Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two ...stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/- 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.
High-grade glioma has a poor prognosis, and radiation therapy plays a crucial role in its management. Every step of treatment planning should thus be optimised to maximise survival chances and ...minimise radiation-induced toxicity. Here, we compare structures needed for target volume delineation between an immediate postoperative magnetic resonance imaging (MRI) and a radiation treatment planning MRI to establish the need for the latter. Twenty-eight patients were included, with a median interval between MRIs (range) of 19.5 (8-50) days. There was a mean change in resection cavity position (range) of 3.04 ± 3.90 (0-22.1) mm, with greater positional changes in skull-distant (>25 mm) resection cavity borders when compared to skull-near (≤25 mm) counterparts (
< 0.001). The mean differences in resection cavity and surrounding oedema and FLAIR hyperintensity volumes were -32.0 ± 29.6% and -38.0 ± 25.0%, respectively, whereas the mean difference in midline shift (range) was -2.64 ± 2.73 (0-11) mm. These data indicate marked short-term volumetric changes and support the role of an MRI to aid in target volume delineation as close to radiation treatment start as possible. Planning adapted to the actual anatomy at the time of radiation limits the risk of geographic miss and might thus improve outcomes in patients undergoing adjuvant radiation for high-grade glioma.
Autoantibody‐related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25‐year‐old patient with new‐onset epilepsy and psychotic ...syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T‐lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV‐6B). However, astrocytic expression of HHV‐6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV‐6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV‐6 IgM antibodies strongly argue for an additional active HHV‐6B infection. Review of the literature reveals singular reports of patients with GAD antibody‐positive limbic encephalitis and central nervous system infections with HHV‐6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N‐methyl‐D‐aspartate receptor antibody encephalitis, it is tempting to speculate that HHV‐6B infections may trigger a non‐paraneoplastic form of limbic encephalitis in a parallel cascade.
Volumetric computed tomography (VCT) is a technology in which area detectors are used for imaging large volumes of a subject with isotropic imaging resolution. We are experimenting with a prototype ...VCT scanner that uses flat-panel X-ray detectors and is designed for high-resolution three-dimensional (3D) imaging. Using this technique, we have demonstrated microangiography of xeno-transplanted skin squamous cell carcinomas in nude mice. VCT shows the vessel architecture of tumors and animals with greater detail and plasticity than has previously been achieved, and is superior to contrast-enhanced magnetic resonance (MR) angiography. VCT and MR images correlate well for larger tumor vessels, which are tracked from their origin on 3D reconstructions of VCT images. When compared with histology, small tumor vessels with a diameter as small as 50 μm were clearly visualized. Furthermore, imaging small vessel networks inside the tumor tissue improved discrimination of vital and necrotic regions. Thus, VCT substantially improves imaging of vascularization in tumors and offers a promising tool for preclinical studies of tumor angiogenesis and antiangiogenic therapies.
Objective
Epistaxis is a common clinical problem, and the majority of bleedings can be managed conservatively. However, due to extensive and sometimes life-threatening bleeding, further treatment, ...such as superselective embolization, may be required. We report our experience with endovascular treatment of life-threatening epistaxis.
Methods
All patients presenting with excessive epistaxis, which received endovascular treatment at a German tertiary care facility between January 2001 and December 2009, were retrospectively identified. Demographic data, etiology, origin and clinical relevance of bleeding, interventional approach, therapy-associated complications, and outcome were assessed.
Results
A total of 48 patients required 53 embolizations. Depending on the etiology of bleeding, patients were assigned to three groups: 1) idiopathic epistaxis (31/48), 2) traumatic or iatrogenic epistaxis (12/48), and 3) hereditary hemorrhagic telangiectasia (HHT) (5/48). Eleven of 48 patients required blood transfusions, and 9 of these 11 patients (82%) were termed clinically unstable. The sphenopalatine artery was embolized unilaterally in 10 of 53 (18.9%) and bilaterally in 41 of 53 (77.4%) procedures. During the same procedure, additional vessels were embolized in three patients (3/53; 5.7%). In 2 of 53(3.8%) cases, the internal carotid artery (ICA) was occluded. Long-term success rates of embolization were 29 of 31 (93.5%) for group 1 and 11 of 12 (91.7%) for group 2 patients. Embolization of patients with HHT offered at least a temporary relief in three of five (60%) cases. Two major complications (necrosis of nasal tip and transient hemiparesis) occurred after embolization.
