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Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2

BACKGROUND Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12���g���dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (���week 3) onwards. OBJECTIVE To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN A multicentre observational study. SETTING The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g���dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g���dl-1 in week 2 and 8.0 [7.3 to 9.0] g���dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml���kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g���dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION ClinicalTrials.gov, identifier: NCT02350348.

Background Casper-RX (MicroVention, Aliso Viejo, California, USA) is a dual-layer closed cell stent recently introduced as a carotid artery revascularization device. Although its effectiveness and safety has been proved in elective cases, there are contradictive results regarding its patency in emergency settings. The purpose of the study is to present our single-center experience with the Casper-RX stent in the emergency interventions. Patients and methods Consecutive patients who underwent emergency carotid artery stenting using Casper-RX system with or without additional intracranial thrombectomy between August 2016 and June 2019 at our institution were included. Primary end point was the short-term patency of the carotid stents evaluated before hospital discharge by use of Doppler ultrasonography. Results Twenty-nine procedures performed on 28 patients were included in the study. All stents were patent on final angiograms. Acute stent occlusion was observed only in one case (3.4%) with a spontaneous cervical internal carotid artery dissection the day after the procedure. In 26 (89.6%) cases, an additional intracranial thrombectomy was performed with a successful recanalization rate of 96.1%. Seven adverse events occurred peri-/post-procedural: two cases (6.9%) with iatrogenic dissection of distal cervical internal carotid artery during intracranial thrombectomy, two parenchymal hematoma type 2 (6.8%), and three patients (10.3%) developed massive infarction. Conclusion This study supports the safety and efficacy of the Casper-RX stent in emergency endovascular carotid artery revascularization procedures.

Introduction: Cranial nonenhanced CT (NECT) imaging in hyperacute ischemic stroke is rarely used for assessing arterial obstruction of middle cerebral artery by identifying hyperdense artery sign (HAS). Considering, however, its growing importance due to its impact on the decision-making process of thrombolysis with or without mechanical thrombectomy improved sensitivity to HAS is necessary, particularly in the group of less experienced clinicians being frequently the first one assessing the presence of HAS on NECT. Objective: The present study aimed to investigate the effect of different NECT image reconstructions on the correct detection of hyperdense middle cerebral artery sign in a cohort of observers with lower experience level on NECT. Particularly, MIP image reconstructions were expected to be useful for less experienced observers due to both strengthening of the hyperdensity of HAS and streamlining to less image slices. Methods: Twenty-five of 100 patients’ NECT image data presented with HAS. Sixteen observers with lower practice level on NECT (10 radiologists and 6 neurologists) evaluated independently the 3 image reconstructions of each data set with thin slice 1.5 mm, thick slab 5 mm, and 6-mm maximum intensity projection (MIP) and rated the presence of HAS in middle cerebral artery. A GEE model with random observer effect was used to examine the influence of the 3 image reconstructions on sensitivity to HAS. A linear mixed effects regression model was used to investigate the ranking of detectability of HAS. Interrater reliability was determined by Fleiss’ kappa coefficient (κ). Results: Recognition of HAS and sensitivity to HAS significantly differed between the 3 image reconstructions (p = 0.0106). MIP and thin slice reconstructions yielded each on average the highest sensitivities with 73% compared to thick slab reconstruction with 45% sensitivity. The interobserver reliability was fair (κ, 0.3–0.4). Detectability of HAS was significantly easier and better visible ranked on MIP and thin slice reconstructions compared to thick slab (p < 0.05). Conclusion: MIP and thin slice reconstructions increased the sensitivity to HAS (73%), whereas thick slab reconstructions seemed to be less appropriate (45%).

Background The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide—version 3—(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. Methods Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. Results One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. Conclusions CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

The authors regret that errors were present in the above article. On page 1174, in the second paragraph of the Statistical methods section, the second sentence should read as follows: The incidence of difficult intubation was determined including those whose tracheas were already intubated and is reported as a percentage with a 95% exact binomial CI. On page 1175, in the third paragraph of the Statistical methods section ‘mean standardised difference (MSD)’ should read ‘standardised mean difference (SMD)’ The authors would like to apologise for any inconvenience caused.

Background: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. Results: Infants (n=5609) born at mean (standard deviation [SD]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2

WEB (Woven EndoBridge) device is an intrasaccular flow diverter designed for endovascular treatment of intracranial aneurysms. Recent clinical trials showed good feasibility, safety, and efficacy profiles. In most of the published studies however, aneurysms treated with adjunctive devices other than WEB such as coils or stents were included which might make it difficult to reflect the real potential of this device. The purpose of this single-center study was to present the results of ruptured and unruptured aneurysms treated only with WEB device. Between April 2013 and July 2018, 47 (ruptured, 12; 25.5%) intracranial aneurysms treated only with WEB and a follow-up of at least 3 months were included in the study. Angiographic outcome at follow-up, peri-procedural complication rate, and rate of retreatment were recorded. Of the 47 aneurysms, 12 (25.5%) were ruptured. The mean size of the aneurysms was 6.3 mm (ruptured, 5.4 mm; unruptured, 6.6 mm). Median follow-up period was 9 months. Complete occlusion was observed in 26/47 aneurysms (55.3%; ruptured, 66.6%; unruptured, 51.4%). Thirteen aneurysms (27.6%; ruptured, 16.6%; unruptured, 31.4%) showed a neck remnant. In 4/47 aneurysms (8.5%; ruptured, 8%; unruptured, 8.5%), persistent contrast enhancement inside the WEB was recorded. In 4/47 patients (8.5%; ruptured, 8%; unruptured, 8.5%), an aneurysm remnant was noted. Adequate occlusion (complete occlusion and neck remnant) was observed in 43/47 aneurysms (91.4%; ruptured, 91.6%; unruptured, 91.4%). Retreatment rate was 6.3% (ruptured, 8%; unruptured, 5.7%). Six (12.7%; ruptured, 25%; unruptured, 8.5%) thromboembolic events were recorded. Hemorrhagic complications occurred in two patients (4.2%; ruptured, 16.6%; unruptured, 0%). WEB enables adequate occlusion of ruptured and unruptured intracranial aneurysms mostly without requirement of long-term antiplatelet therapy. The benefit is seen especially by the wide-necked aneurysms, but indications should be extended to include narrow-necked, smaller, and side-wall aneurysms.

