Intraoperative application of triamcinolone - a risk factor for delayed CSF fistula formation?

PURPOSE: Cerebrospinal fluid (CSF) leaks are a well-known complication in spinal surgery, caused mostly by incidental durotomy (ID). However, delayed pseudomeningocele formation has been described in patients following an unremarkable surgery - without ID. Intraoperative and epidural triamcinolone application has been suspected to be a potential risk factor. This study was conducted to evaluate the management of ID and identify further risk factors for secondary CSF fistula formation. METHODS: After obtaining approval from the institutional ethics committee, a total of about 5512 patients, who underwent spine surgery between January 2014 and December 2017, were retrospectively reviewed. Of those, 139 cases with intraoperative ID and 15 with delayed pseudomeningocele formation were extracted and analyzed to identify potential risk factors for a late presenting dural injury (LPDI). RESULTS: The incidence of delayed CSF fistulas was 0.27%, with 15 patients presenting with a secondary symptomatic CSF fistula following an unremarkable surgery. Triamcinolone was identified as a risk factor (p<0.001) for pseudomeningocele formation with an OR of 11.5, as it was applied in 80.0% (n=12) of these cases. Revision surgery was performed at a mean period of 6 weeks after initial surgery. CONCLUSION: In our retrospective analysis, intraoperative application of triamcinolone was significantly associated with a high rate of delayed CSF fistulas. It should therefore be used with caution and only after weighing in potential negative side effects.

Link between both infratentorial and supratentorial intracranial pressure burdens and final outcome in patients with infratentorial brain injury.

OBJECTIVE: Increased intracranial pressure (ICP) is most likely not being transmitted uniformly within the cranium. The ICP profiles in the supra- and infratentorial compartments remain largely unclear. Increased ICP in the cerebellum, however, is insufficiently captured by supratentorial ICP (ICPsup) monitoring due to compartmentalization through the tentorium. The authors hypothesized that additional infratentorial ICP (ICPinf) monitoring can be clinically valuable in selected patients. The aims of this study were to demonstrate the safety and feasibility of ICPinf monitoring and to investigate the influence of the ICPinf on clinical outcome in a real-world setting. METHODS: Fifteen consecutive patients with posterior fossa (PF) lesions requiring surgery and anticipated prolonged neurointensive care between June 2019 and December 2021 were included. Simultaneous ICPsup and ICPinf were recorded. ICP burden was defined as a 15-minute interval with a mean ICP > 22 mm Hg. The Glasgow Outcome Scale score was assessed after 3 months. RESULTS: The mean ICPinf was substantially higher compared with ICPsup throughout the entire period of ICP recording (16.08 ± 4.44 vs 10.74 ± 3.6 mm Hg, p < 0.01). ICPinf was significantly higher in patients with unfavorable outcome when compared with those with favorable outcome (mean 17.2 ± 4.1 vs 11.4 ± 3.5 mm Hg, p < 0.05). Patients with unfavorable outcome showed significantly higher ICPinf burden compared with those with favorable outcome (mean 40.6 ± 43.8 vs 0.3 ± 0.4 hours, p < 0.05). Neither absolute ICPsup nor ICPsup burden was significantly associated with unfavorable outcome (p = 0.13). No monitoring-associated complications occurred. CONCLUSIONS: Supplementary ICPinf monitoring is safe and reliable. There is a significant transtentorial pressure gradient within the cranium showing elevated ICPs in the PF. Elevated ICP levels in the PF were strongly associated with unfavorable neurological outcome irrespective of ICPsup values.

Influence of MMR, MGMT Promotor Methylation and Protein Expression on Overall and Progression-Free Survival in Primary Glioblastoma Patients Treated with Temozolomide.

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 <70 years of age revealed a significantly longer OS using a log-rank test and a significance threshold of 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 <70 years. In the elderly, the extent of surgery has an impact on OS rather than the MGMT promoter methylation or protein expression.

The relationship between connexin-43 expression and Ki67 in non-glial central nervous system tumors.

BACKGROUND: Advanced intercellular communication is a known oncogenic factor. In the central nervous system, Connexin-43 (Cx43) forms this junctional networking. Moreover, it correlates with the proliferation rate, and thus behavior, of gliomas. We assessed the expression of Cx43 and its relationship to Ki67 in other common central nervous system tumors. METHODS: The expression of Cx43 and Ki67 were assessed in formalin-fixed paraffin embedded samples of human brain metastases, meningiomas, and neurinomas using immunohistochemistry. Neurinomas and meningiomas were jointly evaluated due to similar non-malignant behavior. RESULTS: A total of 14 metastases of different extracerebral carcinomas, 6 meningiomas, and 10 neurinomas were evaluated. Five (36%) metastases and 5 (31%) meningiomas/neurinomas showed minor expression, whereas 6 (43%) metastases and 2 (13%) meningiomas/neurinomas showed no Cx43 expression at all. In 3 (21%) metastases and 9 (56%) meningiomas/neurinomas, moderate or strong expression of Cx43 was identified. The higher expression of Cx43 in meningiomas and neurinomas directly correlated with Ki67, r = 0.53 (P = 0.034). For metastases no significant correlation was found. Mitotic index in meningiomas/neurinomas correlated with Ki67 expression, r = 0.74 (P < 0.001), but did not show statistically significant correlation with Cx43 expression in these tumors. CONCLUSIONS: The expression of Cx43 as a marker of cell-to-cell networking exposed a significant correlation with the Ki67-defined proliferation index in case of primary central nervous system neuroectodermal neoplasms. However, it does not seem to play a comparable role in metastases with extracerebral origin.

