathing on home ventilators. They clearly show that ventilators have individual patterns, which should be considered carefully, long term machine-according effects are not yet known.

[Goal-oriented measurement of short-, medium- and long-term effects in pneumological rehabilitation]. / Zielorientierte Messung von kurz-, mittel- und langfristigen Effekten in der pneumologischen Rehabilitation.

UNLABELLED: Assessment of goal-oriented short-, mean-, and long-term effects in pneumological rehabilitation: Despite of increasing quality in rehabilitation, the amount of treatment in pneumological rehabilitation has decreased by 40% in the last few years. A typical mark of quality is determination of individual objectives to reach a goal of therapy. METHODS: In 566 patients (381 male, 185 female, mean age 47.0 year, body mass index 27.5 kg/m2) goals have been assessed by a questionnaire given at the beginning, the end, 6, and 12 months after rehabilitation. The effect size (ES) of single symptoms, defined as difference between initial and following score values, divided by their standard deviation was used as mild (ES < 0.4), mean (ES < 0.8), or strong (ES > = 0.8) effect. Only those patients were considered, who initially rated for "often" and "very often" in a single symptom. RESULTS: At the end of rehabilitation the effect size was strong in 22 of 24 symptoms, mainly nocturnal symptoms. After 12 months 9 symptoms still revealed strong, and 12 mean effect sizes. These mainly again concerned nocturnal symptoms as palpation of the heart, breathlessness, cough, sweating, and headache, but even diurnal tiredness, spontaneously falling asleep, and lack of concentration revealed ES > 0.8. Additionally in 46 patients, who were incapable for work in more than 6 weeks the year before rehabilitation, a reduction of 81 days off job was measured in the year after rehabilitation. DISCUSSION: The definition of aims of therapy is a mark of quality, and ES proves as a sensitive instrument of assessment, giving remarkable effects even one year after medical rehabilitation.