Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

Prior Thrombectomy Does Not Affect the Surgical Complication Rate of Decompressive Hemicraniectomy in Patients with Malignant Ischemic Stroke.

BACKGROUND: Even though mechanical recanalization techniques have dramatically improved acute stroke care since the pivotal trials of decompressive hemicraniectomy for malignant courses of ischemic stroke, decompressive hemicraniectomy remains a mainstay of malignant stroke treatment. However, it is still unclear whether prior thrombectomy, which in most cases is associated with application of antiplatelets and/or anticoagulants, affects the surgical complication rate of decompressive hemicraniectomy and whether conclusions derived from prior trials of decompressive hemicraniectomy are still valid in times of modern stroke care. METHODS: A total of 103 consecutive patients who received a decompressive hemicraniectomy for malignant middle cerebral artery infarction were evaluated in this retrospective cohort study. Surgical and functional outcomes of patients who had received mechanical recanalization before surgery (thrombectomy group, n = 49) and of patients who had not received mechanical recanalization (medical group, n = 54) were compared. RESULTS: The baseline characteristics of the two groups did significantly differ regarding preoperative systemic thrombolysis (63.3% in the thrombectomy group vs. 18.5% in the medical group, p < 0.001), the rate of hemorrhagic transformation (44.9% vs. 24.1%, p = 0.04) and the preoperative Glasgow Coma Score (median of 7 in the thrombectomy group vs. 12 in the medical group, p = 0.04) were similar to those of prior randomized controlled trials of decompressive hemicraniectomy. There was no significant difference in the rates of surgical complications (10.2% in the thrombectomy group vs. 11.1% in the medical group), revision surgery within the first 30 days after surgery (4.1% vs. 5.6%, respectively), and functional outcome (median modified Rankin Score of 4 at 5 and 14 months in both groups) between the two groups. CONCLUSIONS: A prior mechanical recanalization with possibly associated systemic thrombolysis does not affect the early surgical complication rate and the functional outcome after decompressive hemicraniectomy for malignant ischemic stroke. Patient characteristics have not changed significantly since the introduction of mechanical recanalization; therefore, the results from former large randomized controlled trials are still valid in the modern era of stroke care.

Isocitrate-dehydrogenase-mutant lower grade glioma in elderly patients: treatment and outcome in a molecularly characterized contemporary cohort.

PURPOSE: Lower-grade glioma (LGG) is rare among patients above the age of 60 ("elderly"). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. METHODS: Elderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes. RESULTS: 207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors. CONCLUSION: Elderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

[Oral anticoagulant-associated intracerebral haemorrhage]. / Intrazerebrale Blutungen unter oraler Antikoagulation.

Intracerebral haemorrhage during treatment with oral anticoagulants is associated with high rates of morbidity and mortality. Impaired haemostasis can lead to progressive haematomas and, therefore, it should be identified early in order to initiate measures to reverse anticoagulation. Substitution of coagulation factors is essential in the treatment of these patients, but other intensive care measures such as blood pressure control are mandatory as well.

[Traumatic brain injury in anticoagulated patients : Hemostatic therapy for the treatment of intracranial hemorrhage]. / Schädel-Hirn-Trauma unter antithrombotischer Medikation : Hämostaseologische Therapie bei intrakraniellen Blutungen.

Impaired hemostasis represents a major risk factor for increased morbidity and mortality in patients with traumatic intracranial hemorrhage. In cases of polytrauma with major bleeding, hyperfibrinolysis may develop and this may result in excessive coagulopathy. Patients receiving antithrombotic medication and suffering from intracranial hemorrhage are at particular risk for the development of neurological sequelae due to the increased tendency to bleeding. This article outlines the principles of hemostatic therapy of traumatic intracranial hemorrhage during antithrombotic treatment. The basic principles of the pathophysiology and effects of coagulation impairment in this patient population are reviewed. Furthermore, the use of specific coagulation tests and the administration of hemostatic substances are discussed.

[Traumatic brain injury]. / Schädel-Hirn-Trauma.

