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Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days (p < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.

Abstract Background The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies. Methods A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted. Results A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak). Conclusions This consensus provides practical recommendations to support a clinician’s decision making in the management of tSCI polytrauma patients.

Abstract Background Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone. Methods This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results). Discussion We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care. Trial registration IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).

Introduction: The age of patients requiring surgery for spinal metastasis, primarily those over 65, has risen due to improved cancer treatments. Surgical intervention targets acute neurological deficits and instability. Anticoagulants are increasingly used, especially in the elderly, but pose challenges in managing bleeding complications. The study examines the correlation between preoperative anticoagulant/antiplatelet use and bleeding risks in spinal metastasis surgery, which is crucial for optimizing patient outcomes. Material and Methods: In a retrospective study at our department from 2010 to 2023, spinal tumor surgery patients were analyzed. Data included demographics, neurological status, surgical procedure, preoperative anticoagulant/antiplatelet use, intra-/postoperative coagulation management, and the incidence of rebleeding. Coagulation management involved blood loss assessment, coagulation factor administration, and fluid balance monitoring post-surgery. Lab parameters were documented at admission, preop, postop, and discharge. Results: A cohort of 290 patients underwent surgical treatment for spinal metastases, predominantly males (63.8%, n = 185) with a median age of 65 years. Preoperatively, 24.1% (n = 70) were on oral anticoagulants or antiplatelet therapy. Within 30 days, a rebleeding rate of 4.5% (n = 9) occurred, unrelated to preoperative anticoagulation status (p > 0.05). A correlation was found between preoperative neurologic deficits (p = 0.004) and rebleeding risk and the number of levels treated surgically, with fewer levels associated with a higher incidence of postoperative bleeding (p < 0.01). Conclusions: Surgical intervention for spinal metastatic cancer appears to be safe regardless of the patient’s preoperative anticoagulation status. However, it remains imperative to customize preoperative planning and preparation for each patient, emphasizing meticulous risk–benefit analysis and optimizing perioperative care.

Abstract Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial prognostic factors. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43, Cx43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. 118 patients with a median age of 46 years (IqR: 35–57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. Tumors with higher expression of GAP-43 (p = 0.024, HR = 1.71/rank) and actin (p

Metastases are the most frequent intracranial malignant tumors in adults. While Karnofsky Performance Status (KPS) and Clinical Frailty Scale (CFS) are known to have significant impact on overall survival (OS), temporal muscle thickness (TMT) has been postulated to be a promising new parameter to estimate prognosis. Patients who received a resection of one to three brain metastases in our institution were included. Temporal muscle thickness was measured in preoperative MRI scans according to a standardized protocol. In 199 patients, the mean TMT was 7.5 mm (95CI 7.3–7.7) and the mean OS during follow-up was 31.3 months (95CI 24.2–38.3). There was no significant correlation of TMT and preoperative or follow-up CFS and KPS. While CFS and KPS did significantly correlate with OS (p < 0.001 for each), no correlation was demonstrated for TMT. CFS showed a superior prognostic value compared to KPS. TMT failed to show a significant impact on OS or patient performance, whereas the clinical scales (KPS and CFS) demonstrate a good correlation with OS. Due to its superiority over KPS, we strongly recommend the use of CFS to estimate OS in patients with brain metastases.

Until recently, no disease-specific health-related quality of life (HRQoL) questionnaire existed for pediatric traumatic brain injuries (TBIs). In this revalidation study, the psychometric properties and the validity of the 35-item QOLIBRI-KID/ADO questionnaire in its final German version were examined in 300 children and adolescents. It is the first self-reported TBI-specific tool for measuring pediatric HRQoL in individuals aged between 8 and 17 years. The six-factor model fits the data adequately. The questionnaire’s internal consistency was excellent for the total score and satisfactory to excellent for the scale scores. Intraclass correlations indicated good test–retest reliability, and the measure’s construct validity was supported by the overlap between the QOLBRI-KID/ADO and the PedsQL, which measures generic HRQoL. The discriminant validity tests showed that older children and girls reported a significantly lower HRQoL than comparison groups, and this was also true of children who were anxious or depressed, or who suffered from post-concussion symptoms, replicating the results of the questionnaire’s first developmental study. Our results suggest that the QOLIBRI-KID/ADO is a reliable and valid multidimensional tool that can be used together with the adult version in clinical contexts and research to measure disease-specific HRQoL after pediatric TBI throughout a person’s life. This may help improve care, treatment, daily functioning, and HRQoL after TBI.