Conclusions
Endovascular treatment proves to be effective for prolonged and life-threatening epistaxis. It is easily repeatable if the first procedure is not successful and offers a good risk–benefit profile.
We evaluated microfocal X-ray-computed tomography (micro-CT) as a method to visualize lung architecture two and three dimensionally and to obtain morphometric data. Inflated porcine lungs were fixed ...by formaldehyde ventilation. Tissue samples (8-mm diameter, 10-mm height) were stained with osmium tetroxide, and 400 projection images (1,024 x 1,024 pixel) were obtained. Continuous isometric micro-CT scans (voxel size 9 microm) were acquired to reconstruct two- and three-dimensional images. Tissue samples were sectioned (8-microm thickness) for histological analysis. Alveolar surface density and mean linear intercept were assessed by stereology-based morphometry in micro-CT scans and corresponding histological sections. Furthermore, stereology-based morphometry was compared with morphometric semi-automated micro-CT analysis within the same micro-CT scan. Agreement of methods was assessed by regression and Bland-Altman analysis. Comparing histology with micro-CT, alveolar surface densities (35.4 +/- 2.4 vs. 33.4 +/- 1.9/mm, P < 0.05) showed a correlation (r = 0.72; P = 0.018) with an agreement of 2 +/- 1.6/mm; the mean linear intercept (135.7 +/- 14.5 vs. 135.8 +/- 15 microm) correlated well (r = 0.97; P < 0.0001) with an agreement of -0.1 +/- 3.4 microm. Semi-automated micro-CT analysis resulted in smaller alveolar surface densities (33.4 +/- 1.9 vs. 30.5 +/- 1/mm; P < 0.01) with a correlation (r = 0.70; P = 0.023) and agreement of 2.9 +/- 1.4/mm. Non-destructive micro-CT scanning offers the advantage to visualize the spatial tissue architecture of small lung samples two and three dimensionally.
Noninvasive radiologic imaging has recently gained considerable interest in basic, preclinical research for monitoring disease progression, therapeutic efficacy. In this report, we introduce ...flat-panel volumetric computed tomography (fpVCT) as a powerful new tool for noninvasive imaging of different organ systems in preclinical research. The three-dimensional visualization that is achieved by isotropic high-resolution datasets is illustrated for the skeleton, chest, abdominal organs, brain of mice. The high image quality of chest scans enables the visualization of small lung nodules in an orthotopic lung cancer model, the reliable imaging of therapy side effects such as lung fibrosis. Using contrast-enhanced scans, fpVCT displayed the vascular trees of the brain, liver, kidney down to the subsegmental level. Functional application of fpVCT in dynamic contrast-enhanced scans of the rat brain delivered physiologically reliable data of perfusion, tissue blood volume. Beyond scanning of small animal models as demonstrated here, fpVCT provides the ability to image animals up to the size of primates.
To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung ...injury model.
Randomized, controlled, prospective experimental study.
Academic research laboratory.
Twelve anesthetized and mechanically ventilated pigs.
Acute lung injury was induced by central venous oleic acid injection and abdominal hypertension in seven animals. Five healthy pigs served as control group. Animals were ventilated with positive end-expiratory pressure of 0, 5, 10, 15, 20, and 25 cm H2O, respectively, in a randomized order.