CT-resolution depends on tube focal spot size. To investigate the effect of reducing focal spot on vessel wall clarity, 22 patients underwent head and neck CTA acquisition with large and small focal spot size. Hounsfield density profile was assessed for each head and neck vessel separately, and significantly sharper density increase at vessel borders was observed using smaller tube focus by an average of 9.9% to 82° angle degrees (p

Recently, treatment of cerebral aneurysms with the Woven EndoBridge (WEB) device has become an established endovascular strategy. However, over time, neurosurgeons and neuroradiologists will be confronted with the challenge of how to treat aneurysm recanalization. The authors report the case of a 49-year-old woman who underwent re-treatment with clipping after the recanalization of a 4 × 3–mm anterior communicating artery aneurysm that had previously been treated using a 4 × 3 WEB device. In contrast to the authors’ prior experiences with clipping of previously coiled aneurysms, the WEB device was found to have a responsive softness during clip placement, and the aneurysm was more maneuverable. Moreover, evaluation with indocyanine green angiography was easy to perform because of the transparent mesh of the WEB device. No profound scarring or WEB protrusion was noted during surgery, making the procedure easier and less dangerous with regard to additional complications. The authors suggest that re-treatment via clipping should be considered in select cases of aneurysm recurrence after treatment with an intraaneurysmal flow diverter.

Purpose: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide - version 3 - (CUSP9v3) to address this issue. The aim of this proof-of-concept clinical trial was to assess the safety of CUSP9v3. Study Design: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. Results: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. Progression-free survival after 12 months was 50%. Conclusions: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

BACKGROUND AND PURPOSE: After endovascular treatment of intracranial aneurysms with the Woven EndoBridge (WEB) device, worsening of aneurysm occlusion or re-opening was reported to be possibly associated with WEB shape modification. This study analyzed quantitatively the WEB shape modification with time in association with anatomic results. MATERIALS AND METHODS: Thirty patients with 32 WEB-treated intracranial aneurysms fulfilled the inclusion criteria of cranial CT at baseline (day of intervention) and a follow-up CT at least >1 months' later (median follow-up time, 11.4 months; interquartile range, 6.5–21.5 months). Adequate occlusion was observed in 84.4%, and aneurysm remnant, in 15.6%. WEB shape modification was quantified by a semiautomated approach on CT scans. Time courses were evaluated graphically and analytically; association analyses were performed by linear mixed-effects regression models. RESULTS: In 29/32 WEB devices (90.6%), the reduction in height was found to be at least 5%. The decrease in height with time was significantly associated with the time interval in days since the intervention (P < .0001): A stronger decrease in WEB height was associated with a longer time since the intervention (median reduction in 1 year, 19.2%; range, 8.6%–52.3%). No significant association was found with the quality of aneurysm occlusion, device size, rupture status of the aneurysm, aneurysm location, and reintervention rate. CONCLUSIONS: Shape modification was common in WEB-treated intracranial aneurysms with a median height reduction of 19.2% in 1 year. The quality of aneurysm occlusion was not associated with WEB modification.

Background and Purpose— The recent Save ChildS study provides multicenter evidence for the use of mechanical thrombectomy in children with large vessel occlusion arterial ischemic stroke. However, device selection for thrombectomy may influence rates of recanalization, complications, and neurological outcomes, especially in pediatric patients of different ages. We, therefore, performed additional analyses of the Save ChildS data to investigate a possible association of different thrombectomy techniques and devices with angiographic and clinical outcome parameters. Methods— The Save ChildS cohort study (January 2000–December 2018) analyzed data from 27 European and United States stroke centers and included all pediatric patients ( Results— Seventy-three patients with a median age of 11.3 years were included. Currently available stent retrievers were used in 59 patients (80.8%), of which 4×20 mm (width×length) was the most frequently chosen size (36 patients =61%). A first-line ADAPT approach was used in 7 patients (9.6%), and 7 patients (9.6%) were treated with first-generation thrombectomy devices. In this study, a first-line ADAPT approach was neither associated with the rate of successful recanalization (ADAPT 85.7% versus 87.5% No ADAPT) nor with the complication rate or the neurological outcome. Moreover, there were no associations of stent retriever sizes with rates of recanalization, complication rates, or outcome parameters. Conclusions— Our study suggests that neurological outcomes are generally good regardless of any specific device selection and suggests that it is important to offer thrombectomy in eligible children regardless of technique or device selection. Registration— URL: https://www.drks.de/ ; Unique identifier: DRKS00016528.

Importance Randomized clinical trials have shown the efficacy of thrombectomy of large intracranial vessel occlusions in adults; however, any association of therapy with clinical outcomes in children is unknown. Objective To evaluate the use of endovascular recanalization in pediatric patients with arterial ischemic stroke. Design, Setting, and Participants This retrospective, multicenter cohort study, conducted from January 1, 2000, to December 31, 2018, analyzed the databases from 27 stroke centers in Europe and the United States. Included were all pediatric patients ( Exposures Endovascular recanalization. Main Outcomes and Measures The decrease of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) score from admission to day 7 was the primary outcome (score range: 0 [no deficit] to 34 [maximum deficit]). Secondary clinical outcomes included the modified Rankin scale (mRS) (score range: 0 [no deficit] to 6 [death]) at 6 and 24 months and rate of complications. Results Seventy-three children from 27 participating stroke centers were included. Median age was 11.3 years (interquartile range [IQR], 7.0-15.0); 37 patients (51%) were boys, and 36 patients (49%) were girls. Sixty-three children (86%) received treatment for anterior circulation occlusion and 10 patients (14%) received treatment for posterior circulation occlusion; 16 patients (22%) received concomitant intravenous thrombolysis. Neurologic outcome improved from a median PedNIHSS score of 14.0 (IQR, 9.2-20.0) at admission to 4.0 (IQR, 2.0-7.3) at day 7. Median mRS score was 1.0 (IQR, 0-1.6) at 6 months and 1.0 (IQR, 0-1.0) at 24 months. One patient (1%) developed a postinterventional bleeding complication and 4 patients (5%) developed transient peri-interventional vasospasm. The proportion of symptomatic intracerebral hemorrhage events in the HERMES meta-analysis of trials with adults was 2.79 (95% CI, 0.42-6.66) and in Save ChildS was 1.37 (95% CI, 0.03-7.40). Conclusions and Relevance The results of this study suggest that the safety profile of thrombectomy in childhood stroke does not differ from the safety profile in randomized clinical trials for adults; most of the treated children had favorable neurologic outcomes. This study may support clinicians’ practice of off-label thrombectomy in childhood stroke in the absence of high-level evidence.