One of the main causes of the dismal prognosis in patients who survive the initial bleeding after aneurysmal subarachnoidal hemorrhage is the delayed cerebral ischaemia caused by vasospasm. Studies suggest that cerebral magnesium and pH may potentially play a role in the pathophysiology of this adverse event. Using phosphorous magnetic resonance spectrocopy (31P-MRS), we calculated the cerebral magnesium (Mg) and pH levels in 13 patients who suffered from aSAH. The values between the group that developed clinically significant vasospasm (n = 7) and the group that did not (n = 6) were compared. The results of this study show significantly lower cerebral Mg levels (p = 0.019) and higher pH levels (p < 0.001) in the cumulative group (all brain voxels together) in patients who developed clinically significant vasospasm. Further clinical studies on a larger group of carefully selected patients are needed in order to predict clinically significant vasospasm.

Objective: Patients with idiopathic trigeminal neuralgia (TN) live in constant fear of triggering shock-like pain episodes, which may cause symptoms of depression and a reduction in quality of life. Microvascular decompressive surgery has been demonstrated to achieve satisfactory and stable results. With this study, we wanted to investigate prevalence and risk factors for depression and perceived stress in correlation with symptom relief after surgical treatment. Methods: In this prospective study, patients undergoing microvascular decompression (MVD) for TN were included. The Barrow Neurological Institute Pain Score (BNI), Beck Depression Inventory (BDI), Chronic Pain Acceptance Questionnaire (CPAQ), Perceived Stress Questionnaire (PSQ) and McGill questionnaire were used to evaluate depression, stress and anxiety disorders before and 3 months after MVD. Results: A total of 35 patients (16 male (46%)) with a mean age of 55.4 (SD 15) years were included in this study. The BDI revealed that 24 (68.8%) patients harbored mild-to-extreme depression preoperatively (2.4 ± 1.4), which improved to 1.2 (±0.6, p < 0.0001). Pain acceptance also changed from 64 (±11.3) to 67.7 (±9.3, p = 0.006). Perceived stress decreased from 46.9 (±21.9) to 19.6 (±18.6) (p < 0.0001) postoperatively, and pain decreased from 31.0 (±11.7) to 9.4 (±12.9, p < 0.0001). Microvascular decompression reduced the mean BNI pain score significantly from 4.6 to 1.8 postoperatively (p < 0.00001). Conclusions: Depression and perceived stress are prevalent in patients with idiopathic TN. Adequate treatment not only provides a high rate of satisfaction through pain relief, but also leads to immediate and significant improvements in depression and stress. Thus, in patients with TN who do not reach an adequate and timely pain reduction through medical management and develop signs of depression, early treatment with microvascular decompression should be considered.

BackgroundGBM research is constantly assessing potential valuable prognostic biomarkers to better understand the disease and prognosticate future outcomes. Measuring temporal muscle thickness (TMT) has appeared to be a promising new surrogate marker for skeletal muscle mass and sarcopenia, which further indicates frailty and predicts overall survival (OS). The aim of this study was to determine its usefulness as a prognostic marker in patients with high-grade glioma compared to functional status scales.MethodsTMT was measured in preoperative axial T1-weighted contrast-enhanced magnetic resonance images in 277 patients who received surgical treatment of newly diagnosed WHO III and IV gliomas in our institution between 2015 and 2020. Clinical Frailty Scale (CFS) and Karnofsky Performance Scale (KPS) were assessed preoperatively and during a follow-up visit.ResultsFemale gender has shown significant correlation with TMT, while TMT did not correlate with preoperative and follow-up functional scores, age, WHO classification, IDH mutation, MGMT promoter methylation, EGFR and ATRX expression, or 1p/19q co-deletion. No significant prognostic value of TMT could be shown in 6, 12, and 24 months OS, while changes in CFS and KPS proved to have a significant impact.ConclusionOnly female gender, but no other clinical, histological, or molecular marker showed any interrelation with TMT. Functional scores outclass measuring TMT as a reliable prognostic factor for predicting OS in patients with high-grade glioma.

Abstract Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th–April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017–2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017–2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.

