To use or not to use antithrombotics in unruptured cerebrovascular malformations? A systematic review focusing on this clinical and surgical dilemma.

OBJECTIVE: Antithrombotic medications (ATMs), including antiplatelet therapy (APT) and oral anticoagulants (OACs), are widely used in current clinical practice for the prevention and treatment of a variety of cardiovascular diseases, deep vein thrombosis, and pulmonary thromboembolisms. The long-term usage of these drugs, associated with an inherent risk of bleeding, raises concerns for unruptured cerebrovascular malformations (UCVMs), such as arteriovenous malformations (AVMs), cerebral cavernous malformations (CCMs), and intracranial aneurysms (IAs), in which the bleeding risk also poses a major threat. The aim of this study was to assess the safety and risk-benefit ratio of ATMs in these various neurosurgical diseases and to give neurosurgeons a safe and reasonable choice regarding whether to administer ATMs to these patients during the course of the disease. METHODS: The authors conducted a systematic review of the literature (PubMed/MEDLINE and Embase) according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines, which yielded 4 papers about CCMs, 2 about AVMs, and 9 about IAs. The risk of bias was assessed using the Cochrane Collaboration's tool. RESULTS: For AVMs, only 2 studies with a total of only 14 patients were included. Data on AVMs and ATMs are limited and weak, relying on small case series. Nevertheless, there is no evidence for either an increased risk of intracranial hemorrhage in patients with AVMs who are receiving ATMS or the need to interrupt ATMs in those patients who have been diagnosed with sporadic, unruptured brain AVMs. With respect to CCMs, the literature search resulted in 4 cohort studies and 1 meta-analysis. These studies affirmed the absence of a correlation between ATMs and an increased risk of CCM bleeding while simultaneously suggesting a protective role of ATMs against bleeding. Concerning IAs, the topic is more complex and debated, despite larger case series on IAs than on AVMs or CCMs. The benefits of ATMs for IAs may vary according to the type of intervention and specific drug administered. Evidence supports the continuation of long-term APT for all patients newly diagnosed with an IA, whereas starting APT in patients with incidentally discovered IA as a means of prophylaxis against rupture is unclear. CONCLUSIONS: The findings of this review should be taken as a wide overview of UCVM and ATM. Future research should consider the relationship of AVM, CCM, and IA with APT and OAC independently.

A Novel Patient-Personalized Nanovector Based on Homotypic Recognition and Magnetic Hyperthermia for an Efficient Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the deadliest brain tumor, characterized by an extreme genotypic and phenotypic variability, besides a high infiltrative nature in healthy tissues. Apart from very invasive surgical procedures, to date, there are no effective treatments, and life expectancy is very limited. In this work, an innovative therapeutic approach based on lipid-based magnetic nanovectors is proposed, owning a dual therapeutic function: chemotherapy, thanks to an antineoplastic drug (regorafenib) loaded in the core, and localized magnetic hyperthermia, thanks to the presence of iron oxide nanoparticles, remotely activated by an alternating magnetic field. The drug is selected based on ad hoc patient-specific screenings; moreover, the nanovector is decorated with cell membranes derived from patients' cells, aiming at increasing homotypic and personalized targeting. It is demonstrated that this functionalization not only enhances the selectivity of the nanovectors toward patient-derived GBM cells, but also their blood-brain barrier in vitro crossing ability. The localized magnetic hyperthermia induces both thermal and oxidative intracellular stress that lead to lysosomal membrane permeabilization and to the release of proteolytic enzymes into the cytosol. Collected results show that hyperthermia and chemotherapy work in synergy to reduce GBM cell invasion properties, to induce intracellular damage and, eventually, to prompt cellular death.

Radiofrequency Ablation in Vertebral Body Metastasis with and without Percutaneous Cement Augmentation: A Systematic Review Addressing the Need for SPINE Stability Evaluation.