Background: Intravesical instillation of bacillus Calmette-Guerin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. Objective: NIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participants: A total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. Intervention: The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysis: The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitations: In total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. Conclusions: The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summary: After surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guerin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today's perspective, complete tumour resection and a standard number of instillations remain the standard of care. In high-grade non–muscle-invasive bladder cancer, a reduced frequency of bacillus Calmette-Guerin (BCG) instillations during induction and maintenance is inferior to the standard BCG schedule regarding time to first recurrence. Repeated transurethral resection followed by the standard BCG regimen, as recommended by the European Association of Urology guideline, remains the state of the art. (Less)

The aim of our study was to compare depicted pre-, intra-, and postoperative tumor volume of met-PET, perfusion-weighed MRI (PWI), and Gd-DTPA MRI. Further, to assess their sensitivity and specificity in correlation with histopathological specimen. Inclusion criteria of the prospective study were histological confirmed glioblastoma (GB), age > 18, and eligible for gross total resection (GTR). Met-PET was performed before and after surgery. Gd-DTPA MRI and PWI were performed before, during, and after surgery. A combined 5-aminolevulinic acid (5-ALA) and iMRI-guided surgery was performed. Volumetric analysis was evaluated for all imaging modalities except for 5-ALA. A total of 59 navigated biopsies were taken. Sensitivity and specificity were calculated for Gd-DTPA MRI, PWI, met-PET, and 5-ALA according to the histology of specimen. Met-PET depicted significantly larger tumor volume before surgery (p = 0.01) compared to PWI and Gd-DTPI MRI. We found no significant difference in tumor volume between met-PET and PWI after surgery (p = 0.059). Both PWI and met-PET showed significantly larger tumor volume after surgery when compared to Gd-DTPA (p = 0.018 and p = 0.003, respectively). Intraoperative PWI reading was impaired in 33.3% due to artifacts. Met-PET showed the highest sensitivity for detection of GB with 95%. The lowest sensitivity was found with Gd-DTPA MRI (50%), while 5-ALA and intraoperative PWI showed similar results (69 and 67%). Met-Pet is the imaging modality with the highest sensitivity to detect a residual tumor in GB. Intraoperative PWI seems to have a synergistic effect to Gd-DTPA and 5-ALA. However, its value may be limited by artifacts. Both pre- and intraoperative PWI cannot substitute met-PET in tumor detection.

Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are major factors that limit good outcome in patients with spontaneous subarachnoid hemorrhage (SAH). Continuous therapy with intra-arterial calcium channel blockers has been introduced as a new step in the invasive treatment cascade of CV and DCI. Sedation is routinely necessary for this procedure. We report about the feasibility to apply this therapy in awake compliant patients without intubation and sedation. Out of 67 patients with invasive endovascular treatment of cerebral vasospasm due to spontaneous SAH, 5 patients underwent continuous superselective intracarotid nimodipine therapy without intubation and sedation. Complications, neurological improvement, and outcome at discharge were summarized. Very good outcome was achieved in all 5 patients. The Barthel scale was 100 and the modified Rankin scale 0-1 in all cases at discharge. We found no severe complications and excellent neurological monitoring was possible in all cases due to patients' alert status. Symptoms of DCI resolved within 24 h in all 5 cases. We could demonstrate the feasibility and safety of selective intracarotid arterial nimodipine treatment in awake, compliant patients with spontaneous SAH and symptomatic CV and DCI. Using this method, an excellent monitoring of neurological function as well as early detection of other complications is possible. It might be an important step in the risk reduction of invasive CV therapy to improve the outcome with CV and DCI after SAH in selected patients.

CUSP9v3 is a new treatment regimen for glioblastoma. It consists of continuous daily use of 9 drugs repurposed from general medicine. Their primary non-oncology uses are given in parentheses: aprepitant (nausea), auranofin (rheumatoid arthritis), celecoxib (pain), captopril (hypertension), disulfiram (alcohol abuse), itraconazole (fungal infection), minocycline (bacterial infection), ritonavir (viral infection) and sertraline (depression). All drugs have preclinical or clinical data indicating that they can retard glioblastoma growth, as reviewed in the published background papers. In CUSP9v3 all 9 medicines are given daily with added metronomic, low-dose (20 mg/m2 BSA twice daily) temozolomide. After 3 years of daily, uninterrupted use of CUSP9v3, of an initial cohort of 10 recurrent glioblastoma patients, as of May 2021, 3 are alive, functioning well, progression-free at 44, 44, and 57 months after recurrence and CUSP9v3 started. We report now that there were no unexpected toxicities from this combination of 10 daily drugs, although all patients required dose reduction of one or more of the drugs. CUSP9v3 was reasonably well-tolerated. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose reduction or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. There were no treatment-related deaths. In the 3 long-term survivors, the median neutrophil-to-lymphocyte ratio decreased from 2.5 to 1.5 during CUSP9v3 treatment. In the group of the 3 shortest-term survivors that ratio increased from 4.7 to 14.3. CUSP9v3 follows the injunction of Palmer et al. that cancer therapy can be constructed using drug combinations that are independently effective, with non-overlapping mechanisms of action, and non-overlapping resistance pathways. We interpret the data accrued over the last few decades on the ever-shifting spatial and temporal growth drives active at any given moment in glioblastoma as requiring a complex pharmacological approach like CUSP9v3.

Background World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking. Methods The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol. Results We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma. Conclusion The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG.

Disc herniations can present with unusual findings at unusual locations, mimic different pathologies and create confusion in the daily practice. Extra-foraminal intraneural location of L5-S1 disc herniation is extremely rare and may not be noticed on initial imaging extending the time to reach the diagnosis. There is no specific imaging finding suggesting the intraneural location of the lesion. Here, we report a case of an extra-foraminal intraneural L5-S1 disc herniation mimicking a retroperitoneal peripheral nerve sheath tumour and review similar cases in the literature.

BACKGROUND AND PURPOSE Capabilities of CTA for evaluation of intracranial aneurysms treated with the Woven EndoBridge (WEB) system has not been thoroughly studied yet. Our aim is to compare the ability of CTA to that of DSA to depict the occlusion status of aneurysms treated with WEB device and present the level of reproducibility of results from CTA. METHODS Patients with intracranial aneurysm treated only with the WEB device and having a CTA and a DSA during the same hospital stay were included. Aneurysm occlusion was evaluated by two methods: a simplified binomial system grading as either adequate occlusion (complete occlusion or neck remnant) or aneurysm remnant and a four-grade scale. Interobserver and intermodality agreement were determined using the κ statistic. Using DSA as a reference test, the diagnostic capabilities of CTA were calculated. RESULTS Sixteen patients with 16 aneurysms were included. Interobserver agreement was fair for DSA (κ = .26) and good for CTA (κ = .78) using the four-grade scale, and moderate for DSA (κ = .44) and good for CTA (κ = .63) using the binomial scale. CTA and DSA were in agreement in 15 of 16 aneurysms (93.75%) using the binomial scale meaning good intermodality agreement for aneurysm remnant detection (κ = .63). Sensitivity of CTA for detection of an aneurysm remnant was 50%, specificity was 100%, positive prediction value was 100%, and negative prediction value was 93.33%. CONCLUSION CTA is a reliable and reproducible method to evaluate the aneurysm occlusion status and could be implemented on the follow-up of aneurysms treated with WEB.