Background: Radiation necrosis (RN) is a possible late complication of stereotactic radiosurgery (SRS), but only a few risk factors are known. The aim of this study was to assess tumor location in correlation to the development of radiation necrosis for skull base (SB) and non-skull base tumors. Methods: All patients treated with radiosurgery for benign neoplasms (2004–2020) were retrospectively evaluated. The clinical, imaging and medication data were obtained and the largest axial tumor diameter was determined using MRI scans in T1-weighted imaging with gadolinium. The diagnosis of RN was established using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors in non-skull base locations. Results: 205 patients could be included. Overall, 157 tumors (76.6%) were located at the SB and compared to 48 (23.4%) non-SB tumors. Among SB tumors, the most common were vestibular schwannomas (125 cases) and meningiomas (21 cases). In total, 32 (15.6%) patients developed RN after a median of 10 (IqR 5–12) months. Moreover, 62 patients (30.2%) had already undergone at least one surgical resection. In multivariate Cox regression, SB tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p < 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). Conclusions: The risk for the development of RN for SB tumors appears to be low but should not be underestimated. No difference was found between recurrent tumors and newly diagnosed tumors, which may support the value of radiosurgical treatment for patients with recurrent SB tumors.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research question: The study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methods: In this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. Results: Ten patients across four dose groups were treated with NicaPlant® (3–13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusion: The placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies. Editor highlights: • Post-hemmorrhagic vasospasm with neurological deterioration is one major concern in this disease. • Oral or intravenous nimodipine is standard of care after aSAH, but systemic side-effects often hinders adequate application. • Local delivery of spasmolytics during angiography is short lasting and has not proven a benefit in terms of outcome. • Local delivery over the critical period via prolonged released formulation may overcome the systemic side effects and have a beneficial effect in terms of outcome.

Abstract With the rising life expectancy and availability of neuroimaging, increased number of older patients will present with diffuse and anaplastic gliomas. The aim of our study was therefore to investigate age-related prognostic clinical, neuropathological and radiological features of lower-grade gliomas. All consecutive patients with diffuse or anaplastic glioma WHO grade 2 and 3 who underwent first tumor resection between 2010 and 2018, were selected from the institutional neuro-oncological database and evaluated. The mean age of 55 males and 44 females was 46 years (SD ± 16). Wild-type IDH1 (p = 0.012), persistent nuclear ATRX expression (p = 0.012) and anaplasia (p

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

Introduction:Tumor-treating fields (TTFs) are a specific local oncological treatment modality in glioblastoma multiforme WHO° IV (GBM). Their mechanism of action is based on the effect of electrical fields interfering with the mitotic activity of malignant cells. Prospective studies have demonstrated efficacy, but TTF benefits are still controversially discussed. This treatment was implemented in our center as the standard of care in January 2016. We thus discuss the current state of the art and our long-term experience in the routine application of TTF.MethodsThe data of 48 patients suffering from GBM and treated with TTF were assessed and compared with previously published studies. Up-to-date information from open sources was evaluated.ResultsA total of 31 males and 17 females harboring a GBM were treated with TTF, between January 2016 and August 2021, in our center. In 98% of cases, TTFs were started within 6 weeks after concomitant radiochemotherapy (Stupp protocol). Mean overall survival was 22.6 months (95% CI: 17.3–27.9). Current indications, benefits, and restrictions were evaluated. Future TTF opportunities and ongoing studies were reviewed.ConclusionTTFs are a feasible and routinely applicable specific oncological treatment option for glioblastoma multiforme WHO° IV. Further research is ongoing to extend the indications and the efficacy of TTF.