Vertebral body metastases (VBM) are one of the most frequent sites of bone metastasis, and their adequate therapeutic management still represents an insidious challenge for both oncologists and surgeons. A possible alternative treatment for VBM is radiofrequency ablation (RFA), a percutaneous technique in which an alternating current is delivered to the tumor lesion producing local heating and consequent necrosis. However, RFA alone could alter the biomechanics and microanatomy of the vertebral body, thus increasing the risk of post-procedure vertebral fractures and spine instability, and indeed the aim of the present study is to investigate the effects of RFA on spine stability. A systematic review according to PRISMA-P guidelines was performed, and 17 papers were selected for the systematic review. The results show how RFA is an effective, safe, and feasible alternative to conventional radiotherapy for the treatment of VBM without indication for surgery, but spine stability is a major issue in this context. Although exerting undeniable benefits on pain control and local tumor recurrence, RFA alone increases the risk of spine instability and consequent vertebral body fractures and collapses. Concomitant safe and feasible therapeutic strategies such as percutaneous vertebroplasty and kyphoplasty have shown synergic positive effects on back pain and improvement in spine stability.

Anticoagulant therapy in high grade gliomas: a systematic review on state of the art and future perspectives.

INTRODUCTION: Anticoagulation management in high-grade gliomas is a widely studied but still debated topic, since the increased thrombotic risk is accompanied by the high background rate of intralesional bleeding. Currently, the main challenge when prescribing anticoagulants to HGG patients is to balance the risk between ICH and VTE both in the perioperative period and in the postoperative follow-up during adjuvant chemo- and radiotherapic treatment. EVIDENCE ACQUISITION: A systematic review according to PRISMA-P Guidelines was performed: 12 observational studies were selected, eight retrospective and four prospective. Regarding the reviews 3 were selected, two of which analyzed bleeding complications of anticoagulation therapy and one on thrombotic events. EVIDENCE SYNTHESIS: In the selected studies, the risk of VTEs was between 4 and 33%, while in patients with VTEs subsequently subjected to anticoagulant therapy the cases of ICH ranged from 0% to 15.4%. Regarding the reviews, two meta-analyses have evaluated the incidence of ICH in patients undergoing anticoagulation therapy following thromboembolic events, they agree in quantifying the increased risk of bleeding. CONCLUSIONS: The results of our review are generally consistent in stating that the thrombotic risk is increased in patients with HGG, suggesting that more extensive antithrombotic prophylaxis could positively impact the outcome of these patients, even if currently there are no conclusive elements in indicating or contraindicating prolonged antithrombotic prophylaxis - considering that anticoagulant administration in these patients involves an increased risk of ICH. All the studies examined have considered a prolonged heparin treatment without considering the new oral anticoagulants, so further studies about this topic are needed.

Role of Anterior Nasal Packing in Endoscopic Skull Base Surgery: Italian Survey.

BACKGROUND: Nowadays, the endoscopic endonasal approach to sellar and parasellar region tumors is a common technique in neurosurgery, and surgical nuances, complications, and management strategies are shared in a multidisciplinary setting between neurosurgeons and ear, nose, and throat surgeons. Due to the heterogeneity of its variations, the role of the anterior nasal packing in endoscopic endonasal approach to the skull base surgery (EESBS) has not yet been unanimously accepted and no consensus or guidelines on its use exist. MATERIALS AND METHODS: A survey containing 10 questions about indications, management advantages, and pitfalls of the use of anterior nasal packing in EESBS was created by using an online open-source tool (SurveyMonkey). The questionnaire was sent to 39 Italian neurosurgical departments, which routinely adopt the endoscopic endonasal approach. RESULTS: Almost half of 39 selected centers (19; 48.7%) answered our survey. The main results can be summarized as 1) anterior nasal packing after EESBS is considered useful by 84% of participants, 2) prevention of epistaxis is the principal indication for anterior nasal packing, 3) the type of approach and skull base reconstruction influence the use of anterior nasal packing, and 4) nasal discomfort is considered the principal negative aspect of nasal packing. CONCLUSIONS: Our study identified that anterior nasal packing is commonly adopted in certain conditions, namely when extensive nasal dissection is performed. Furthermore, the choice to adopt or not the anterior nasal packing should be tailored taking in account specific conditions, such as acromegaly and Cushing disease. It represents an important factor in reducing postoperative sinonasal complications of EESB.

