The "state of the art" of intraoperative neurophysiological monitoring: An Italian neurosurgical survey.

Introduction: Intraoperative Neurophysiological Monitoring (IOM) is widely used in neurosurgery but specific guidelines are lacking. Therefore, we can assume differences in IOM application between Neurosurgical centers. Research question: The section of Functional Neurosurgery of the Italian Society of Neurosurgery realized a survey aiming to obtain general data on the current practice of IOM in Italy. Materials and methods: A 22-item questionnaire was designed focusing on: volume procedures, indications, awake surgery, experience, organization and equipe. The questionnaire has been sent to Italian Neurosurgery centers. Results: A total of 54 centers completed the survey. The annual volume of surgeries range from 300 to 2000, and IOM is used in 10-20% of the procedures. In 46% of the cases is a neurologist or a neurophysiologist who performs IOM. For supra-tentorial pathology, almost all perform MEPs (94%) SSEPs (89%), direct cortical stimulation (85%). All centers perform IOM in spinal surgery and 95% in posterior fossa surgery. Among the 50% that perform peripheral nerve surgery, all use IOM. Awake surgery is performed by 70% of centers. The neurosurgeon is the only responsible for IOM in 35% of centers. In 83% of cases IOM implementation is adequate to the request. Discussion and conclusions: The Italian Neurosurgical centers perform IOM with high level of specialization, but differences exist in organization, techniques, and expertise. Our survey provides a snapshot of the state of the art in Italy and it could be a starting point to implement a consensus on the practice of IOM.

Idiopathic normal pressure hydrocephalus diagnosis: Quantitative and qualitative score predicting outcome of extended lumbar drainage.

Image 1.

Consensus-based recommendations for diagnosis and surgical management of cranioplasty and post-traumatic hydrocephalus from a European panel.

Introduction: Planning cranioplasty (CPL) in patients with suspected or proven post-traumatic hydrocephalus (PTH) poses a significant management challenge due to a lack of clear guidance. Research question: This project aims to create a European document to improve adherence and adapt to local protocols based on available resources and national health systems. Methods: After a thorough non-systematic review, a steering committee (SC) formed a European expert panel (EP) for a two-round questionnaire using the Delphi method. The questionnaire employed a 9-point Likert scale to assess the appropriateness of statements inherent to two sections: "Diagnostic criteria for PTH" and "Surgical strategies for PTH and cranial reconstruction." Results: The panel reached a consensus on 29 statements. In the "Diagnostic criteria for PTH" section, five statements were deemed "appropriate" (consensus 74.2-90.3 %), two were labeled "inappropriate," and seven were marked as "uncertain."In the "Surgical strategies for PTH and cranial reconstruction" section, four statements were considered "appropriate" (consensus 74.2-90.4 %), six were "inappropriate," and five were "uncertain." Discussion and conclusion: Planning a cranioplasty alongside hydrocephalus remains a significant challenge in neurosurgery. Our consensus conference suggests that, in patients with cranial decompression and suspected hydrocephalus, the most suitable diagnostic approach involves a combination of evolving clinical conditions and neuroradiological imaging. The recommended management sequence prioritizes cranial reconstruction, with the option of a ventriculoperitoneal shunt when needed, preferably with a programmable valve. We strongly recommend to adopt local protocols based on expert consensus, such as this, to guide patient care.

Pilocytic astrocytoma: The paradigmatic entity in low­grade gliomas (Review).

Among low-grade gliomas, representing 10-20% of all primary brain tumours, the paradigmatic entity is constituted by pilocytic astrocytoma (PA), considered a grade 1 tumour by the World Health Organization. Generally, this tumour requires surgical treatment with an infrequent progression towards malignant gliomas. The present review focuses on clinicopathological characteristics, and reports imaging, neurosurgical and molecular features using a multidisciplinary approach. Macroscopically, PA is a slow-growing soft grey tissue, characteristically presenting in association with a cyst and forming a small mural nodule, typically located in the cerebellum, but sometimes occurring in the spinal cord, basal ganglia or cerebral hemisphere. Microscopically, it may appear as densely fibrillated areas composed of elongated pilocytic cells with bipolar 'hairlike' processes or densely fibrillated areas composed of elongated pilocytic cells with Rosenthal fibres alternating with loosely fibrillated areas with a varied degree of myxoid component. A wide range of molecular alterations have been encountered in PA, mostly affecting the MAPK signalling pathway. In detail, the most frequent alteration is a rearrangement of the BRAF gene, although other alterations include neurofibromatosis type-1 mutations, BRAFV600E mutations, KRAS mutations, fibroblast growth factor receptor-1 mutations of fusions, neurotrophic receptor tyrosine kinase family receptor tyrosine kinase fusions and RAF1 gene fusions. The gold standard of PA treatment is surgical excision with complete margin resection, achieving minimal neurological damage. Conventional radiotherapy is not required; the more appropriate treatment appears to be serial follow-up. Chemotherapy should only be applied in younger children to avoid the risk of long-term growth and developmental issues associated with radiation. Finally, if PA recurs, a new surgical approach should be performed. At present, novel therapy involving agents targeting MAPK signalling pathway dysregulation is in development, defining BRAF and MEK inhibitors as target therapeutical agents.