BackgroundThe median age for diagnosis of glioblastoma is 64 years and the incidence rises with increasing age to a peak at 75-84 years. As the total number of high-grade glioma patients is expected to increase with an aging population, neuro-oncological surgery faces new treatment challenges, especially regarding aggressiveness of the surgical approach and extent of resection. In the elderly, aspects like frailty and functional recovery time have to be taken into account before performing surgery.Material & MethodsPatients undergoing surgery for malignant glioma (WHO grade III and IV) at our institution between 2015 and 2020 were compiled in a centralized tumor database and analyzed retrospectively. Karnofsky Performance Scale (KPS) and Clinical Frailty Scale (CFS) were used to determine functional performance pre- and postoperatively. Overall survival (OS) was compared between age groups of 65-69 years, 70-74 years, 75-79 years, 80-84 years and >85 years in view of extent of resection (EOR). Furthermore, we performed a literature evaluation focusing on surgical treatment of newly diagnosed malignant glioma in the elderly.ResultsWe analyzed 121 patients aged 65 years and above (range 65 to 88, mean 74 years). Mean overall survival (OS) was 10.35 months (SD = 11.38). Of all patients, only a minority (22.3%) received tumor biopsy instead of gross total resection (GTR, 61.2%) or subtotal resection (STR, 16.5%). Postoperatively, 52.9% of patients were treated according to the Stupp protocol. OS differed significantly between extent of resection (EOR) groups (4.0 months after biopsy vs. 8.3 after STR vs. 13.8 after GTR, p < 0.05 and p < 0.001 correspondingly). No significant difference was observed regarding EOR across different age groups.ConclusionGTR should be the treatment of choice also in elderly patients with malignant glioma as functional outcome and survival after surgery are remarkably better compared to less aggressive treatment. Elderly patients who received GTR of high-grade gliomas survived significantly longer compared to patients who underwent biopsy and STR. Age seems to have little influence on overall survival in selected surgically extensive treated patients, but high preoperative functional performance is mandatory.

Abstract The world currently faces the novel severe acute respiratory syndrome coronavirus 2 pandemic. Little is known about the effects of a pandemic on non-elective neurosurgical practices, which have continued under modified conditions to reduce the spread of COVID-19. This knowledge might be critical for the ongoing second coronavirus wave and potential restrictions on health care. We aimed to determine the incidence and 30-day mortality rate of various non-elective neurosurgical procedures during the COVID-19 pandemic. A retrospective, multi-centre observational cohort study among neurosurgical centres within Austria, the Czech Republic, and Switzerland was performed. Incidence of neurosurgical emergencies and related 30-day mortality rates were determined for a period reflecting the peak pandemic of the first wave in all participating countries (i.e. March 16th–April 15th, 2020), and compared to the same period in prior years (2017, 2018, and 2019). A total of 4,752 emergency neurosurgical cases were reviewed over a 4-year period. In 2020, during the COVID-19 pandemic, there was a general decline in the incidence of non-elective neurosurgical cases, which was driven by a reduced number of traumatic brain injuries, spine conditions, and chronic subdural hematomas. Thirty-day mortality did not significantly increase overall or for any of the conditions examined during the peak of the pandemic. The neurosurgical community in these three European countries observed a decrease in the incidence of some neurosurgical emergencies with 30-day mortality rates comparable to previous years (2017–2019). Lower incidence of neurosurgical cases is likely related to restrictions placed on mobility within countries, but may also involve delayed patient presentation.

Glioblastoma is the most common malignant brain tumor in adults. Standard treatment includes tumor resection, radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ). TMZ methylates DNA, whereas O6-methylguanine DNA methyltransferase (MGMT) counteracts TMZ effects by removing the intended proteasomal degradation signal. Non-functional MGMT mediates the mismatch repair (MMR) system, leading to apoptosis after futile repair attempts. This study investigated the associations between MGMT promoter methylation, MGMT and MMR protein expression, and their effect on overall survival (OS) and progression-free survival (PFS) in patients with glioblastoma. MGMT promoter methylation was assessed in 42 treatment-naïve patients with glioblastoma WHO grade IV by pyrosequencing. MGMT and MMR protein expression was analyzed using immunohistochemistry. MGMT promoter methylation was present in 52%, whereas patients p ≤ 0.05. MGMT protein expression and methylation status showed no correlation. MMR protein expression was present in all patients independent of MGMT status and did not influence OS and PFS. Overall, MGMT promoter methylation implicates an improved OS in patients with glioblastoma aged MGMT promoter methylation or protein expression.