OBJECTIVEThe level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called “high-risk” patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery.METHODSBased on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma.RESULTSOne hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8–6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance.CONCLUSIONSIn this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.

Zusammenfassung Einleitung Bei Leberzirrhose mit Pfortaderhochdruck kann es zu lebensbedrohlichen gastrointestinalen Blutungen kommen. Fallvorstellung Wir berichten über einen 67-jährigen Patienten mit äthyltoxischer Leberzirrhose und endoskopisch nicht kontrollierbaren Rektalvarizenblutungen. Beschrieben wird eine im interdisziplinären Konsens getroffene Entscheidung eines Therapieversuchs mittels perkutaner paraumbilikaler Embolisation. Diskussion Bei gastrointestinalen Blutungen bei Pfortaderhochdruck stehen als Therapiemöglichkeiten die endoskopische oder chirurgische Intervention, medikamentöse Therapie oder die TIPS (transjugulärer intrahepatischer portosystemischer Shunt)-Anlage im Vordergrund. Sollten diese Optionen nicht infrage kommen oder frustran verlaufen sein, besteht die Möglichkeit einer radiologischen Intervention mit perkutaner transumbilikaler Embolisation des die Blutung speisenden Pfortaderumgehungskreislaufs. Sowohl in unserem Fall als auch bei den in der Literatur beschriebenen Embolisationen von Ösophagusvarizen kam es zu einem Sistieren der Blutungen, ohne dass für den jeweiligen Patienten ein großer Eingriff nötig gewesen war.

Background The presence of residual tumor is crucial in decision-making for low-grade gliomas (LGGs), because patients older than 40 years of age with residual tumor are considered for adjuvant treatment. There are hints that early postoperative fluid-attenuated inversion recovery (FLAIR) and T2 (within 48 hours) may overestimate residual tumor volume in LGG. Intraoperative magnetic resonance imaging (MRI) without subsequent resection or ultra-early postoperative MRI may assess the amount of residual tumor more adequately. To evaluate the utility of postoperative imaging in LGG, we volumetrically analyzed intraoperative, early, and late (3–4 months after surgery) postoperative MRIs of LGGs. Patients and Methods A total of 33 patients with LGG were assessed retrospectively. Residual tumor was defined as signal-enhanced tissue in T2 and FLAIR. Volumetric assessment was performed with intraoperative, early, and late postoperative T2/FLAIR via Brainlab-iPlan 3.0. Wilcoxon and χ 2 tests were used for statistical analysis. Results A significant difference of FLAIR/T2 abnormalities was found in intraoperative and early postoperative MRIs (FLAIR mean volume = 5.433 cm 3 , T2 mean volume = 3.374 cm 3 vs. FLAIR mean volume = 14.090 cm 3 , P = 0.002, T2 mean volume = 7.597 cm 3 , P = 0.006). There was no significant difference between intraoperative and late postoperative FLAIR/T2 abnormalities (late postoperative FLAIR/T2 mean volume = 5.560 cm 3 and 2.370 cm 3 , P = 0.520, P = 0.398), whereas a significant difference was detected between early and late postoperative images (FLAIR, P P Conclusion Intraoperative MRI without further resection or ultra-early postoperative MRI seems to reflect the actual volume of residual tumor in LGG more precisely compared with early postoperative MRI and therefore seems to be more useful regarding decisions for adjuvant therapy.

Endovascular therapy is now considered as the standard treatment for acute ischemic stroke in the setting of large vessel occlusion. However, it took time to come to this setting. In this review, first briefly the evolution and actual status of endovascular therapy for acute ischemic stroke are presented. The second part focuses on the daily clinical practice at the authors’ institution with respect to the endovascular stroke therapy. While doing this, different aspects will be briefly discussed.

OBJECTIVEDelayed cerebral ischemia (DCI) is a major factor contributing to the inferior outcome of patients with spontaneous subarachnoid hemorrhage (SAH). Nimodipine and induced hypertension using vasopressors are an integral part of standard therapy. Consequences of the opposite effect of nimodipine and vasopressors on blood pressure on patient outcome remain unclear. The authors report the detailed general characteristics and influence of nimodipine and vasopressors on outcome in patients with SAH.METHODSThe authors performed a 2-center, retrospective, clinical database analysis of 732 SAH patients treated between 2008 and 2016. Demographic and clinical data such as age, sex, World Federation of Neurosurgical Societies (WFNS) grade, BMI, Fisher grade, history of arterial hypertension and smoking, aneurysm location, C-reactive protein (CRP) level, and detailed dosage of vasopressors and nimodipine during the treatment period were evaluated. Clinical outcome was analyzed using the modified Rankin Scale (mRS) 6 months after treatment. Univariate and multivariate regression analyses were performed. Additionally, mean arterial pressure (MAP), age, nimodipine, and vasopressor dose cutoff were evaluated with regard to outcome. The level of significance was set at ≤ 0.05.RESULTSFollow-up was assessed for 397 patients, 260 (65.5%) of whom achieved a good outcome (defined as an mRS score of 0–3). Univariate and multivariate analyses confirmed that nimodipine (p = 0.049), age (p = 0.049), and CRP level (p = 0.002) are independent predictors of good outcome. WFNS grade, Fisher score, hypertension, initial hydrocephalus, and total vasopressor dose showed significant influence on outcome in univariate analysis, and patient sex, smoking status, BMI, and MAP showed no significant association with outcome. A subgroup analysis of patients with milder initial SAH (WFNS grades I–III) revealed that initial hydrocephalus (p = 0.003) and CRP levels (p = 0.001) had significant influence on further outcome. When evaluating only patients with WFNS grade IV or V, age, CRP level (p = 0.011), vasopressor dose (p = 0.030), and nimodipine dose (p = 0.049) were independent predictors of patient outcome. Patients with an MAP < 93 mm Hg, a nimodipine cutoff dose of 241.8 mg, and cutoff total vasopressor dose of 523 mg had better outcomes.CONCLUSIONSAccording to the authors’ results, higher doses of vasopressors can safely provide a situation in which the maximum dose of nimodipine could be administered. Cutoff values of the total vasopressor dose were more than 3 times higher in patients with severe SAH (WFNS grade IV or V), while the nimodipine cutoff remained similar in patients with mild and severe SAH. Hence, it seems encouraging that a maximum nimodipine dosage can be achieved despite the need for a higher vasopressor dose in patients with SAH.