Association between the morphological features of the central sulcus and the somatomotory representation: anatomo-functional evaluation of neuroplasticity through nTMS.

In recent years navigated transcranial magnetic stimulation (nTMS) has emerged as a useful tool for the preoperative mapping of brain cortical areas surrounding neoplastic tissues allowing for maximal safe tumor resection and minimizing new postoperative permanent neurological deficits. Three patients presenting with an intrinsic brain tumor (one metastasis from mammary carcinoma, one high-grade glioma, and one low-grade glioma) located within or in close relationship to the central sulcus were enrolled for this study. The MRI-based morphological and nTMS mapping of the central sulcus of the intact hemisphere was complemented by the examination of the contralateral region harboring the lesion. The findings were independently compared, in search of evidence of tumor-induced neuroplasticity and/or signs of parenchymal dislocation/infiltration caused by the tumor. An individual description of each mapping session is provided. Significant discrepancies were observed between morphological MRI and functional nTMS mapping in two patients, demonstrating a tumor-induced shift of distinct cortical areas controlling hand and/or facial movements. In the cases of gliomas, a lower MT was detected in the lesioned hemisphere, possibly due to increased electrical excitability caused by the tumor itself. The integration of MRI-based morphological mapping of the central sulcus with the detection of its somatomotor representations through nTMS can assist neurosurgeons when planning the resection of a motor-eloquent tumor, stratifying the risks of secondary neurological deficits. The combination of the two preoperative techniques is able to disclose tumor-induced neural plasticity subsequently guiding a more precise resection.

Avoiding the Blinded Funnel: A Combined Single Piece Fronto-Temporo-Orbito-Zygomatic Craniotomy Endoscopic-Assisted Approach with Multimodal Assistance for an Epidermoid Tumor of Meckel's Cave-Case Report.

A Meckel's cave tumor poses a great challenge because of the peculiar neurovascular structure of the area and the deep location. Multiple surgical approaches have been designed for this area. In this report, we describe a case treated with a combined one step single piece fronto-temporo-orbito-zygomatic craniotomy (FTOZ) endoscopic-assisted approach for the treatment of an epidermoid tumor of Meckel's cave. A 51-year-old woman presented with a clinical history of left trigeminal neuralgia and paresthesia. CT imaging revealed a left basal temporal tumor. MR showed a tumor located in Meckel's cave near the cavernous sinus, with a good enhancement after gadolinium administration. The tumor was resected through a lateral basal subtemporal extradural approach followed by an intradural approach using intraoperative neuronavigation, endoscopic assistance, neurophysiological monitoring, and an intraoperative ultrasound probe. The lesion was completely removed. No new onset neurological damage has occurred. The symptoms improved following surgery. The aesthetic appearance of the patient was respected. The combined approach with a single piece fronto-temporo-orbito-zygomatic craniotomy has enabled us to work on a wider operating field to completely remove the lesion avoiding blind spots.

Neuronavigated Retropharyngeal Anterior Screw Fixation of the Odontoid for the Treatment of C2 Type II Fractures: Case Report.

Odontoid fractures, frequently observed in patients over the age of 70, often involve the base of the axis (Anderson-D'Alonzo type 2). For surgical treatment, posterior C1-C2 fixation is the traditional method, whose fusion rates range between 93 and 100%. However, morbidity and mortality rates are high. In addition, cervical motion, especially axial rotation, is postoperatively reduced. Nakanishi and Bohler introduced the anterior screw fixation approach for the surgical treatment of odontoid fracture type II. This procedure preserves the atlantoaxial complex motion, provides immediate stability and high fracture healing rates, and, most importantly, has a low incidence of complications with good fusion rates. The surgical strategy must take into account the patient's anatomy, the morphological characteristics of the fracture, the quality of the bone, and any concomitant injuries. In this chapter, we describe a C2 type II fracture treated via a neuronavigated anterior retropharyngeal approach.

Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis of these in patients is still very unfavorable. The limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors, are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood-brain barrier, which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, a penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, a large surface area, and easy modification with molecules, which render them as suitable candidates for deliver drugs. In this review, we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas and discuss the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

A novel 3D anatomical visualization system to avoid injuries of nerves in retrosigmoid approach.

The retro-sigmoid approach (RA), widely used during different neurosurgical procedures, is burdened by the risk of injuries of the nerves that cross that region contributing to possible postoperative complications. By using, anatomage table (AT), a novel 3D anatomical visualization system, we described the nerves passing through the retromastoid area including the great occipital nerve (GON), the lesser occipital nerve (LON) and the great auricular nerve (GAN), and their courses from the origins, till terminal branches. Moreover, using dedicated software, we measured distances between the nerves and well-recognizable bony landmarks. After identifying the nerves and their distances from bony landmarks, we observed that the safest and risk-free skin incision should be made in an area delimited, superiorly from the superior nuchal line (or slightly higher), and inferiorly from a plane passing at 1-1.5 cm above the mastoid tip. The lateral aspect of such an area should not exceed 9.5-10 cm from the inion, while the medial one should be more than 7 cm far from the inion. This anatomical information has been useful in defining anatomical landmarks and reducing the risk of complications, mainly related to nerve injury, in RA. In-depth neuroanatomic knowledge of the cutaneous nerves of the retromastoid area is essential to minimize the complications related to their injury during different neurosurgical approaches. Our findings suggest that the AT is a reliable tool to enhance understanding of the anatomy, and thus contributing to the refinement of surgical techniques.

Amplification of protease-activated receptors signaling in sporadic cerebral cavernous malformation endothelial cells.

In the central nervous system, thrombin-mediated activation of protease-activated receptors (PARs) results in neuroinflammation and increased vascular permeability. These events have been linked to cancer and neurodegeneration. Endothelial cells (ECs) isolated from sporadic cerebral cavernous malformation (CCM) specimens showed dysregulation of genes involved in "thrombin-mediated PAR-1 activation" signaling. CCM is a vascular disease involving brain capillaries. In CCM, ECs show defective cell junctions. Oxidative stress and neuroinflammation play a key role in disease onset and progression. In order to confirm the possible role of thrombin pathway in sporadic CCM pathogenesis, we evaluated PARs expression in CCM-ECs. We found that sporadic CCM-ECs overexpress PAR1, PAR3 and PAR4, together with other coagulation factor encoding genes. Moreover, we investigated about expression of the three familial CCM genes (KRIT1, CCM2 and PDCD10) in human cerebral microvascular ECs, following thrombin exposure, as well as protein level. Thrombin exposure affects EC viability and results in dysregulation of CCM gene expression and, then, in decreased protein level. Our results confirm amplification of PAR pathway in CCM suggesting, for the first time, the possible role of PAR1-mediated thrombin signaling in sporadic CCM. Thrombin-mediated PARs over activation results in increased blood-brain barrier permeability due to loss of cell junction integrity and, in this context, also the three familial CCM genes may be involved.

Molecular Investigation of DKK3 in Cerebral Ischemic/Reperfusion Injury.

Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. Its role in the mechanisms of cellular degeneration and protection is still unknown. The aim of our work is to investigate the endogenous activation of the DKK3 pathway in a model of transient occlusion of the middle cerebral artery in rats. In particular, the animals were subjected to 1 h of ischemia followed by different reperfusion times (1 h, 6 h, 12 h and 24 h) to evaluate the downstream pathway and the time course of its activation. Western blot analysis showed increased Dkk3 expression in animals with the highest time of reperfusion. The increased levels of Dkk3 were accompanied by reduced Wnt3a, Frz1 and PIWI1a expression in the cytosol while FOXM1 and ß-catenin decreased in the nucleus. These molecular changes led to an increase in the apoptotic pathway, as showed by the increased expression of Caspase 3 and Bax and the reduced levels of Bcl-2, and to a decrease in neurogenesis, as shown by the decreased expression of Tbr2, Ngn2 and Pax6. In the second part of the study, we decided to employ curcumin, an activator of the Wnt/ß-catenin signaling, to investigate its effect on Dkk3. In particular, curcumin was administered 1 and 6 h after ischemia, and animals were sacrificed 24 h later when the expression of Dkk3 was higher. Our data displayed that curcumin administration decreased Dkk3 expression, and increased Wnt3a, Frz1 and PIWI1a levels. Well in line with these data, curcumin administration increased nuclear ß-catenin and FOXM1 expression. The down-regulation of Dkk3 by curcumin led to reduced apoptosis and increased neurogenesis. Summarizing, our results showed that Dkk3 acts as an inhibitor of Wnt/ß-catenin signaling during cerebral ischemia. Additionally, its inhibition and the contextual activation of the Wnt/ß-catenin pathway are protective against ischemic stroke.