BackgroundAcute changes of cerebral energy metabolism in early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) may play a crucial role for overall neurological outcome. However, direct detection of these alterations is limited. Phosphorous magnetic resonance spectroscopy (31P-MRS) is a molecular-based advanced neuroimaging technique allowing measurements of pathophysiological processes and tissue metabolism based on various phosphorous compound metabolites. This method may provide objective assessment of both primary and secondary changes.ObjectiveThe aim of this pilot study was to evaluate the feasibility and the diagnostic potential of early 31P-MRS in aSAH.MethodsPatients with aSAH treated for ruptured aneurysms between July 2016 and October 2017 were prospectively included in the study. 3-Tesla-MRI including 31P-MRS was performed within the first 72 h after hemorrhage. Data of the vascular territories of the anterior, middle, and posterior cerebral arteries (ACA, MCA, PCA) and the basal ganglia were separately analyzed and compared with data of a healthy age- and sex-matched control group. Phosphorous compound metabolites were quantified, and ratios of these metabolites were further evaluated. Influence of treatment modality, clinical conditions, and analgosedation were analyzed.ResultsData of 13 patients were analyzed. 31P-MRS showed significant changes in cerebral energy metabolism after aSAH in all cerebrovascular territories. Both PCr/ATP and PCr/Pi ratio were notably increased (P < 0.001). Also, Pi/ATP was significantly decreased in all cerebrovascular territories (P = 0.014). PME/PDE ratio was overall significant decreased (P < 0.001).Conclusion31P-MRS is a promising non-invasive imaging tool for the assessment of changes in energy metabolism after aSAH. It allows a detailed insight into EBI and seems to harbor a high potential for clinical practice.

Objective Anterior-only reconstructions for cervical multilevel corpectomies are prone to fail under continuous mechanical loading. This study sought to define the mechanical characteristics of different constructs in reducing a range of motion (ROM) of the 3-column destabilized cervical spine, including posterior cobalt-chromium (CoCr)-rods, outrigger-rods (OGR), and a novel triple rod construct using lamina screws (6S3R). The clinical implications of biomechanical findings are discussed in depth from the perspective of the challenges surgeons face cervical deformity correction. Methods Three-column deficient cervical spinal models were produced based on reconstructed computed tomography scans. The corpectomy defect between C3 and C7 end-level vertebrae was restored with anterior titanium (Ti) mesh-cage. The ROM was evaluated in a customized 6-degree of freedom spine tester. Tests were performed with different rod materials (Ti vs. CoCr), varying diameter rods (3.5 mm vs. 4.0 mm), with and without anterior plating, and using different construct patterns: bilateral rod fixation (standard-group), OGR-group, and 6S3R-Group. Construct stability was expressed in changes and differences of ROM (°). Results The largest reduction of ROM was noticed in the 6S3R-group compared to the standard- and the OGR-group. All differences observed were emphasized with an increasing number of corpectomy levels and if anterior plating was not added. For all simulated 1-, 2-, and 3-level corpectomy constructs, the OGR-group revealed decreased ROM for all motion directions compared to the standard-group. An increase of construct stiffness was also recorded for increased rod diameter (4.0 mm) and stiffer rod material (CoCr), though these effects lacked behind the more advanced construct pattern. Conclusion A novel reconstructive technique, the 6S3R-construct, was shown to outperform all other constructs and might resemble a new standard of reference for advanced posterior fixation.

Introduction: Conventional microscopes have certain limitations in terms of posture and ergonomics. Monitor-based exoscopes could solve this problem and thereby lead to less work-related sick leave for surgeons. Research question: The aim of this study was to assess the ergonomics, usability, and neurosurgeon's comfort of a novel three-dimensional head-mounted display-based exoscope in a standardized setting. Material & Methods: 34 neurosurgeons participated in a workshop on the exoscope, which features a head-mounted display and a head gesture-triggered control panel. After completion of a custom-made 10-step microsurgical exercise, image quality and comfort were assessed using a questionnaire. The participants' posture during the exercise was analyzed using a video motion analysis software. Results: 34 participants (median neurosurgical experience: 6 years) were included. The median time to complete the exercise was 12 ​min [IqR 9.4, 15.0]. Younger participants (p ​= ​0.005) and those with video game experience (p ​= ​0.03) had a significantly steeper learning curve. The median overall satisfaction was at 80% in general and 82% for image quality. The median upper body as well as the median head coronal displacement from the neutral axis were 0°. Participants with less microsurgical experience showed less head/body displacement during the exercise (p ​= ​0.01). Discussion and conclusion: Using the microsurgical training tool, we were able to depict a steep learning curve with a sufficient learnability of the most relevant commands. The exoscope excelled in usability, image quality as well as in ergonomic and favorable posture and could thus become an alternative to conventional microscopes due to the potentially elevated surgeons' comfort.