Clinical and Radiological Predictors of Biochemical Response to First-Line Treatment With Somatostatin Receptor Ligands in Acromegaly: A Real-Life Perspective.

Background: First-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medical treatment for acromegaly, recommended in patients with persistent disease after neurosurgery, or when surgical approach is not feasible. Despite the lack of strong recommendations from guidelines and consensus statements, data from national Registries report an increasing use of medical therapy as first-line treatment in acromegaly. Objective: We retrospectively evaluated the potential role of a large number of clinical and radiological parameters in predicting the biochemical response to 6-month treatment with fg-SRLs, in a cohort of naïve acromegaly patients referred to a single tertiary center for pituitary diseases. Methods: Univariable and multivariable logistic regression and linear regression analyses were performed. Biochemical response was defined based on IGF-1 levels, represented as both categorical (tight control, control, >50% reduction) and continuous (linear % reduction) variables. Results: Fifty-one patients (33 females, median age 57 years) were included in the study. At univariable logistic regression analysis, we found that younger age (≤ 40 years; OR 0.04, p=0.045) and higher BMI (OR 0.866, p=0.034) were associated with a lower chance of achieving >50% IGF-1 reduction. On the contrary, higher IGF-1 xULN values at diagnosis (OR 2.304, p=0.007) and a T2-hypointense tumor (OR 18, p=0.017) were associated with a significantly higher likelihood of achieving >50% IGF-1 reduction after SRL therapy. Of note, dichotomized age, IGF1 xULN at diagnosis, and T2-hypointense signal of the tumor were retained as significant predictors by our multivariable logistic regression model. Furthermore, investigating the presence of predictors to the linear % IGF-1 reduction, we found a negative association with younger age (≤ 40 years; ß -0.533, p<0.0001), while a positive association was observed with both IGF-1 xULN levels at diagnosis (ß 0.330, p=0.018) and the presence of a T2-hypointense pituitary tumor (ß 0.466, p=0.019). All these variables were still significant predictors at multivariable analysis. Conclusions: Dichotomized age, IGF-1 levels at diagnosis, and tumor T2-weighted signal are reliable predictors of both >50% IGF-1 reduction and linear % IGF-1 reduction after 6 month fg-SRL treatment in naïve acromegaly patients. These parameters should be considered in the light of an individualized treatment for acromegaly patients.

Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST2 in Mediating Ligand Effects.

First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

Middle Cranial Fossa Approach: Anatomical Study on Skull Base Triangles as a Landmark for a Safe Anterior Petrosectomy.

Objective The Kawase approach provides access to the petroclival and posterior cavernous sinus regions, cerebellopontine angle, and upper basilar artery territory. Nevertheless, it remains one of the most challenging approach for neurosurgeons, due to the considerable related morbidity and mortality. The goal of this study was to evaluate the relationship between anatomical landmarks and their possible variations, and to measure the extension of the Kawase space, to define the reliability of these landmarks while performing an anterior petrosectomy. Design Using eight cadaveric specimens (15 sides), an anatomical dissections and extradural exposure of the Kawase area were performed. Settings A two-step analysis of the distances between the mandibular branch of the trigeminal nerve (V3) and the structures at risk of iatrogenic damage was performed. Main outcome measures We measured the distance between V3 and the basal turn of the cochlea, and between V3 and the internal acoustic canal (IAC), analyzing the limits of bone resection without causing hearing damage. Results We analyzed eight cadaveric (15 sides) formalin-fixed heads injected with colored silicone: four males and four females of Caucasian race (mean age: 73.83 years). We found a mean distance of 10.46 ± 1.13 mm between the great superficial petrous nerve (GSPN) intersection with V3 and the basal turn of the cochlea, and of 11.92 ± 1.71 mm between the origin point of V3 from the Gasserian ganglion and the fundus of the IAC. Conclusion The knowledge of the safe distance between the most applicable anatomic landmarks and the hearing structures is a practical and useful method to perform this approach reducing related comorbidity.

