Optimal drainage time after evacuation of chronic subdural haematoma (DRAIN TIME 2): a multicentre, randomised, multiarm and multistage non-inferiority trial in Denmark.

BACKGROUND: Postoperative drainage after surgical evacuation of chronic subdural haematoma reduces the risk of recurrence, but the optimum drainage time is uncertain. We aimed to investigate the shortest possible drainage time without increasing the haematoma recurrence rate. METHODS: We conducted a randomised, multi-arm and multistage non-inferiority trial at four neurosurgical centres in Denmark. We enrolled adult patients (aged ≥18 years) with symptomatic chronic subdural haematoma. All patients were treated according to the national standard practice with a burr hole above the maximum width of the haematoma. Patients were randomly assigned in a 1:1:1 ratio via a centralised web server to receive 6 h, 12 h, or 24 h of postoperative passive subdural drainage. Randomisation was done by an independent on-call neurosurgeon and was masked until 6 h after surgery. The primary outcome was symptomatic haematoma recurrence at 3 months after surgery; the rate of recurrence was assessed in a regression model for non-inferiority testing, with no missing data. Personnel assessing the primary outcome were masked to group allocation. Non-inferiority was assessed with a prespecified margin of 7%, in a modified intention-to-treat population-defined as patients with randomly assigned treatment excluding those withdrawing from study participation after randomisation, or experiencing acute rebleedings or accidental drain removal. This trial is registered with ISRCTN (number 15186366); the trial was stopped after the first interim analysis on the advice of an independent safety advisory committee. FINDINGS: Between March 1, 2021, and June 30, 2022, 347 patients were enrolled and 331 were followed up to 3 months, 105 were assigned to 6 h of drainage, 111 to 12 h of drainage, and 115 to 24 h of drainage. At admission, 83 (25%) participants were women and 248 (75%) were men, mean age was 75·7 years (SD 10·5), median modified Rankin Scale score was 4 (IQR 3-5), and median Glasgow Coma Scale score was 15 (IQR 14-15). At 3 months after surgery, haematoma recurrence was reported in 28 (27%) of 105 patients who were assigned to 6 h drainage (predicted haematoma recurrence rate 27·0%, 95% CI 18·5 to 35·4), 22 (20%) of 111 assigned to 12 h drainage (19·5%, 12·0 to 27·0), and 12 (10%) of 115 assigned to 24 h drainage (10·4%, 4·8 to 16·0). The risk of haematoma recurrence was increased by 16·5 percentage points (95% CI 6·5 to 26·6) in patients drained for 6 h compared with 24 h, and by 9·1 percentage points (-0·4 to 18·5) in patients drained for 12 h compared with 24 h. Therefore, non-inferiority of 6 h and 12 h of drainage to 24 h of drainage was not established. 20 patients had died by 3 months, seven in the 6 h group, eight in the 12 h group, and five in the 24 h group. The most frequent known causes of death were haematoma recurrence (three in 12 h group), comorbidity (three in 12 h group), and pneumonia (one each in 6 h and 12 h groups, two in 24 h group). The most frequent complication was postoperative infection, reported in 20 (20%) patients in the 6 h group, 25 (23%) in the 12 h group, and 19 (17%) in the 24 h group. The most common infection source was the urinary tract. INTERPRETATION: Patients surgically treated for symptomatic chronic subdural haematoma and postoperatively drained for 6 h or 12 h had higher rates of haematoma recurrence than did patients drained for 24 h. The findings from this non-inferiority trial provide evidence to support 24 h of postoperative drainage as the standard drain time when a fixed drain time approach is used. To provide solid evidence of generalisability of the results to countries other than Denmark, a multinational randomised controlled trial will be needed. FUNDING: None.

Intracranial Mesenchymal Tumor, FET-CREB Fusion Positive, Evaluated With 18 F-FET and 18 F-FDG PET/CT.