Impact of GAP-43, Cx43 and actin expression on the outcome and overall survival in diffuse and anaplastic gliomas.

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 < 0.001, HR = 2.28/rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of all proteins: GAP-43 (p = 0.009), Cx43 (p = 0.003) and actin (p < 0.001). The same was confirmed for anaplasia (GAP-43 p = 0.028, actin p = 0.029), higher proliferation rate (GAP-43 p = 0.016, actin p = 0.038), contrast-enhancement in MRI (GAP-43 p = 0.023, actin p = 0.037) and age (GAP-43 p = 0.004, actin p < 0.001; Cx43 n.s. in all groups). The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with unfavorable prognostic features. Cx43 did not show relevant impact on OS.

Current trends and outcomes of non-elective neurosurgical care in Central Europe during the second year of the COVID-19 pandemic.

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.

The advanced development of Cx43 and GAP-43 mediated intercellular networking in IDH1 wildtype diffuse and anaplastic gliomas with lower mitotic rate.

PURPOSE: The biologic behavior and the therapeutic resistance of diffuse and anaplastic gliomas varies greatly. This may be explained by differences in cell-to-cell communication, determined by the Cx43-associated junctional activity and the microtubules-defined network, in which GAP-43 is the dominant structural component. We assessed the expression of these crucial communication proteins in samples of patients harboring WHO°II and III gliomas, graded according to the current 4th revised WHO classification. METHODS: Tissue of adult patients with WHO°II and III gliomas, who underwent surgery between 2014 and 2018, were selected from our institutional biobank. GAP-43 and Cx43 expression was analyzed using IHC. Routine clinical and neuropathological findings were additionally retrieved from our institutional prospective database. RESULTS: 43 (57%) males and 33 (43%) females with a median age of 47 (IqR: 35-61) years were selected. IDH1 wildtype tumors showed a significantly higher expression of Cx43 (p = 0.014) and a tendency for increased GAP-43 production. Advanced Cx43 expression significantly correlated with lower mitosis rate (p = 0.014): more in IDH1 wildtype (r = - 0.57, p = 0.003) than in mutated gliomas (r = - 0.37, p = 0.019). There was no difference in Cx43 or GAP-43 expression in relation to anaplastic phenotype, Gadolinum-contrasted enhancement (CE) on MRI and advanced EGFR or p53 expression. CONCLUSIONS: Intercellular communication tends to be more relevant in slower proliferating, e.g. lower malignant tumors. They could have more time to establish this network, providing longitudinally acquired resistance against specific oncological therapy. This feature matches the unfavorable IDH1 wildtype status of glioma and supports the noted malignant behavior of these tumors in the upcoming 5th WHO classification of gliomas.

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors.

Introduction: The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question: This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods: A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results: The total sample of 4864 patients had a mean age of 56.4 â€‹± â€‹14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. Discussion: Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion: Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.

Early surgery determines recovery of motor deficits in lumbar disc herniations-a prospective single-center study.

BACKGROUND: Patients with intervertebral disc herniation undergo surgical removal of herniated disc material in cases of persisting symptoms and/or neurologic deficits. While motor deficits often prompt surgery, little is known about the optimal timing of surgery in these cases. The aim of this study was to prospectively evaluate the impact of timing of disc surgery on motor recovery. Does postponing surgical treatment worsen outcome? METHOD: In total, 120 patients with sciatica and/or sensorimotor deficits due to a lumbar disc herniation were surgically treated at the authors' center within a 3-month period. In 60 patients, motor deficits were present at the time of admission. Motor function was assessed using manual muscle testing and subdivided according to the Medical Research Council (MRC) scale. Patient demographics, neurologic deficits, duration of motor deficits, treatment characteristics, and outcome were assessed. At a minimum follow-up of 1 year, functional recovery and complications were collated. Patients were subdivided into groups according to the severity of the paresis (MRC ≤ 3/5 vs. MRC 4/5). Intra-group differences were compared based on the duration of the neurologic deficits. RESULTS: Patients with moderate and severe paresis (MRC ≤ 3/5) benefit from treatment within 72 h as they were shown to have a significantly higher complete recovery rate at 1-year follow-up (75% vs. 0%; p < 0.001). CONCLUSION: Immediate surgery should be offered to patients with moderate and severe motor deficits to increase the likelihood of neurologic recovery. This prospective data may have an impact on emergency triage in these patients.