How do you manage ANTICOagulant therapy in neurosurgery? The ANTICO survey of the Italian Society of Neurosurgery (SINCH).

BACKGROUND: Anticoagulant assumption is a concern in neurosurgical patient that implies a delicate balance between the risk of thromboembolism versus the risk of peri- and postoperative hemorrhage. METHODS: We performed a survey among 129 different neurosurgical departments in Italy to evaluate practice patterns regarding the management of neurosurgical patients taking anticoagulant drugs. Furthermore, we reviewed the available literature, with the aim of providing a comprehensive but practical summary of current recommendations. RESULTS: Our survey revealed that there is a lack of knowledge, mostly regarding the indication and the strategies of anticoagulant reversal in neurosurgical clinical practice. This may be due a lack of national and international guidelines for the care of anticoagulated neurosurgical patients, along with the fact that coagulation and hemostasis are not simple topics for a neurosurgeon. CONCLUSIONS: To overcome this issue, establishment of hospital-wide policy concerning management of anticoagulated patients and developed in an interdisciplinary manner are strongly recommended.

The role of external ventricular drainage for the management of posterior cranial fossa tumours: a systematic review.

Posterior cranial fossa tumours frequently develop hydrocephalus as first presentation in up to 80% of paediatric patients and 21.4% of adults, although it resolves after tumour removal in 70-90% and 96%, respectively. New onset hydrocephalus is reported in about 2.1% of adult and 10-40% of paediatric patients after posterior fossa surgery. There is no consensus concerning prophylactic external ventricular drainage (EVD) placement that is frequently used before posterior fossa lesion removal, as well in those cases without clear evidence of hydrocephalus. The aim of the study was to define the most correct management for patients who undergo posterior fossa tumour surgery, thus identifying cohorts of patients who are at risk of persistent hydrocephalus prior to surgery. A systematic review of literature has been performed, following PRISMA guidelines. Most of the studies reported CSF shunt only in the presence of hydrocephalus, whereas only a few authors suggested its prophylactic use in the absence of signs of ventricular dilatation. Predictive factors for postoperative hydrocephalus has been identified, including young age (< 3 years), severe symptomatic hydrocephalus at presentation, EVD placement before surgery, FOHR index > 0.46 and Evans index > 0.4, pseudomeningocele, CSF leak and infection. The use of pre-resection CSF shunt in case of signs and symptoms of hydrocephalus is mandatory, although it resolves in the majority of cases. As reported by several studies included in the present review, we suggest CSF shunt also in case of asymptomatic hydrocephalus, whereas it is not indicated without evidence of ventricular dilatation.

Clinical practice for antiplatelet and anticoagulant therapy in neurosurgery: data from an Italian survey and summary of current recommendations - part I, antiplatelet therapy.

The use of antiplatelet medication is widespread as reducing risk of death, myocardial infarction, and occlusive stroke. Currently, the management of neurosurgical patients receiving this type of therapy continues to be a problem of special importance. In this paper, we present the results of an Italian survey focused on the management neurosurgical patient under antiplatelet therapy and, for any item of the investigation, the relative advices coming from literature. This survey was conducted including 129 neurosurgery units in Italy. The present paper was designed by following each question posed in the survey by a brief discussion on literature data. There is a considerable lack of consensus regarding management of antiplatelet therapy in neurosurgery, with critical impact on patient's treatment. What is clearly evident from the present survey is the considerable variability in neurosurgical care for antiplatelet patients; it is reasonable to assume that this scenario reflects the paucity of evidence regarding this issue.