ABSTRACT: Intracranial mesenchymal tumor, FET-CREB fusion positive, is a newly recognized and rare CNS tumor that occurs primarily in children and young adults. It is regarded as the intracranial variant of angiomatoid fibrous histiocytoma. Extracranial angiomatoid fibrous histiocytomas are typically located in the extremities and usually discernible on a 18 F-FDG PET/CT scanning. We present a 50-year-old man with recurrence of a primary intracranial mesenchymal tumor with equivocal 18 F-FDG PET/CT findings but with subsequent highly increased metabolic activity using 18 F-FET PET/CT confirming tumor recurrence. This case highlights the importance of 18 F-FET PET/CT, as opposed to 18 F-FDG, in the clinical evaluation of this rare intracranial mesenchymal tumor.

The cellular composition of chronic subdural hematoma.

INTRODUCTION: The pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence. This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH. METHODS: Systemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit. RESULTS: Of the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017). CONCLUSION: This study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence. CLINICAL TRIAL REGISTRATION: The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073.

Treatment of chronic subdural haematoma.

A further rise in chronic subdural haematoma (CSDH) prevalence is expected with an ageing population, and evidence-based guidelines are needed to direct treatment, while creating a platform for research. The Danish Chronic Subdural Hematoma Study (DACSUHS) has implemented the first Danish national CSDH guidelines in 2018 and have standardised CSDH management on a national level. Based on CSDH literature published between 2016 and 2022, these guidelines were updated in 2022. The updated guidelines are presented in this review.

Intraoperative Videogrammetry and Photogrammetry for Photorealistic Neurosurgical 3-Dimensional Models Generated Using Operative Microscope: Technical Note.

BACKGROUND AND OBJECTIVES: Intraoperative orientation during microsurgery has a prolonged learning curve among neurosurgical residents. Three-dimensional (3D) understanding of anatomy can be facilitated with realistic 3D anatomic models created from photogrammetry, where a series of 2-dimensional images is converted into a 3D model. This study implements an algorithm that can create photorealistic intraoperative 3D models to exemplify important steps of the operation, operative corridors, and surgical perspectives. METHODS: We implemented photograph-based and video-based scanning algorithms for uptakes using the operating room (OR) microscope, targeted for superficial structures, after surgical exposure, and deep operative corridors, in cranial microsurgery. The algorithm required between 30-45 photographs (superficial scanning), 45-65 photographs (deep scanning), or approximately 1 minute of video recording of the entire operative field to create a 3D model. A multicenter approach in 3 neurosurgical departments was applied to test reproducibility and refine the method. RESULTS: Twenty-five 3D models were created of some of the most common neurosurgical approaches-frontolateral, pterional, retrosigmoid, frontal, and temporal craniotomy. The 3D models present important steps of the surgical approaches and allow rotation, zooming, and panning of the model, enabling visualization from different surgical perspectives. The superficial and medium depth structures were consistently presented through the 3D models, whereas scanning of the deepest structures presented some technical challenges, which were gradually overcome with refinement of the image capturing process. CONCLUSION: Intraoperative photogrammetry is an accessible method to create 3D educational material to show complex anatomy and demonstrate concepts of intraoperative orientation. Detailed interactive 3D models, displaying stepwise surgical case-based anatomy, can be used to help understand details of the operative corridor. Further development includes refining or automatization of image acquisition intraoperatively and evaluation of other applications of the resulting 3D models in training and surgical planning.

Urokinase Plasminogen Activator Receptor: An Important Focal Player in Chronic Subdural Hematoma?

Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845-33,237) and significantly higher than the median systemic blood level of 789 pg/L (465-2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54-44.8) and significantly higher than the dural uPAR level of 0.81 (0.3-1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane.

Intraoperative Irrigation and Risk of Chronic Subdural Hematoma Recurrence.

BACKGROUND AND OBJECTIVES: In most neurosurgical centers, irrigation is an essential part of the surgical procedure for chronic subdural hematoma (CSDH). However, it is unknown whether the volume of irrigation fluid affects the risk of CSDH recurrence. This study aimed to investigate a potential association between the volume of irrigation fluid used during burr hole evacuation of CSDH and the risk of CSDH recurrence. METHODS: This study is a subanalysis of 2 randomized trials (Drain Time & Drain Time 2) designed to investigate the effect of drainage duration on the recurrence of CSDH. Intraoperative irrigation volume was measured, and patients were followed for 90 days for recurrent CSDH. RESULTS: A total of 525 patients with CSDH were included. There was no significant difference in the volume of irrigation fluid used between patients with recurrence (mean = 938 mL, SD = ±552) and without recurrence (mean = 852 mL, SD = ±454) ( P -value = .15). Patients with recurrent CSDH had larger primary CSDH volumes (mean = 134 cm 3 , SD = ±69) than patients without recurrence (mean = 119 cm 3 , SD = ±58) ( P = .04). Multiple logistic regression analysis revealed no association between irrigation volume and recurrence, also when stratified for hematoma size. CONCLUSION: There was no significant association between irrigation volume and recurrent CSDH within 90 days in patients undergoing burr hole surgery for CSDH.