Purpose Enteral nutrition (EN) often fails to achieve nutritional goals in neurocritical care patients. We sought to investigate the safety and utility of supplemental parenteral nutrition (PN) in subarachnoid hemorrhage (SAH) patients. Materials and methods Data of 70 consecutive patients with non-traumatic SAH admitted to the neurological intensive care unit of a tertiary referral center were prospectively collected and retrospectively analyzed. We targeted the provision of 20–25 kilocalories per kilogram bodyweight per day (kcal/kg/d) by enteral nutrition. Supplemental PN was given when this target could not be reached. Nutritional data were analyzed for up to 14 days of ICU stay. Hospital complications were tested for associations with impaired enteral feeding. The amounts of EN and PN were tested for associations with the level of protein delivery and functional outcome. Repeated measurements within subjects were handled utilizing generalized estimating equations. Results Forty (27 women and 13 men) of 70 screened patients were eligible for the analysis. Median age was 61 (IQR 49–71) years, 8 patients (20%) died in the hospital. Thirty-six patients (90%) received PN for a median duration of 8 (IQR 4–12) days. The provision of 20 kcal/kg by EN on at least 1 day of ICU stay was only achieved in 24 patients (60%). Hydrocephalus (p = 0.020), pneumonia (p = 0.037) and sepsis (p = 0.013) were associated with impaired enteral feeding. Neither the amount nor the duration of PN administration was associated with an increased risk of severe complications or poor outcome. Supplemental PN was associated with significantly increased protein delivery (pConclusions Enteral feeding was insufficient to achieve nutritional goals in subarachnoid hemorrhage patients. Supplemental PN was safe and associated with increased protein delivery. A higher protein supply was associated with good functional outcome in patients who developed sepsis or pneumonia.

Biological but not chronological age plus performance have more impact on decision making in glioblastoma patients. We investigated how progression-free survival (PFS) and overall survival (OS) in older patients with IDH wild-type glioblastoma were influenced by concomitant radio-chemotherapy and MGMT promotor methylation status in real-life settings. In total, 142 out of 273 (52%) evaluated patients were older than 65 years, and 77 (55%) of them received concomitant radio-chemotherapy. In senior patients, the initiation of concomitant radio-chemotherapy was associated with significantly better PFS: 15.3 months (CI95: 11.7–18.9) vs. 7.0 months (CI95: 4.3–9.6; p = 0.002). The favorable influence on PFS was not related to MGMT promotor methylation status as it was in the younger cohort. In seniors, concomitant radio-chemotherapy was related to significantly better OS: 20.0 months (CI95: 14.3–26.7) vs. 4.9 months (CI95: 3.5–6.2), p < 0.001. MGMT promotor methylation was related to a more favorable OS only, if concomitant radio-chemotherapy was initiated. In conclusion, more than half of the glioblastoma cohort was older than 65 years of age. Even if PFS and OS were shorter than in the younger cohort, concomitant radio-chemotherapy provided a survival advantage. In real life, MGMT promotor methylation had a positive impact on OS only if the adjuvant therapy was applied.

Radiation necrosis represents a potentially devastating complication after radiation therapy in brain tumors. The establishment of the diagnosis and especially the differentiation from progression and pseudoprogression with its therapeutic implications requires interdisciplinary consent and monitoring. Herein, we want to provide an overview of the diagnostic modalities, therapeutic possibilities and an outlook on future developments to tackle this challenging topic. The aim of this report is to provide an overview of the current morphological, functional, metabolic and evolving imaging tools described in the literature in order to (I) identify the best criteria to distinguish radionecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments to tackle this challenging topic. Additionally, we provide the experience of a tertiary tumor center with this important issue in neuro-oncology and provide an institutional pathway dealing with this problem.

Both neuromonitoring and early magnetic resonance imaging (MRI) provide crucial information for treatment management and prognosis in patients with severe traumatic brain injury (sTBI). So far, neuromonitoring in situ impedes the routine implementation of MRI due to safety concerns. We aimed to evaluate the brain tissue damage induced by inserted neuromonitoring devices and its clinical relevance. Nineteen patients with sTBI and being exposed to at least one MRI with neuromonitoring in situ and one follow-up MRI after neuromonitoring removal were analyzed. All MRIs were reviewed for specific tissue damage. Three females and sixteen males (aged 20–74 years, mean 42.8 years) with an initial median GCS of 5 (range 3–8) were analyzed. No lesion was observed in six patients (31.6%), whereas another six patients (31.6%) demonstrated a detectable probe trajectory. Probe-related tissue damage was visible in seven patients (36.8%) with the size of the lesion prone to further enlarge with increasing cumulative duration of MRI examinations. Upon interdisciplinary evaluation, the lesions were not considered clinically relevant. Neuromonitoring probes in situ during MRI examinations may cause local brain tissue damage, yet without any clinical implications if placed correctly. Therefore, indications must be strictly based on joint decision from all involved disciplines.