Ipsilateral Nasoseptal Flap Pedicle for Transpterygoid Approach: Technical Note.

INTRODUCTION: Transpterygoid approach is an expanded endonasal approach (EEA) that allows surgical access to the medial infratemporal fossa, to the skull base area of petrous bone and to the Meckel's cave. During this approach, a sacrifice of sphenopalatine artery is often required, leading to the need of contralateral Hadad-Bassagasteguy flap (HBF) or alternative reconstructive techniques. MATERIALS AND METHODS: We report a case of spontaneous CSF leak due to a meningo-encephalocele in the left lateral recess of sphenoid sinus, in which an ispilateral nasoseptal flap was harvest and sphenopalatine artery was preserved. RESULTS: We described the surgical technique adopted to preserve the ipsilateral nasoseptal vascular pedicle during transpterygoid approach and we performed a review of the pertinent literature. CONCLUSION: Wide exposure of the pterygoid base through transpterygoid approach could be obtained preserving the sphenopalatine artery, allowing skull base reconstruction with ipsilateral nasoseptal flap.

Escalation therapy in severe traumatic brain injury: how long is intracranial pressure monitoring necessary?

Traumatic brain injury frequently causes an elevation of intracranial pressure (ICP) that could lead to reduction of cerebral perfusion pressure and cause brain ischemia. Invasive ICP monitoring is recommended by international guidelines, in order to reduce the incidence of secondary brain injury; although rare, the complications related to ICP probes could be dependent on the duration of monitoring. The aim of this manuscript is to clarify the appropriate timing for removal and management of invasive ICP monitoring, in order to reduce the risk of related complications and guarantee adequate cerebral autoregulatory control. There is no universal consensus concerning the duration of invasive ICP monitoring and its related complications, although the pertinent literature seems to show that the longer is the monitoring maintenance, the higher is the risk of technical issues. Besides, upon 72 h of normal ICP values or less than 72 h if the first computed tomography scan is normal (none or minimal signs of injury) and the neurological exam is available (allowing to observe variations and possible occurrence of new-onset pathological response), the removal of invasive ICP monitoring can be justified. The availability of non-invasive monitoring systems should be considered to follow up patients' clinical course after invasive ICP probe removal or for substituting the invasive monitoring in case of contraindication to its placement. Recently, optic nerve sheath diameter and straight sinus systolic flow velocity evaluation through ultrasound methods showed a good correlation with ICP values, demonstrating their potential role in place of invasive monitoring or in the early weaning phase from the invasive ICP monitoring.

Escalate and De-Escalate Therapies for Intracranial Pressure Control in Traumatic Brain Injury.

Severe traumatic brain injury (TBI) is frequently associated with an elevation of intracranial pressure (ICP), followed by cerebral perfusion pressure (CPP) reduction. Invasive monitoring of ICP is recommended to guide a step-by-step "staircase approach" which aims to normalize ICP values and reduce the risks of secondary damage. However, if such monitoring is not available clinical examination and radiological criteria should be used. A major concern is how to taper the therapies employed for ICP control. The aim of this manuscript is to review the criteria for escalating and withdrawing therapies in TBI patients. Each step of the staircase approach carries a risk of adverse effects related to the duration of treatment. Tapering of barbiturates should start once ICP control has been achieved for at least 24 h, although a period of 2-12 days is often required. Administration of hyperosmolar fluids should be avoided if ICP is normal. Sedation should be reduced after at least 24 h of controlled ICP to allow neurological examination. Removal of invasive ICP monitoring is suggested after 72 h of normal ICP. For patients who have undergone surgical decompression, cranioplasty represents the final step, and an earlier cranioplasty (15-90 days after decompression) seems to reduce the rate of infection, seizures, and hydrocephalus.