Inflammatory human leucocyte antigen genotypes are not a risk factor in chronic subdural hematoma development.

BACKGROUND: Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH. METHODS: Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH. RESULTS: We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence. CONCLUSION: This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population.

Combined cone-beam CT imaging and microsurgical dissection of cadaver specimens to study cerebral venous anatomy: a technical note.

PURPOSE: Cadaver dissections and X-ray based 3D angiography are considered gold standards for studying neurovascular anatomy. We sought to develop a model that utilize the combination of both these techniques to improve current tools for anatomical research, teaching and preoperative surgical planning, particularly addressing the venous system of the brain. MATERIALS AND METHODS: Seven ethanol-fixed human cadaveric heads and one arm were injected with a latex-barium mixture into the internal jugular veins and the brachial artery. After the ethanol-based fixation, specimens were scanned by high-resolution cone-beam CT and images were post-processed on a 3D-workstation. Subsequent, microsurgical dissections were performed by an experienced neurosurgeon and venous anatomy was compared with relevant 3D venograms. RESULTS: Latex-barium mixtures resulted in a homogenous cast with filling of the cerebral venous structures down to 150 µm in diameter. The ethanol-based preparation of the cadaveric brains allowed for near-realistic microsurgical maneuverability during dissection. The model improves assessment of the venous system for anatomical education and hands-on surgical training. CONCLUSION: To our knowledge we describe the first preparation method which combines near-realistic microsurgical dissection of human heads with high-resolution 3D imaging of the cerebral venous system in the same specimens.

Simplified Easy-Accessible Smartphone-Based Photogrammetry for 3-Dimensional Anatomy Presentation Exemplified With a Photorealistic Cadaver-Based Model of the Intracranial and Extracranial Course of the Facial Nerve.

BACKGROUND AND OBJECTIVES: Smartphone-based photogrammetry (SMPhP) was recently presented as a practical and simple algorithm to create photorealistic 3-dimensional (3D) models that benefit from volumetric presentation of real anatomic dissections. Subsequently, there is a need to adapt the techniques for realistic depiction of layered anatomic structures, such as the course of cranial nerves and deep intracranial structures; the feasibility must be tested empirically. This study sought to adapt and test the technique for visualization of the combined intracranial and extracranial course of the facial nerve's complex anatomy and analyze feasibility and limitations. METHODS: We dissected 1 latex-injected cadaver head to depict the facial nerve from the meatal to the extracranial portion. A smartphone camera alone was used to photograph the specimen, and dynamic lighting was applied to improve presentation of deep anatomic structures. Three-dimensional models were created with a cloud-based photogrammetry application. RESULTS: Four 3D models were generated. Two models showed the extracranial portions of the facial nerve before and after removal of the parotid gland; 1 model showed the facial nerve in the fallopian canal after mastoidectomy, and 1 model showed the intratemporal segments. Relevant anatomic structures were annotated through a web-viewer platform. The photographic quality of the 3D models provided sufficient resolution for imaging of the extracranial and mastoid portions of the facial nerve, whereas imaging of the meatal segment only lacked sufficient precision and resolution. CONCLUSION: A simple and accessible SMPhP algorithm allows 3D visualization of complex intracranial and extracranial neuroanatomy with sufficient detail to realistically depict superficial and deeper anatomic structures.

Early spontaneous cessation of subdural drainage after burr hole evacuation of chronic subdural hematoma and risk of recurrence.