Quality of life is an important factor in the decision making for the treatment of unruptured intracranial aneurysms (UIA). The data dealing with QoL in patients after the treatment are spare. We have evaluated QoL of patients after endovascular or surgical treatment of incidental intracranial aneurysm.We performed a prospective analysis of retrospectively collected data. All patients received 36-Item Short Form Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS), German questionnaire for self-perceived deficits in attention (FEDA) and not standardized questionnaire analyzing personal job-related situation, family circumstances and chronic illnesses.177 patients were treated during the evaluated period. 79 (44.6%) patients responded. In this cohort, 62.03% of patients underwent coiling. Complications were noted in 13.9% of patients. Stroke was the most common complication (7.6%). All SF-36 related data except for pain showed significant lower mean, if compared to the standard German population (p0.01). For both genders, anxiety (males, P = 0.003 and females, P = 0.002) but not depression was more common than in the standard population. According to the FEDA test, treated patients showed significant difference only for fatigue in comparison to healthy population (P 0.001). 54.4% of patients suffered from chronic illnesses, and among them only 1 patient (1.3%) had aneurysm associated chronic disease. No significant differences were found between treatment modalities.The risk for depression and pain is not significantly increased after elective treatment of UIA. According to our results, decreased QoL is common in this cohort of patients but often related to factors not associated with aneurysm treatment.

Background: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV’s efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. Methods: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. Results: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. Conclusions: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV.

Spinal dural arteriovenous fistulas (AVFs), being the most commonly encountered spinal vascular malformations, result in considerable morbidity with progressive spinal cord symptoms. A selective spinal digital subtraction angiography (DSA) is needed to confirm the diagnosis, to better evaluate the fine vascular structures and to plan therapy. With the introduction of three-dimensional rotational angiography (3D-RA), the information available for the treating physician has vastly increased. In the following article, we present a case series of four patients, in which the advantages of 3D-RA over the conventional biplane projections could be observed clearly.

Patients with metastatic bladder cancer (mBC) treated with cisplatin-based chemotherapy have a limited median survival of only around 14 months [1]. Despite over 30 years of basic and clinical research, until recently no therapeutic options beyond cisplatin-based therapy had entered clinical routine and, at least in the US, none of the tested agents had been approved for second-line treatment. This has changed with the advent of immune checkpoint blockade, including especially PD-1/PD-L1 inhibitors. The high response rates of 24% over a 14.4 month follow up led to the first US Food and Drug Administration (FDA) approval for a second line therapy for these patients, and it is likely that this marks the beginning of a new era in the systemic treatment of muscle-invasive bladder cancer [2-4]. The strong clinical need to improve the medical management of this disease for those patients, not responding to current therapy has led to an increased molecular understanding of bladder cancer and has forstered the development of many potential molecular manipulations and targeted strategies beyond the new immune-oncologic approaches. Among the molecular alterations indentified in bladder cancer, cell cycle deregulation appears to be a key driver of disease progression. Target-directed therapy against CDK4/6 is an emerging strategy to regain control of cell cycle deregulation. Here, we provide an overview of the current status of CDK4/6 inhibitors in cancer therapy, their potential use in mBC and the challenges for their clinical use.

OBJECTIVEThe gold standard for evaluation of ventriculoperitoneal (VP) shunt position, dislocation, or disconnection is conventional radiography. Yet, assessment with this modality can be challenging because of low image quality and can result in repetitive radiation exposure with high fluctuation in the radiation dose. Recently, CT-based radiation doses have been significantly reduced by using low-dose protocols. Thus, whole-body low-dose CT (LDCT) has become applicable for routine use in VP shunt evaluation. The authors here compared image quality and approximate radiation dose between radiography and LDCT in patients with implanted VP shunt systems.METHODSVentriculoperitoneal shunt systems have been investigated with LDCT scanning at the authors’ department since 2015. A consecutive series of 57 patients (70 investigations) treated between 2015 and 2016 was retrospectively assessed. A historical patient cohort that had been evaluated with radiography was compared with the LDCT patients in terms of radiation dose and image quality. Three independent observers evaluated projection of the valve pressure level and correct intraperitoneal position, as well as complete shunt projection, using a Likert-type scale of 1–5, where 1 indicated “not assessable” and 5 meant “assessable with high accuracy.” Descriptive statistics and the Mann-Whitney U-test were used for analysis.RESULTSTwenty-seven radiographs (38.6%) and 43 LDCT scans (61.4%) were analyzed. The median dose-length product (DLP) of the LDCT scans was 100 mGy·cm (range 59.9–183 mGy·cm). The median total dose-area product (DAP) of the radiographic images was 3177 mGy·cm2 (range 641–13,833 mGy·cm2). The estimated effective dose (EED) was significantly lower with the LDCT scan (p < 0.001). The median EED was 4.93 and 1.90 mSv for radiographs and LDCT, respectively. Significantly better identification of the abdominal position of the distal shunt catheter was achieved with LDCT (p < 0.001). Simultaneously, significantly improved visualization of the entire shunt system was realized with this technique (p < 0.001). On the contrary, identification of the valve settings was significantly worse with LDCT (p < 0.001).CONCLUSIONSWhole-body LDCT scanning allows good visualization of the distal catheter after VP shunt placement. Despite the fact that only a rough estimation of effective doses is possible in a direct comparison of LDCT and radiography, the data showed that shunt assessment via LDCT does not lead to greater radiation exposure. Thus, especially in difficult anatomical conditions, as in patients who have undergone multiple intraabdominal surgeries, have a high BMI, or are immobile, the use of LDCT shunt evaluation has high clinical value. Further data are needed to determine the value of LDCT for the evaluation of complications or radiation dose in pediatric patients.

CSF outflow through the cribriform plate near the olfactory nerves and the outflow along brain and spinal nerves are together known as peripheral CSF outflow pathway (PCOP). It is still not clear whether the PCOP has pathogenetic relevance. Our previous clinical observations have indicated that CSF may interact with nerves along the PCOP and in this article we present our finding of CSF outflow demonstrated by myelography in a single patient. We also discuss unexplained experimental pain pathomechanisms against the background of the PCOP hypothesis. We observed that CSF flowed along lumbar nerves in distal direction at a speed of about 10 cm per hour on its way through the tissues, mainly muscles. Total CSF outflow volume at the lumbar site was remarkable. CSF outflow at lumbar nerves was also documented by neuroradiology. It is plausible that CSF signaling serves for interaction with nerves along the PCOP, which could explain previously unknown pathomechanisms in pain generation. Experimental findings of tactile pain hypersensitivity within lumbosacral pain pathways could be explained by releasing of molecules, microparticles, or exosomes into the CSF by mast cells, which then move with CSF outflow along the PCOP and interact with nerves, initiating even retrograde synaptic stripping.