Since traumatic brain injury is the most common cause of long-term disability and death among young adults, it represents an enormous socio-economic and healthcare burden. As a consequence of the primary lesion, a perifocal brain edema develops causing an elevation of the intracranial pressure due to the limited intracranial space. This entails a reduction of the cerebral perfusion pressure and the cerebral blood flow. A cerebral perfusion deficit below the threshold for ischemia leads to further ischemic lesions and to a progression of the contusion. As the irreversible primary lesion can only be inhibited by primary prevention, the therapy of traumatic brain injury focuses on the secondary injuries. The treatment consists of surgical therapy evacuating the space-occupying intracranial lesion and conservative intensive medical care. Due to the complex pathophysiology the therapy of traumatic brain injury should be rapidly performed in a neurosurgical unit.

It's all in your head: sinus node dysfunction secondary to a sphenoid wing meningioma.

BACKGROUND: A 57-year-old man presented with recurrent episodes of dizziness, weakness of legs, and presyncope. The electrocardiogram showed a sinus bradycardia and recurrent sinus pauses. RESULTS: Cardiac evaluation revealed a normal left ventricular ejection fraction without ischemic, structural, or valvular heart disease. Pronounced limb weakness prompted neurological consultation. Cranial magnetic resonance imaging showed a large right-sided intracranial tumor adjacent to the medial sphenoid wing. Surgical removal of the tumor was accomplished successfully after application of a transient cardiac pacemaker, while decision upon permanent pacemaker implantation was postponed. Histopathology provided evidence of a meningothelial meningioma. Postoperative assessment displayed the absence of sinus node dysfunction after tumor removal. CONCLUSION: Careful differential diagnostic assessment of patients with symptomatic bradycardias needs to rule out reversible causes before implantation of permanent devices.

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage

"BACKGROUND: Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. METHOD: A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9-12, and avoidance of corticosteroids. CONCLUSION: These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome."

Glibenclamide reduces secondary brain damage after experimental traumatic brain injury.

Following traumatic brain injury (TBI) SUR1-regulated NCCa-ATP (SUR1/TRPM4) channels are transcriptionally up-regulated in ischemic astrocytes, neurons, and capillaries. ATP depletion results in depolarization and opening of the channel leading to cytotoxic edema. Glibenclamide is an inhibitor of SUR-1 and, thus, might prevent cytotoxic edema and secondary brain damage following TBI. Anesthetized adult Sprague-Dawley rats underwent parietal craniotomy and were subjected to controlled cortical impact injury (CCI). Glibenclamide was administered as a bolus injection 15min after CCI injury and continuously via osmotic pumps throughout 7days. In an acute trial (180min) mean arterial blood pressure, heart rate, intracranial pressure, encephalographic activity, and cerebral metabolism were monitored. Brain water content was assessed gravimetrically 24h after CCI injury and contusion volumes were measured by MRI scanning technique at 8h, 24h, 72h, and 7d post injury. Throughout the entire time of observation neurological function was quantified using the "beam-walking" test. Glibenclamide-treated animals showed a significant reduction in the development of brain tissue water content(80.47%±0.37% (glibenclamide) vs. 80.83%±0.44% (control); p<0.05; n=14). Contusion sizes increased continuously within 72h following CCI injury, but glibenclamide-treated animals had significantly smaller volumes at any time-points, like 172.53±38.74mm(3) (glibenclamide) vs. 299.20±64.02mm(3) (control) (p<0.01; n=10; 24h) or 211.10±41.03mm(3) (glibenclamide) vs. 309.76±19.45mm(3) (control) (p<0.05; n=10; 72h), respectively. An effect on acute parameters, however, could not be detected, most likely because of the up-regulation of the channel within 3-6h after injury. Furthermore, there was no significant effect on motor function assessed by the beam-walking test throughout 7days. In accordance to these results and the available literature, glibenclamide seems to have promising potency in the treatment of TBI.

Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

The role of spreading depolarization in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating disease associated with death and poor functional outcome. Despite decades of intense research and improvements in clinical management, delayed cerebral ischaemia (DCI) remains the most important cause of morbidity and mortality after SAH. The key role of angiographic cerebral vasospasm, thought to be the main cause of DCI, has been questioned. Emerging evidence suggests that DCI is likely to have a multifactorial etiology. Over the last few years, spreading depolarization (SD) has been identified as a potential pathophysiological mechanism contributing to DCI. The presence of cortical spreading ischaemia, due to an inverse hemodynamic response to SD, offers a possible explanation for DCI and requires more intensive research. Understanding the role of SD as another mechanism inducing DCI and its relationship with other pathological factors could instigate the development of new approaches to the diagnosis and treatment of DCI in order to improve the clinical outcome.