At any positive end-expiratory pressure level, electrical impedance tomography was obtained during a slow inflation of 12 mL/kg of body weight. Regional-ventilation-delay indices quantifying the time until a lung region reaches a certain amount of impedance change were calculated for lung quadrants and for every single electrical impedance tomography pixel, respectively. Pixel-wise calculated regional-ventilation-delay indices were plotted in a color-coded regional-ventilation-delay map. Regional-ventilation-delay inhomogeneity that quantifies heterogeneity of ventilation time courses was evaluated by calculating the scatter of all pixel-wise calculated regional-ventilation-delay indices. End-expiratory and end-inspiratory computed tomography scans were performed at each positive end-expiratory pressure level to quantify tidal recruitment of the lung. Tidal recruitment showed a moderate inter-individual (r = .54; p < .05) and intra-individual linear correlation (r = .46 up to r = .73 and p < .05, respectively) with regional-ventilation-delay obtained from lung quadrants. Regional-ventilation-delay inhomogeneity was excellently correlated with tidal recruitment intra- (r = .90 up to r = .99 and p < .05, respectively) and inter-individually (r = .90; p < .001).
Regional-ventilation-delay can be noninvasively measured by electrical impedance tomography during a slow inflation of 12 mL/kg of body weight and visualized using ventilation delay maps. Our experimental data suggest that the impedance tomography-based analysis of regional-ventilation-delay inhomogeneity provides a good estimate of the amount of tidal recruitment and may be useful to individualize ventilatory settings.
Given the young age of onset and high probability of long-term disability after subarachnoid hemorrhage (SAH), the financial impact is expected to be substantial. Our primary objective was to ...highlight subsequent treatment costs after the acute in-hospital stay, including rehabilitation and home care, compared with costs for ischemic stroke.
The study included 101 patients (median age 52 years, 70 women) with aneurysmal SAH treated from July 2007 to April 2009. In-hospital costs were calculated using German diagnosis related groups. Rehabilitation costs depended on rehabilitation phase/grade and daily rate. Level of severity of care requirements determined the costs for home care.
Of patients, 54% received coiling and 46% received clipping. The clipping group included more poor-grade patients than the coiling group (P = 0.039); 23 patients died. Of 78 surviving patients, 70 received rehabilitation treatment (68 in Germany). Mean rehabilitation costs were €16,030 per patient. Patients in the clipping group generated higher rehabilitation costs and longer treatment periods in rehabilitation facilities (P = 0.001 for costs €20,290 vs. €11,771 and P = 0.011 for duration (54.4 days vs. 40.5 days). Of surviving patients, 32% needed home care, of whom 52% required constant care. Multivariate regression analysis identified longer intensive care unit stay and poor Hunt and Hess grade as independent predictors of higher costs.
Aneurysmal SAH prevalently affects working individuals with long-term occupational disability necessitating long-term medical rehabilitation for most patients and subsequent nursing care in one third of survivors. Overall, SAH treatment generates far higher costs than reported for ischemic stroke.
Delayed cerebral ischemia associated with cerebral vasospasm is a common cause of secondary neurological decline after aneurysmal subarachnoid hemorrhage (SAH). Triple-H therapy, induced ...hypertension, hypervolemia, and hemodilution, is often used to treat cerebral vasospasm. However, hypertensive treatment may carry significant medical morbidity, including cardiopulmonary, renal, and intracranial complications. Posterior reversible encephalopathy syndrome (PRES) is a reversible intracranial complication that has rarely been reported in the setting of induced hypertension.
We present an illustrative case of PRES in a patient with induced hypertension for SAH-related cerebral vasospasm and performed a systematic review. Furthermore, the electronic database MEDLINE was searched for additional data in published studies of PRES after induced hypertension.
Overall, 7 case reports presenting 10 patients who developed PRES secondary to induced hypertension were found. Eighty-two percent of the patients were women. In all cases, the clinical symptoms were attributed to cerebral vasospasm before the diagnosis of PRES. The time from onset of induced hypertension to the development of PRES was 7.8±3.8 days. After the diagnosis of PRES and careful taper down of the blood pressure, the neurological symptoms resolved almost completely within a few days in all patients.
PRES in the setting of SAH is an overlooked complication of hypertensive therapy for the treatment of vasospasm. However, the diagnosis of this phenomenon is crucial given the necessity to reverse hypertensive therapy, which is contrary to the usual management of patients with vasospasm.
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