Cochlear implantation in routine cases with normal anatomy is commonly performed without intraoperative image guidance. Revision cochlear implantation as well as surgery in malformations require not only a precise understanding of the underlying complex anatomy, but surgeons need to transform two-dimensional computed tomography (2D CT) scans into the surgical field and use this information for intraoperative surgical navigation. So far, information about the exact position of the electrode during insertion cannot be provided to the surgeon. Here, we present our first operative experience with cochlear implant surgery supported by intraoperative Dyna-CT technology, providing the surgeon with detailed views of the electrode location. To prove the feasibility of the procedure, two cases of cochlear implantation were performed with intraoperative application of cone-beam CT acquired by a C-arm Dyna-CT system (Artis Zeego, Siemens Healthcare, Erlangen, Germany). Image reconstruction was performed intraoperatively in order to assess the correct positioning of the electrodes. Intraoperative Dyna-CT enabled clear visualization of the surgical anatomy and intracochlear electrode position. Dyna-CT technology can be applied with acceptable additional time requirements without adding too much complexity to the surgical procedure. Intraoperative data acquisition by Dyna-CT represents a suitable option for online surgical navigation during cochlear implant surgery. This imaging technology will push further advances in cochlear implant surgery and lateral skull base surgery, particularly if linked to intraoperative navigation.

Structural imaging studies of bipolar affective disorder or major depression have shown a spectrum of abnormal findings. However, a characteristic pattern of abnormality for either disease has not yet emerged. While the majority of studies focused on brain atrophy and the volumes of supratentorial cerebral structures, little attention has been paid to infratentorial structures. This MRI study focused on the pontomesencephalic area including the region of the raphe nuclei. The raphe nuclei are of special interest in affective disorders as they are the origin of the major serotonergic projections in this region. MRI scans of 10 bipolar I patients, 10 patients with major depression and 10 age-matched healthy control subjects were studied. The brain stem and the fourth ventricle areas as well as T2-relaxation times in the area of the raphe nuclei were evaluated. A difference between patients with major depression and control subjects for T(2)-relaxation times was found in a region of interest located along the midline of the pons. No difference was found between patients with bipolar disorder and control subjects. This finding needs to be replicated in a larger sample with more elaborated MRI techniques (multi-echo sequences) for the determination of T2-relaxation times.

Aim To identify whether increased numbers of brainstem lesions are found in the presence of a post-traumatic pupillary function disturbance and classify them anatomically. Materials and methods In this study, a diagnostic magnetic resonance imaging (MRI) examination was performed within 8 days after traumatic brain injury (TBI) in patients who had been unconscious for more than 24 hours post-TBI. The Glasgow Outcome Scale was evaluated 6 months after TBI. The data obtained from 140 consecutively enrolled patients between 2005 and 2011 were analysed. The clinical study parameter comprised the development of post-traumatic anisocoria at least once over the course between onset of trauma and diagnostic MRI, as a yes/no decision. Significance was presumed at p ≤0.05. Results A total of 57 patients (41%) were found to have a lesion at MRI without involvement of the brainstem; in 83 (59%) the brainstem was (multiple) affected. Of the latter, 66 (46%) of patients had lesions in the midbrain, 38 (27%) in the pons, and seven (5%) in the medulla oblongata. By the time of MRI, anisocoria had been diagnosed in 45 (32%) patients. Mortality was highest, at 58%, in patients with anisocoria and a midbrain lesion, whilst it was 23% in those with anisocoria and no lesion in the midbrain. Mortality was 33% in relation to a midbrain lesion without anisocoria. Conclusion Overall, the study demonstrated that there is a significant correlation between midbrain lesions and post-traumatic anisocoria in unconscious trauma patients. A brainstem lesion in this case can be assumed to be a pathomorphological correlate of anisocoria. The rate of damage to the midbrain was approximately 50% in cases of transient anisocoria. It can be assumed in this situation that there are functional disorders of the peripheral oculomotor nerve or identifiable/unidentifiable lesions of the brainstem.

Objective Complex regional pain syndrome I (CRPS I) is a frequent and debilitating condition with unclear etiology. Hypothesizing that maladaptive central processes play a crucial role in CRPS, the current study set out to explore cerebral activation during a task to suppress the feeling of pain under constant painful stimulation. Methods Ten individuals with CRPS I with symptoms on their left hand were subjected to electrical stimulation of both index fingers subsequently in a functional magnetic resonance imaging experiment. Their data were compared with 15 healthy controls. Results Concerning psychophysical measures, patients succeeded similarly as healthy controls in suppressing the feeling of pain. However, during constant painful stimulation and with the task to suppress the feeling of pain, there were significant differences in the interaction analyses of the corresponding cortical activation. Discussion Patients differ from healthy controls by the activation pattern of cerebral areas that belong to the descending opioid pain suppression pathway: PAG and cingulate cortex are activated significantly less during suppression of pain, regardless of whether the symptomatic or asymptomatic hand was stimulated. Thus, there is a generalized functional change in individuals with CRPS I. However, it cannot be deducted whether the abnormality is causative or merely an effect, possibly maladaptive.

Objectives/Hypothesis: Empty nose syndrome (ENS) patients have a persistent sense of impaired nasal patency despite radical resection of nasal turbinates. The aim of this study was to elucidate differences in cerebral activation during free breathing and after inhalation of a fragrance (lemonene) and a pseudodecongestant (menthol) over a nasofacial mask. Our hypothesis was that menthol would be perceived as beneficial and that cerebral activation would show differences in areas corresponding to emotional suffering and air hunger in ENS patients. Study Design: Prospective, controlled intervention with lemonene and menthol during functional magnetic resonance imaging (f-MRI) experiment. Methods: Ten right-handed ENS patients were compared to 15 controls using f-MRI and fully automated data analysis with SPM software. Nasal patency was measured with rhinomanometry and rated on a four-point scale. Results: Despite similar objective nasal flow, ENS patients rated nasal patency significantly worse than did controls. Menthol was perceived to increase nasal patency. In patients, f-MRI data showed different activation of temporal cortex areas after inhalation of menthol. The comparison of patients and controls showed ENS-specific activation of temporal and cerebellar areas and amygdala during the rating task itself. Conclusions: Our experiments showed different cerebral processing of the feeling of nasal patency in ENS patients with prominent activation of areas belonging to the limbic system. The beneficial effect of menthol seems to correspond to activation differences in the temporal pole. These results demonstrate a neuronal substrate for both symptoms and their relief in ENS patients.

Background: Hippocampal sulcal cavities (HSC) have been speculated to contribute to a higher vulnerability of memory pathways and might be a possible etiological factor in transient global amnesia (TGA). Therefore, we evaluated the influence of HSC on cognitive long-term outcome in TGA-patients. Methods: Fourteen otherwise healthy patients with the clinical syndrome of TGA in their history underwent a high-resolution magnetic resolution imaging and a comprehensive neuropsychological test battery. The neuropsychological control group consisted of 15 healthy subjects and was balanced for age, sex and other risk factors as well as intellectual and social status. Results: Magnetic resolution imaging and neuropsychological testing have been performed 1128 days (median) after the TGA. HSC have been detected in nine of the 14 patients and have been bilateral in eight of them. There were no differences in cognitive performance in patients with and without HSC as well as compared to healthy subjects. Even in patients with greater lesion load, only a slight visuospatial deficit was found. Conclusions: Although an increased incidence of HSCs is detected in TGA patients, cavities are not obligatorily in TGA. Moreover, even patients with hippocampal cavities achieve a full neuropsychological recovery independent of the frequency and size of the hippocampal lesions.