Depression of neuronal activity by sedatives is associated with adverse effects after brain injury.

Analgesics and sedatives are frequently used in the treatment of acute brain injury and subsequent brain swelling. Most agents act on specific receptors to modulate neuronal activity, which is normally involved in feedback loops that direct system building and maintenance. We investigated the neurodegenerative effects of midazolam and isoflurane in a rat model of controlled cortical impact injury (CCII). Two hours prior to CCII, four experimental groups were treated with different agents including a minimum alveolar concentration (MAC 1.0) of isoflurane. For additional sedation, isoflurane MAC 1.67, midazolam alone, or midazolam in combination with flumazenil was used. Blood pressure and blood gas analysis were monitored to investigate systemic side effects. Two days after treatment, relative apoptotic cell counts were determined by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. With isoflurane and midazolam, electroencephalographic (EEG) recordings revealed a decrease in amplitude size and altered frequency distribution. Treatment using deep sedation with isoflurane MAC 1.67 or midazolam increased relative apoptotic cell count by 14.8% (95% CI 3.6 to 26.1, p<0.01) and 18.0% (95% CI 6.8 to 29.3, p<0.01), respectively. Co-treatment with flumazenil reversed the neurodegenerative effect of midazolam by -13.2% (95% CI -24.5 to -2.0, p<0.05). Functional neurological outcome was worse after isoflurane MAC 1.67 (18.8 score points; p<0.01) and midazolam (21.4 score points, p<0.001). Flumazenil antagonized the neurodegenerative effects of midazolam. In conclusion, neuronal survival and functional recovery are reduced by sedative use in a rat model of acute brain injury.

[Management of intracerebral hemorrhage: can we still learn something?]. / Management intrazerebraler Blutungen : Lernen wir dazu?

Intracerebral hemorrhage (ICH) is the most devastating form of stroke. It affects approximately 2 million people worldwide every year and is a major cause of mortality and morbidity. Despite the focus of intensive scientific research on ICH for decades there is still no proven treatment strategy for this disease. Advances in knowledge on the underlying pathomechanisms of ICH and the clinical impact have contributed to the development of novel treatment approaches. Currently, surgical treatment, aggressive blood pressure management and intraventricular fibrinolysis in patients with additional severe intraventricular hemorrhage are being investigated in large scale phase III clinical trials.

[Severe traumatic brain injury]. / Schweres Schädel-Hirn-Trauma.

Traumatic brain injury is a leading cause of morbidity and mortality, especially under 45 years of age. The primary brain injury occurs at the moment of trauma and is defined by the direct damage to tissue. In contrast, secondary brain injury develops over time and is accessible to therapeutic interventions. Patients with severe traumatic brain injury have to be transferred to a specialized trauma centre in order to perform appropriate diagnostic and therapeutic procedures. These include surgical management of lesions (e.g. haematoma evacuation) as well as specific neurointensive care. Neurointensive care medicine principles such as treatment of increased intracranial pressure and advanced invasive neuromonitoring of brain tissue have to be followed.

Diagnostic markers for glioblastoma.

Glioblastoma (GBM) is the most malignant form of cerebral gliomas, and despite distinct progress in surgical resection, radiation and chemotherapy, the prognosis of patients with GBM is still very poor. In the past decades knowledge of genomics and proteomics and of diagnostic, prognostic, predictive and pharmakodynamic markers measured in cerebrospinal-fluid (CSF), serum, or tumor tissue biomarkers has improved. This review briefly compiles our concepts on diagnostic markers for GBM, focusing on the latest developments.

Multiparametric characterisation of the perihemorrhagic zone in a porcine model of lobar ICH.