OBJECTIVE: Subdural drainage reduces recurrence after evacuation of chronic subdural hematoma (CSDH). In the present study, the authors investigated the dynamics of drain production and potentially contributing factors for recurrence. METHOD: Patients treated with a single burr hole evacuation of CSDH between April 2019 and July 2020 were included. Patients were also participants in a randomized controlled trial. All patients included, had a passive subdural drain for exactly 24 hours. Drain production, Glasgow Coma Scale score, and degree of mobilization was recorded every hour for 24 hours. A CSDH successfully drained for 24 hours is referred to as a "case". Patients were followed for 90 days. Primary outcome was symptomatic recurrent CSDH requiring surgery. RESULTS: A total of 118 cases from 99 patients were included in the study. Of the 118 cases, 34 (29%) had spontaneous drain cessation within the first 0-8 hours after surgery (Group A), 32 (27%) within 9-16 hours (Group B), and 52 (44%) within 17-24 hours (Group C). Hours of production (P < 0.000) and total drain volume (P = 0.001) were significantly different between groups. The recurrence rate was 26.5% in group A, 15.6% in group B, and 9.6% in group C (P = 0.037). Multivariable logistic regression analysis show that cases in group C (OR: 0.13, P = 0.005) are significantly less likely to recur compared to group A. Only in 8 of the 118 cases (6.8%), the drain started draining again after an interval of three consecutive hours. CONCLUSIONS: Early spontaneous cessation of subdural drain production seems to be associated with increased risk of recurrent hematoma. Patients with early cessation of drainage did not benefit from further drain time. Observations of the present study indicate personalized drainage discontinuation strategy as a potentially alternative to a specific discontinuation time for all CSDH patients.

Subdural Levels of Interleukin 1-receptor Antagonist are Elevated in Patients with Recurrent Chronic Subdural Hematomas.

Anti-inflammatory treatment reduces the risk of recurrent chronic subdural hematoma (CSDH), but clinical implementation is improper due to side effects. Exact knowledge of subdural molecules involved in recurrent CSDH may lead to targeted medical treatment and possibly improve the prospect of a personalized approach by eliminating the broad use of anti-inflammatory drugs on the entire CSDH population. With this study, we aim to (1) describe the associations between cytokine levels at the primary surgery and the risk of subsequent recurrence and (2) describe the association between cytokines in patients with recurrent CSDH between the first and second operations. Systemic and subdural levels of pro- and anti-inflammatory cytokines were measured and compared between patients with the first-time CSDH and recurrent CSDH. Cytokine levels were analyzed using a multiplex antibody bead kit. In case of recurrent CSDH within 90 days of follow-up, the samples were re-collected and analyzed. We included 101 adult CSDH patients of which 20 had a recurrence. The levels of cytokines in the CSDH fluid from patients who were operated on for the first-time CSDH were not associated with the risk of later developing a recurrence. We found interleukin-1 receptor antagonist (IL-1ra) to be elevated in subdural fluid in patients with recurrent CSDH at the time of their second operation (p = 0.0005). This study provides knowledge on cytokine composition in the subdural fluid in patients with CSDH with and without recurrence. IL-1ra is elevated in subdural fluid in patients with recurrent CSDH at the time of the second operation, identifying a possible medical target.

Gene expression analysis during progression of malignant meningioma compared to benign meningioma.

OBJECTIVE: Meningioma is the most common primary intracranial neoplasm. Only 1%-3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown. METHODS: The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients' earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas. RESULTS: The authors' data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation. CONCLUSIONS: The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas.

The intracranial pressure-volume relationship following decompressive hinge craniotomy compared to decompressive craniectomy-a human cadaver study.