A 39-year-old female patient with thoracic syringomyelia underwent routine magnetic resonance imaging (MRI) and 3 T MRI to investigate the value of retrospectively cardiac-gated cine steady-state free precession (SSFP) MRI in the preoperative and postoperative diagnosis of arachnoid membranes in the spinal subarachnoid space. Therefore, 3T MRI included sagittal and transverse retrospectively cardiac-gated cine balanced fast-field echo (balanced-FFE) sequences both preoperatively and after microsurgical lysis of arachnoid adhesions and expansive duraplasty. Arachnoid membranes were detected and this result was correlated with intraoperative findings and the results of routine cardiac-gated phase-contrast cerebrospinal fluid (CSF) flow MRI. Retrospectively cardiac-gated cine SSFP MRI enabled imaging of arachnoid membranes with high spatial resolution and sufficient contrast to delineate them from hyperintense CSF preoperatively and postoperatively. The images were largely unaffected by artifacts. Surgery confirmed the presence of arachnoid adhesions in the upper thoracic spine. Not all arachnoid membranes that were seen on cine balanced-FFE sequences caused significant spinal CSF flow blockages in cardiac-gated phase-contrast CSF flow studies. In conclusion, retrospectively cardiac-gated cine SSFP MRI may become a valuable tool for the preoperative detection of arachnoid adhesions and the postoperative evaluation of microsurgical adhesiolysis in patients with idiopathic syringomyelia.

Background Clinical benefits of measuring processed EEG during anaesthesia in adults, such as improved recovery and reduced risk of awareness, may also be valid in children. This study evaluated a rational selection of EEG variables as measures of arousal during surgical anaesthesia in children. Methods Sixty children undergoing surgical anaesthesia with propofol and remifentanil were enrolled. The performance of 33 single EEG variables and bispectral index (BIS) was assessed by simultaneous analysis of prediction probability (Pk) of Children's Hospital of Wisconsin Sedation Scores and their signal-to-noise ratio (SNR). Variables performing best in Pk and SNR analysis were selected as potential measures of arousal. Their performance was investigated in five age groups, 0–1, 1–2, 2–5, 5–8, and 8–13 yr. Results Single EEG variables such as relative power from frequency bands 13–20 and 20–26 Hz, SEF95, and approximate entropy performed best with Pk>0.59 and SNR>5.50. The Pk and SNR of BIS were 0.71 and 15.76, respectively. Their performance was significantly better in children aged 1–13 yr than in 0–1 yr. Conclusions BIS may provide a measure of arousal during propofol anaesthesia in children, but its accuracy is less in infants younger than 12 months. Single EEG variables such as high-frequency components of EEG, SEF95, and approximate entropy may be of limited value to detect arousal in the individual paediatric patient.

Albinism is associated with a misrouting of fibers at the optic chiasm where the majority of fibers cross to the contralateral side. The cause of this abnormal decussation pattern reflects a disturbance of cell cycle regulation in the development of the retina which is in part controlled by melanin. Growing axons from retinal ganglion cells therefore arrive later than usual at the optic chiasm and are misrouted contralaterally. This atypical decussation leads to morphological changes of the optic chiasm including a reduced chiasm width with larger angles between optic nerves and tracts which can be shown by magnetic resonance imaging.

Extracranial MR neurography has so far mainly been used with 2D datasets. We investigated the use of 3D datasets for peripheral neurography of the sciatic nerve. A total of 40 thighs (20 healthy volunteers) were examined with a coronally oriented magnetization-prepared rapid acquisition gradient echo sequence with isotropic voxels of 1 × 1 × 1 mm and a field of view of 500 mm. Anatomical landmarks were palpated and marked with MRI markers. After MR scanning, the sciatic nerve was identified by two readers independently in the resulting 3D dataset. In every volunteer, the sciatic nerve could be identified bilaterally over the whole length of the thigh, even in areas of close contact to isointense muscles. The landmark of the greater trochanter was falsely palpated by 2.2 cm, and the knee joint by 1 cm. The mean distance between the bifurcation of the sciatic nerve and the knee-joint gap was 6 cm (±1.8 cm). The mean results of the two readers differed by 1–6%. With the described method of MR neurography, the sciatic nerve was depicted reliably and objectively in great anatomical detail over the whole length of the thigh. Important anatomical information can be obtained. The clinical applications of MR neurography for the brachial plexus and lumbosacral plexus/sciatic nerve are discussed.

Two neuroimaging studies using fMRI were conducted in order to assess the cortical processes involved in the perception and suppression of pain. In the first study, 15 healthy subjects were stimulated with variable intensities of electrical pulses during a discrimination task. In the second study, the same subjects had to try to suppress the feeling of pain during tonic stimulation. The discrimination task resulted in cortical activation of contralateral SI, corresponding in extent to the intensity of the stimulus. Activation of contralateral operculum/posterior insula (SII) and non-dominant dorsolateral prefrontal cortex (DLPFC) with non-painful stimuli changed to activations of non-dominant anterior insula upon painful stimulation. In the second study, all subjects succeeded in suppressing the feeling of pain during previously painful levels of stimulation. During this suppression task, activations changed from anterior to posterior insula; also there was a suppression of activity in the anterior cingulated cortex (ACC) and caudate nucleus. Subjects seem to be able to suppress to a certain degree the feeling of pain under constant (and previously painful) stimulation. The cortical correlate seems to be a shift of cerebral activation from anterior to posterior right insula and a suppression of activity in the ACC and caudate nucleus.

Objective Performance improvement (PI) programs are an educational tool used to analyze clinical performance of clinicians. The effect of this tool has not been fully explored in orthopedic and trauma surgery. Design and Setting A needs assessment was conducted in connection with a worldwide webinar on magnetic resonance imaging in spinal injuries to identify the clinical need for an educational intervention. A 3-step PI process was defined and implemented over a 6-month period in 1 hospital department. Opportunities for improvement were identified by applying a 10-item quality checklist to 26 cases. A focused educational intervention was delivered to address the identified gaps, and a set of 22 posteducation cases was compared. Participants The department of radiology and the department of trauma surgery of a level I university hospital participated in this study. Results A total of 26 cases collected before the educational intervention showed several areas for potential improvement. Important information was not provided by the surgeons in their communication with the radiologist. The educational intervention outlined the data and suggested actions. Comparing the information transfer of the preintervention and postintervention data, there was a significant improvement following the intervention (p = 0.0013). Conclusion Our PI program was able to demonstrate a significant influence on the behavior and the attitude of surgeons and radiologists.