OBJECTIVES: To describe early perihemorrhagic changes after lobar intracerebral hemorrhage (ICH) using multiparametric neuromonitoring [intracranial pressure (ICP), cerebral blood flow (CBF), tissue oxygenation (PbrO2), microdialysis (MD)]. METHODS: Seven anaesthetized male swine were examined over 12 h. Four cerebral probes were inserted around the ICH (ICP, MD, CBF and PbrO2). A right frontal autologous arterial ICH (1.5 mL) was induced in all animals. RESULTS: Initial ICH creation was hampered by using a soft 22-G cannula. A modified injection technique with a 90° bent steel cannula (20 G) allowed for an 87.5% success rate in ICH formation. After induction of ICH, ICP significantly increased from 2 mmHg to 9 mmHg. No significant PbrO2 or CBF reduction occurred during the monitoring period. Consequently, microdialysis did not indicate overall mean deterioration in the hematoma group over time. The indicator of ischemia (extracellular lactate) did not increase significantly during the monitoring period. Individual monitoring episodes demonstrated hypoxic episodes with consecutive metabolic derangement. These effects were reversible by optimizing CPP and FiO2. CONCLUSION: We established a reproducible cortical ICH model using multiparametric neuromonitoring. Subtle changes in ICP were observed. No evidence for the existence of a perihemorrhagic ischemic area was found, hypothetically because of the small hematoma size. Individual animals underwent critical PbrO2 and CBF decreases with consecutive metabolic derangement. The effect of larger hematoma volumes should be evaluated with this setup in future studies to study volume-dependent deterioration.

Endoscopic intra-hematomal evacuation of intracerebral hematomas - a suitable technique for patients with coagulopathies.

OBJECTIVES: To describe an endoscopic technique to evacuate acute intracerebral hemorrhage (ICH) using the balanced suction-irrigation method in patients with intrinsic or iatrogenic coagulopathies. METHODS: We report on our early experience with four patients with atypical ICH related to intrinsic and iatrogenic coagulopathies. In all patients, an endoscopic hematoma evacuation was performed using a navigated burrhole approach. The entry site and trajectory were planned according to the long axis of the hematoma. RESULTS: Every operation was carried out with the aid of neuronavigation. Gross total removal of the hematoma was not intended as first line, especially if eloquent areas could be avoided. Intra-hematomal evacuation leaving minimal hematoma remnants was performed in three of four patients. We report hematoma removal rates of approximately 90%. In all patients, a significant hematoma reduction was achieved, although residues were tolerated to limit neurological damage. No re-hemorrhage was observed. CONCLUSION: The endoscopic technique with the aid of neuronavigation may be an appropriate method to safely evacuate ICH in the acute stage in patients with intrinsic or iatrogenic coagulopathies.

Effects of lisuride hydrogen maleate on pericontusional tissue metabolism, brain edema formation, and contusion volume development after experimental traumatic brain injury in rats.

After traumatic brain injury (TBI), the primary insult is followed by a cascade of secondary events which lead to enlargement of the primary lesion and are potentially amenable to therapeutic intervention. Lisuride is a dopaminergic agonist with additional serotoninergic, adrenergic, and glutamate antagonistic properties. In lack of previous data on lisuride in TBI, and based on well documented changes of dopamine metabolism after TBI, we speculated that lisuride could provide neuroprotection in the acute and post-acute stage of controlled cortical impact (CCI) injury in rats. The effect of varying dosages of lisuride on physiological parameter was investigated. Cerebral microdialysis (CMD) was employed to provide a temporal profile of lactate, pyruvate, glucose and glutamate in the pericontusional brain tissue. Additionally, brain edema formation and the development of contusion volume were assessed. In this study, no effect of treatment was seen on physiological parameters or microdialysis profiling of tissue metabolites. Whereas posttraumatic increase in brain water content and an increase in contusion volume could be observed, there was no significant effect of treatment. Taken together, our results suggest that lisuride does not provide neuroprotection in the CCI model at the acute and subacute stages. Based on the available literature, however, it might be possible that dopamine agonists such as lisuride, respectively, improve outcome in terms of cognitive function in a chronic setting.

[Acoustic neuroma (vestibular schwannoma). Treatment from a neurosurgical perspective]. / Akustikusneurinome (Vestibularisschwannome). Behandlung aus neurochirurgischer Sicht.

During the last century microsurgical approaches laid emphasis in descending order on preservation of life, total tumor excision and function. Today, the priority of microsurgery has changed to functional preservation. The management of vestibular schwannomas consists of observation, surgical resection, or radiation therapy. In recent years, there has been an increase in observation-only management for small tumors, or radiotherapy in the case of tumor progression. The number of surgical procedures is in decline, with surgery being reserved mainly for large tumors.