To minimize recurrence following resection of a cerebral metastasis, whole-brain irradiation therapy (WBRT) has been established as the adjuvant standard of care. With prolonged overall survival in cancer patients, deleterious effects of WBRT gain relevance. Sector irradiation (SR) aims to spare uninvolved brain tissue by applying the irradiation to the resection cavity and the tumor bed. 40 were randomized to receive either WBRT (n = 18) or SR (n = 22) following resection of a singular brain metastasis. Local tumor control was satisfactory in both groups. Recurrence was observed earlier in the SR (median 3 months, 1–6) than in the WBRT cohort (median 8 months, 7–9) (HR, 0.63; 95% CI, 0.03–10.62). Seventeen patients experienced a distant intracranial recurrence. Most relapses (n = 15) occurred in the SR cohort, whereas only two patients in the WBRT group had new distant tumor manifestation (HR, 6.59; 95% CI, 1.71–11.49; p = 0.002). Median overall survival (OS) was 15.5 months (range: 1–61) with longer OS in the SR group (16 months, 1–61) than in the WBRT group (13 months, 3–52), without statistical significance (HR, 0.55; 95% CI, 0.69–3.64). Concerning neurocognition, patients in the SR group improved in the follow-up assessments, while this was not observed in the WBRT group. There were positive signals in terms of QOL within the SR group, but no significant differences in the global QLQ and QLQ-C30 summary scores were found. Our results indicate comparable efficacy of SR in terms of local control, with better maintenance of neurocognitive function. Unsurprisingly, more distant intracranial relapses occurred.Clinical Trial Registration:ClinicalTrials.gov, identifier NCT01667640.

Object: The aim of this study was to investigate metabolite levels in cerebrospinal fluid (CSF) in their time-dependent course after aneurysmal subarachnoid hemorrhage (aSAH) comparing them to patients harboring unruptured intracranial aneurysms.Methods: Eighty CSF samples of 16 patients were analyzed. The study population included patients undergoing endovascular/microsurgical treatment of ruptured intracranial aneurysms (n = 8), which were assessed for 9 days after aSAH. Control samples were collected from the basal cisterns in elective aneurysm surgery (n = 8). The CSF samples were consecutively collected with extraventricular drain (EVD) placement/intraoperatively, 6 h later, and daily thereafter (day 1–9). The endogenous metabolites were analyzed with a targeted quantitative and quality controlled metabolomics approach using the AbsoluteIDQ®p180Kit. Differences inbetween timepoints and compared to the control group were evaluated.Results: Numerous alterations of amino acid (AA) levels were detected within the first hours after bleeding. The highest mean concentrations occurred 1 week after aSAH. AA levels were continuously increasing over time starting 6 h after aSAH. Taurine concentration was highest briefly after aSAH starting to decrease already after 6 h (vs. day 1–9, p = 0.02). The levels of sphingomyelins/ phosphatidylcholines/ lysophosphatidylcholines/mono-unsaturated fatty acid chain were highly elevated on day 0 (compared to other timepoints or controls, p < 0.01) and decreased over the next several days to concentrations comparable to the control group. Carnitine concentrations were decreased after SAH (vs. day 7, p < 0.01), while they recovered within the next day. The Fischer ratio of branched-chain AA to aromatic AA was lowest immediately after SAH and increased in 7 days (p < 0.001).Conclusion: AA levels in CSF increased overtime and often differ from patients without SAH. There was a peak concentration of structural AA within the first 6 h after aneurysm treatment. Time-dependent alterations of CSF metabolites and compounds may elucidate pathophysiological processes after aSAH, providing potential predictors assessed non-invasively by routine lab testing.