Summary Background Barbiturates are widely held to have hyperalgesic properties. Using functional magnetic resonance imaging (fMRI) techniques we sought to investigate the effects of graded doses of propofol on central pain processing in the lateral and medial pain system in healthy volunteers. Methods Touch stimuli as well as phasic and tonic mechanical pain stimuli were applied to the right hand of 18 volunteers. fMRI was performed on an 1.5 T scanner using EPI-sequences. The experiments were repeated under targeted propofol plasma levels (TCI 0, 1.5, 2.5 and 3.5 μg/ml). Changes of the BOLD signal in different cortical areas (primary and secondary somatosensory cortical areas S1 and S2, insular, anterior cingulate cortex and frontal areas) were investigated during propofol anaesthesia using correlation and clustering analysis. Results Functional activation in cerebral areas belonging to the lateral pain system (S1, S2 and insular cortex) was significantly reduced with increasing propofol plasma levels, whereas activation of the medial system (anterior cingulate and prefrontal cortex) was nearly unaffected. Conclusion Propofol seems to preferentially interfere with pain processing at the cortical level in the lateral projection system while the medial system controlling affective components obviously remains unchanged. Therefore, the clinically observed nocifensive reactions during painful stimulation under propofol anaesthesia are most likely the result of differential effects of the drug on different central nervous system pathways leading to nocifensive hyperreflexia.

The purpose of our study was to prospectively assess 40-MDCT technology in combination with adapted brain reconstruction algorithms to visualize the spinal vasculature, in particular the artery of Adamkiewicz and its anatomic variants.One hundred patients underwent contrast-enhanced MDCT of the thoracolumbar junction with collimation of 40 x 0.625 mm. The adapted brain algorithm reconstructed the spinal canal with a field of view of 90 mm at 0.6-mm slice thickness. Curved multiplanar reformations identified the artery of Adamkiewicz as a continuous vascular tract extending from the aortic orifices of the intercostal or lumbar arteries via the anterior radiculomedullary artery to the anterior spinal artery. Segment of origin and length were noted. Diameter and contrast-to-noise ratio (CNR) were evaluated along the posterior branch, the radiculomedullary artery, the artery of Adamkiewicz, and the anterior spinal artery. Univariate general linear model analysis with Bonferroni post hoc corrections evaluated whether laterality, segment of origin, and length of the artery of Adamkiewicz showed a sex-specific propensity. Multivariate general linear model analysis assessed whether spinal vascular diameters and intraluminal CNR showed correlations with sex, laterality, and segment of origin. Finally, the luminal diameters of the feeding posterior branches were statistically compared with those of the ipsilateral and contralateral adjacent posterior branches.Successful depiction of the artery of Adamkiewicz was achieved in all patients; longitudinally the artery measured 40.1 +/- 13.51 mm. In 63% of patients it originated from the left side of the body, and in 74% it originated from the level of the 10th-12th thoracic vertebrae. Duplications were found in 5% of patients. Segmental distribution, laterality, and length did not show significant sex-specific differences (p0.05). The vascular diameter and luminal contrast did not show significant differences caused by sex, laterality, or segment of origin (p0.05). The diameter of the posterior branches (2.8 +/- 0.71 mm) arising in the segments of origin showed a significantly wider lumen than any of the other posterior branches (contralateral, 1.9 +/- 0.32 mm; upper ipsilateral, 2.0 +/- 0.47 mm; lower ipsilateral, 1.9 +/- 0.39 mm) (p0.0001).Contrast-enhanced 40-MDCT technology, in combination with an adapted brain reconstruction algorithm, can depict the artery of Adamkiewicz and its anatomic variants.

Summary Background : Clinical studies suggest low-dose ketamine may have preemptive effects on postoperative pain in adults. The objective of this study was to determine whether intraoperative low-dose S-ketamine reduces postoperative pain and morphine consumption in children undergoing major urological surgery. Materials : Thirty children scheduled for major urological surgery were included in this prospective study. Anesthesia was performed as total intravenous anesthesia (TIVA) with alfentanil and propofol. Fifteen patients additionally received an intravenous bolus of S-ketamine (0.2 mg·kg−1) followed by a continuous infusion of 5 μg·kg−1·min−1, which was stopped immediately after skin closure (Ketamine Group). Another 15 patients received an infusion of saline (Control group). After transfer to the PACU, pain intensity was evaluated using a numeric rating scale (NRS). First patient controlled analgesia (PCA) request, cumulative morphine consumption and pain intensities within the first 72 h were compared. Results : Morphine consumption was not significantly different during the first 72 h (Control: 0.4 mg·kg−1, 0.24–0.51 mg·kg−1, Ketamine: 0.32 mg·kg−1, 0.19–0.61 mg·kg−1; median, 25–75% percentile; n.s.). However, differences were found in pain intensity during the first postoperative hour (Control: 4.0, 3.2–4.6, Ketamine: 2.5, 1.3–3.5; median, 25–75% percentile; P

High-field magnetic resonance imaging (MRI) (1.5 T) has recently been introduced into the neurosurgical operating room for intraoperative resection control and functional neuronavigational guidance. However, long-lasting neurosurgical procedures in an operating room equipped with a high-field MRI scanner raise new challenges to the anesthesiologist. In particular, monitoring of vital signs during anesthesia requires equipment compatible with working in close vicinity to the strong magnetic field. However, even MRI-compatible electrocardiographic (ECG) monitoring interferes with electromagnetic fields, so several ECG artifacts can be observed in static and pulsed magnetic fields. As shown in this study, pulsed high-frequency fields induce characteristic field frequency-based artifacts in the ECG that can imitate malignant arrhythmia or provoke ST-segment abnormalities. The knowledge of possible and characteristic ECG artifacts during high-field MRI is therefore essential to prevent misinterpretation. Moreover, interference-free parameters such as pulse oximetry or invasive blood pressure curves are highly relevant during intraoperative MRI scans.

Human albinism is characterized by a disturbance of the chiasmatic projection system leading to predominant representation of just one eye in the contralateral hemisphere. Patients show congenital nystagmus without perceiving oscillopsia. The purpose of the present study was to demonstrate the consequences of atypical chiasmatic crossing with monocular visual stimulation using functional magnetic resonance imaging (fMRI). Sixteen patients with albinism and fifteen normally pigmented controls were stimulated with a monocular visual activation paradigm using flickering checkerboards. In patients, we observed contralaterally dominated activation of visual cortices correlating to clinical albinism parameters. This confirms albinism as a continuous range of hypopigmentation disorders. Additionally, albinos showed activation of the superior colliculus and of visual motion areas although the stimulus was stationary. Activation of visual motion areas is due probably to congenital nystagmus without a conscious correlate like oscillopsia.