OBJECTIVE: Decompressive hinge craniotomy (DHC) is an alternative treatment option to decompressive craniectomy (DC) for elevated intracranial pressure (ICP). The aim of this study was to characterize the difference in pressure-volume relationship between DHC and DC. METHODS: We compared the intracranial pressure-volume relationship in a human cadaver model following either DHC, DC, or fixing of the bone plate by titanium clamps. We inserted an intracranial expandable device in two human cadaver specimens, performed either DHC, DC, or bone plate fixation, and gradually increased the intracranial volume while measuring ICP. Following DHC, we also performed CT-scans at pre-defined intervals. RESULTS: Before ICP exceeded a threshold of 20 mmHg, a fixed bone plate tolerated an increase of 130 ml of intracranial volume, while DHC and DC allowed an increase of 190 ml and 290 ml, respectively. CT-derived calculations following DHC determined that the increase in intracranial volume at ICP 22 mmHg was 65 ml, the maximal increase of intracranial volume was 84 ml, the maximal bone displacement was 21 mm, and the bone plate volume to be 82 ml. Manual stress test of the hinged bone plate did not allow misalignment or intracranial displacement of the bone plate. CONCLUSION: DHC increases the intracranial volume by up to 84 ml and allows for approximately 60 ml increase of intracranial volume before ICP exceeds 20 mmHg. This indicates, when comparing with results from previous studies of herniation volumes, that DHC will be sufficient in many patients with head injury or cerebral infarction with treatment refractory intracranial hypertension.

The Danish Chronic Subdural Hematoma Study-Risk Factors for Second Recurrence.

BACKGROUND: Treatment of multiple recurrent chronic subdural hematomas (CSDH) is challenging. Identification of specific risk factors for multiple recurrences may allow a higher degree of personalized treatment, including closer postoperative follow-up, detailed prognostication, and a more aggressive initial surgical strategy, such as craniotomy, adjuvant embolization of the middle meningeal artery, or adjuvant medical treatment, such as steroids. The aim of this study was to identify pretreatment risk factors for a second recurrence of CSDH (re-re-CSDH) and risk factors for developing re-re-CSDH once operated for the first recurrence. METHODS: Clinical and demographic data on all Danish patients admitted to a neurosurgical department with CSDH between 2010 and 2012 were retrospectively recorded. Data were retrieved before the evacuation of a primary CSDH, a first recurrent CSDH (re-CSDH), and a re-re-CSDH. We compared patients undergoing first, second, and third CSDH evacuation to identify risk factors for re-CSDH and re-re-CSDH. RESULTS: The cohort comprised 1052 patients, with 172 patients with re-CSDH and 29 patients with re-re-CSDH. Risk factors for re-re-CSDH included radiological subtype, midline shift, and hematoma volume, while postoperative drainage lowered the risk of re-re-CSDH. These risk factors were not specific for re-re-CSDH. CONCLUSIONS: We found similar independent risk factors for re-CSDH and re-re-CSDH, and for re-re-CSDH once treated for re-CSDH. Hence, it was not possible to identify specific risk factors for patients at risk of re-re-CSDH at the time of the primary diagnosis.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

Case Report: Giant Paraganglioma of the Skull Base With Two Somatic Mutations in SDHB and PTEN Genes.

Head and neck paragangliomas (HNPGLs) are neuroendocrine tumors. They arise from the parasympathetic ganglia and can be either sporadic or due to hereditary syndromes (up to 40%). Most HNPGLs do not produce significant amounts of catecholamines. We report a case of a giant paraganglioma of the skull base with an unusually severe presentation secondary to excessive release of norepinephrine, with a good outcome considering the severity of disease. A 39-year-old Caucasian woman with no prior medical history was found unconscious and emaciated in her home. In the intensive care unit (ICU) the patient was treated for multi-organ failure with multiple complications and difficulties in stabilizing her blood pressure with values up to 246/146 mmHg. She was hospitalized in the ICU for 72 days and on the 31st day clinical assessment revealed jugular foramen syndrome and paralysis of the right n. facialis. A brain MRI confirmed a right-sided tumor of the skull base of 93.553 cm3. Blood tests showed high amounts of normetanephrine (35.1-45.4 nmol/L, ref <1.09 nmol/L) and a tumor biopsy confirmed the diagnosis of a paraganglioma. Phenoxybenzamine and Labetalol were used in high doses ((Dibenyline®, 90 mg x 3 daily) and labetalol (Trandate®, 200 + 300 + 300 mg daily) to stabilize blood pressure. The patient underwent two tumor embolization procedures before total tumor resection on day 243. Normetanephrine and blood pressure normalized after surgery (0.77 nmol/L, ref: < 1.09 nmol/L). The damage to the cranial nerve was permanent. Our patient was comprehensively examined for germline predisposition to PPGLs, however we did not identify any causal aberrations. A somatic deletion and loss of heterozygosity (LOH) of the short arm (p) of chromosome 1 (including SDHB) and p of chromosome 11 was found. Analysis showed an SDHB (c.565T>G, p.C189G) and PTEN (c.834C>G, p.F278L) missense mutation in tumor DNA. The patient made a remarkable recovery except for neurological deficits after intensive multidisciplinary treatment and rehabilitation. This case demonstrates the necessity for an early tertiary center approach with a multidisciplinary expert team and highlights the efficacy of the correct treatment with alpha-blockade.