Introduction: Early magnetic resonance imaging (MRI) provides important information for management and prognosis in patients with severe traumatic brain injury (sTBI). Yet, optimal timing of MRI remains unknown. The aim of our study was to evaluate the safety of early MRI and to identify a method for appropriate patient selection to minimize adverse events related to the intrahospital transport (IHT) and the MRI examination.Methods: Twenty-six patients with sTBI [mean Glasgow Coma Scale (GCS) 6, range 3–8] admitted to our neurosurgical ICU from 03/2015 to 12/2017 and receiving at least one MRI within the first 14 days after initial traumatic event were prospectively included in the study. The following requirements were fulfilled for at least 4 h prior to anticipated MRI: MAP > 70 mmHg, aPCO2 30–40 mmHg, stable ICP < 25 mmHg. All relevant cardiopulmonary and cerebral parameters and medication were recorded. The following MRI sequences were performed: DWI, FLAIR, 3D T2-space, 3D T1 MPRAGE, 3D SWI, 3D TOF, pASL, and 1H/31P-MRS.Results: Four females and 22 males (aged 23–78 years, mean 46.4 years) with a median GCS on admission of 5 (range 3–8) were analyzed. In total, 40 IHTs were performed within the first 14 days (mean 6 days, range 1–14 days). Mean pre-MRI ICP was 14.1 mmHg (range 3–32 mmHg). The mean post-MRI ICP was 14.3 mmHg (range 3–29 mmHg), decreasing to a mean ICP of 13.2 mmHg after 1 h (range 3–29 mmHg). There were no significant differences in ICP measurements before and after MRI (p = 0.30). MAP remained stable with no significant changes during the entire IHT and MRI. No other adverse events were observed as well.Conclusion: Early MRI in acute severe TBI is feasible and safe. Yet, careful patient selection with prior adequate testing of cardiopulmonary and cerebral parameters is crucial to minimize transport- or examination-related morbidity.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) raises concerns as to whether it contributes to an increased mortality. The incidence of CAPA varies widely within hospitals and countries, partly because of difficulties in obtaining a reliable diagnosis. We implemented a routine screening of respiratory specimens in COVID-19 ICU patients for Aspergillus species using culture and galactomannan (GM) detection from serum and/or bronchoalveolar lavages (BAL). Out of 329 ICU patients treated during March 2020 and April 2021, 23 (7%) suffered from CAPA, 13 of probable, and 10 of possible. In the majority of cases, culture, microscopy, and GM testing were in accordance with CAPA definition. However, we saw that the current definitions underscore to pay attention for fungal microscopy and GM detection in BALs, categorizing definitive CAPA diagnosis based on culture positive samples only. The spectrum of Aspergillus species involved Aspergillus fumigatus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans. We noticed changes in fungal epidemiology, but antifungal resistance was not an issue in our cohort. The study highlights that the diagnosis and incidence of CAPA is influenced by the application of laboratory-based diagnostic tests. Culture positivity as a single microbiological marker for probable definitions may overestimate CAPA cases and thus may trigger unnecessary antifungal treatment.

Abstract Background Spinal fusion with pedicle screw fixation represents the gold standard for lumbar degenerative disc disease with instability. Although it is an established technique, it is nevertheless an invasive intervention with high complication rates. Therefore, minimally invasive approaches have been developed, the medialized bilateral screw pedicel fixation (mPACT) being one of them. The study objective is to evaluate prospectively the efficacy and safety of the mPACT technique compared with the traditional trajectory for degenerative lumbar spondylolisthesis. Methods/design This is a single-center, randomized, controlled, parallel group, superiority trial. A total of 154 adult patients are allocated in a ratio of 1:1. Sample size and power calculation were performed to detect the minimal clinically important difference of 10%, with an expected standard deviation of 20% in the primary outcome parameter, the Oswestry Disability Index, with power of 80%, based on an assumed maximal dropout rate of 20%. Secondary outcome parameters include the EuroQoL 5-Dimension questionnaire, the Beck Depression Inventory, the painDETECT questionnaire and the “timed up and go” test. Furthermore, radiological and health economic outcomes will be evaluated. Follow up is performed until 5 years after surgery. Major inclusion criteria are lumbar degenerative spondylolisthesis with Meyerding grade I or II, which qualifies for decompression and fusion by medialised posterior screw placement with cortical trajectory (mPACT) or by a traditional trajectory for lumbar pedicle screw placement. Discussion This trial will contribute to the understanding of the short-term and long-term clinical and radiological postoperative course in patients with lumbar degenerative disc disease, in which the mPACT technique is used. Trial registration ISRCTN registry, ISRCTN99263604. Registered on 3 November 2016.