Development and external validation of a clinical prediction model for functional impairment after intracranial tumor surgery.

OBJECTIVE: Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impairment. METHODS: The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS: In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS: Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.

Immediate Versus Delayed Surgical Treatment of Lumbar Disc Herniation for Acute Motor Deficits: The Impact of Surgical Timing on Functional Outcome.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of the study was to assess the impact of time to surgery in patients with motor deficits (MDs) on their functional outcome. The current single-center study presents results of emergency surgery for LDH in a group of patients with acute paresis in a "real-world" setting. SUMMARY OF BACKGROUND DATA: MDs are a frequent symptom of lumbar disc herniation (LDH). Although surgery within 48 hours has been recommended for cauda-equina syndrome, the best timing of surgery for acute MDs continues to be debated. The effect of early surgery has been proposed but remains to be unproven. METHODS: A total of 330 patients with acute paresis caused by LDH acutely referred to our department and surgically treated using microsurgical discectomy from January 2013 to December 2015 were included. Based on the duration of MD and surgical timing, all patients were classified into two categories: Group I included all patients with paresis <48 hours and Group II included all patients with paresis >48 hours. Patient demographics, LDH/clinical/treatment characteristics, and outcomes were collected prospectively.Severity of paresis [Medical Research Council (MRC) Grade 0-4], surgery-related complications, functional recovery of motor/sensory deficits, sciatica, retreatment/recurrence rates, and overall neurological outcome were analyzed. RESULTS: Group I showed significantly faster recovery of moderate/severe paresis (MRC 0-3) at discharge, and 6-weeks/3-months follow up (P ≤ 0.001), whereas there were no significant differences in recovery for mild paresis (MRC 4). Sensory deficits also recovered substantially faster in Group I at 6-weeks (P = 0.003) and 3-months follow up (P = 0.045). Body mass index, preoperative MRC-grade, and duration of MDs were identified as significant predictors for recovery of paresis at all follow ups with substantial impact on patient reported outcomes including sciatica and/or dermatomal sensory deficits. CONCLUSION: Given the superior rates of neurological recovery of acute moderate/severe MDs, immediate surgery should be the primary option. However, a prospective randomized clinical trial is needed to confirm the superiority of emergency surgery. LEVEL OF EVIDENCE: 3.

Efficacy of D,L-methadone in the treatment of glioblastoma in vitro.

AIM: Recently, D,L-methadone has been put forward as adjuvant treatment in glioblastoma (GBM). METHODS: We analyzed the µ-opioid receptor expression in a set of GBM cell lines and investigated the efficacy of D,L-methadone alone and in combination with temozolomide (TMZ). Results & conclusion: Expression of the µ-opioid receptor was similar in the tested cell lines. High concentrations of D,L-methadone induced apoptosis in all cell lines and showed treatment interaction with TMZ. However, in lower dosages, reflecting clinically attainable concentrations, D,L-methadone alone showed no efficacy, and induced even higher proliferation in one specific cell line. Also, no interaction with TMZ was observed. These results suggest caution to the premature use of D,L-methadone in the treatment of GBM patients.

Optical Neuronavigation without Rigid Head Fixation During Awake Surgery.

OBJECTIVE: Optical neuronavigation without rigid pin fixation of the head may lead to inaccurate results because of the patient's movements during awake surgery. In this study, we report our results using a skull-mounted reference array for optical tracking in patients undergoing awake craniotomy for eloquent gliomas. METHODS: Between March 2013 and December 2014, 18 consecutive patients (10 men, 8 women) with frontotemporal (n = 16) or frontoparietal (perirolandic; n = 2) lesions underwent awake craniotomy without rigid pin fixation. All patients had a skull-mounted reference array for optical tracking placed on the forehead. Accuracy of navigation was determined with pointer tip deviation measurements on superficial and bony anatomic structures. Good accuracy was defined as a tip deviation <2 mm. RESULTS: Gross total resection (>98%) was achieved in 7 patients (38%); >90% of tumor was resected in 8 patients (44%). In 3 patients, only subtotal resection or biopsy was performed secondary to stimulation results. In all patients, good accuracy of the optical neuronavigation system could be demonstrated without intraoperative peculiarities or complications. The reference array had to be repositioned because of loosening in 1 patient. Neuronavigation could be reliably applied to support stimulation-based resection. CONCLUSIONS: A skull-mounted reference array is a simple and safe method for optical neuronavigation tracking without rigid pin fixation of the patient's head.

Dual Anti-angiogenic Chemotherapy with Temozolomide and Celecoxib in Selected Patients with Malignant Glioma Not Eligible for Standard Treatment.

AIM: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status. PATIENTS AND METHODS: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis. RESULTS: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded. CONCLUSION: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.

Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines.

The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 µM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.