Postoperative drainage for 6, 12, or 24 h after burr-hole evacuation of chronic subdural hematoma in symptomatic patients (DRAIN-TIME 2): study protocol for a nationwide randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common acute or subacute neurosurgical condition, typically treated by burr-hole evacuation and drainage. Recurrent CSDH occurs in 5-20% of cases and requires reoperation in symptomatic patients, sometimes repeatedly. Postoperative subdural drainage of maximal 48 h is effective in reducing recurrent hematomas. However, the shortest possible drainage time without increasing the recurrence rate is unknown. METHODS: DRAIN-TIME 2 is a Danish multi-center, randomized controlled trial of postoperative drainage time including all four neurosurgical departments in Denmark. Both incapacitated and mentally competent patients are enrolled. Patients older than 18 years, free of other intracranial pathologies or history of previous brain surgery, are recruited at the time of admission or no later than 6 h after surgery. Each patient is randomized to either 6, 12, or 24 h of passive subdural drainage following single burr-hole evacuation of a CSDH. Mentally competent patients are asked to complete the SF-36 questionnaire. The primary endpoint is CSDH recurrence rate at 90 days. Secondary outcome measures include SF-36 at 90 days, length of hospital stay, drain-related complications, and complications related to immobilization and mortality. DISCUSSION: This multi-center trial will provide evidence regarding the shortest possible drainage time without increasing the recurrence rate. The potential impact of this study is significant as we believe that a shorter drainage period may be associated with fewer drain-related complications, fewer complications related to immobilization, and shorter hospital stays-thus reducing the overall health service burden from this condition. The expected benefits for patients' lives and health costs will increase as the CSDH patient population grows. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15186366 . Registered in December 2020 and updated in October 2021. This protocol was developed in accordance with the SPIRIT Checklist and by use of the structured study protocol template provided by BMC Trials.

Granular clinical history and outcome in 51 patients with primary and secondary malignant meningioma.

OBJECTIVE: WHO grade III meningiomas, also known as malignant meningiomas (MMs), are rare, and the heterogenous clinical course in patients with MM is not well described. To characterize the clinical course of patients with MM, granular clinical data were gathered from 51 patients treated at the Department of Neurosurgery and Radiation Oncology, Rigshospitalet, in Copenhagen, Denmark, between 2000 and 2020. METHODS: The authors investigated outcome and timing in terms of 1) tumor progression and grade transformation in patients previously diagnosed with WHO grade I or II meningiomas (patients with a secondary MM [sMM]); 2) performance status and complications following surgery; and 3) transition to noncurative treatment and ultimately death. Complications, time between recurrences, and outcome (modified Rankin Scale [mRS] score) for every surgery were analyzed, both malignant and premalignant. RESULTS: Of the 51 patients, 24 (47%) had an sMM. The time to WHO grade III transformation in the sMM group varied widely (median 5.5 years, range 0.5-22 years), but after transformation to a WHO grade III tumor, patients with an sMM and those with a primary MM (pMM) did not differ significantly in overall survival and cumulative risk of progression. Median overall survival for all 51 patients was 4.2 years (95% CI 2.6-7.2 years). Time from the decision to shift from curative to noncurative treatment until death was 3.8 months and the 30-day mortality rate following surgery was 11.8%. From a cumulative number of 151 surgeries, 10 surgeries were followed by improvement on the mRS, mRS score was unchanged in 70, and it worsened in 71. The MM was the underlying cause of death in 30 of 31 patients who had died at the end of follow-up. CONCLUSIONS: Together, these findings clearly show a significant morbidity and mortality from the disease itself and from the treatment. These findings warrant studies of prognostic factors for earlier support and adjuvant measures in MM and identify a need for better palliative strategies in this patient group.