Surgical management of Glioma Grade 4: technical update from the neuro-oncology section of the Italian Society of Neurosurgery (SINch®): a systematic review.

PURPOSE: The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal. METHODS: A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients. RESULTS: A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B). CONCLUSIONS: A growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity.

Minimally Invasive Surgery of Deep-Seated Brain Lesions Using Tubular Retractors and Navigated Transcranial Magnetic Stimulation-Based Diffusion Tensor Imaging Tractography Guidance: The Minefield Paradigm.

BACKGROUND: Surgical treatment of deep-seated brain lesions is a major challenge for neurosurgeons. Recently, tubular retractors have been used to help neurosurgeons in achieving the targeting and resection of deep lesions. OBJECTIVE: To describe a novel surgical approach based on the combination of tubular retractors and preoperative mapping by navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging (DTI) tractography for the safe resection of deep-seated lesions. METHODS: Ten consecutive patients affected by deep-seated brain lesions close to eloquent motor/language/visual pathways underwent preoperative nTMS mapping of motor/language cortical areas and nTMS-based DTI tractography of adjacent eloquent white matter tracts, including optic radiations. The nTMS-based information was used to plan the optimal surgical trajectory and to guide the insertion of tubular retractors within the brain parenchyma without causing injury to the eloquent cortical and subcortical structures. After surgery, all patients underwent a new nTMS-based DTI tractography of fascicles close to the tumor to verify their structural integrity. RESULTS: Gross total resection was achieved in 8 cases, subtotal resection in 1 case, and a biopsy in 1 case. No new postoperative deficits were observed, except in 1 case where a visual field defect due to injury to the optic radiations occurred. Postoperative nTMS-based DTI tractography showed the integrity of the subcortical fascicles crossed by tubular retractors trajectory in 9 cases. CONCLUSION: The novel strategy combining tubular retractors with functional nTMS-based preoperative mapping enables a safe microsurgical resection of deep-seated lesions through the preservation of eloquent cortical areas and subcortical fascicles, thus reducing the risk of new permanent deficits.

The Role of Nanotechnologies in Brain Tumors.

The treatment of glioma remains one of the most interesting topics in neurooncology. Glioblastoma multiforme is the most aggressive and prevalent malignant brain tumor. Nowadays, technologies and new tools are helping the neurosurgeons to define a tailored surgery. However, there are few pharmaceutical strategies in operated and nonoperated patients. There are still few anticancer drugs approved by FDA and EMA. Moreover, these drugs are not so effective and have a lot of side effects due to their toxicity. Nanoparticles are a new strategy which could help to create and carry new drugs. In fact, NPs improve the pharmacokinetic properties of anticancer drugs, reduce side-effects, and increase drug half-life and its selectivity. Nanoparticle drug delivery system has been studied for targeting different molecular biomarkers and signaling pathways. Furthermore, the first problem of anticancer drugs in the treatment of gliomas is penetrating the blood brain barrier which represents an insurmountable wall for most of synthetic and natural particles. In the last 15 years, a lot of researches tried to design a perfect nanoparticle both able to cross blood-brain barrier and to selectively target glioma cells, unfortunately, without great results. In vivo human trials are still ongoing and many of them have already failed. In this chapter we evaluate the effectiveness of nanotechnologies in the treatment of brain tumors. There is not yet, currently, a nanoparticle drug designed for the treatment of gliomas approved by FDA and EMA. Advancements in discovery of molecular characteristics of tumors lead to the development of targeted nanoparticles that are tested in numerous in vitro and in vivo studies on gliomas. Novel and repurposed drugs, as well as novel drug combinations, have also been already studied but those are not included in this chapter because the carried drugs (active substances) are not included among the approved anticancer drug used in the treatment of gliomas.

The Role of Nanotechnology in Spinal Cord Tumors.

The efficacy of current multimodal therapeutic strategies in spinal cord tumors is limited by the lack of specific therapies. Importantly, sufficient amount of therapeutic materials should be concentrated in tumors in order to be efficient. Overcoming the blood-brain barrier is the major obstacle for chemotherapeutics, which cannot reach the tumor bed in efficacious doses. The intrinsic properties of nanoparticles make them suitable for activating numerous processes both at the cellular and subcellular levels, making them good candidates to be used for different purposes in medicine. Furthermore, the adaptability characteristic of NPs may enable them to pass through the blood-brain barrier and transport different pharmacological compounds. Nanoparticle systems provide prolonged drug delivery directly to the tumor or by functionalizing the material surface with peptides and ligands allowing the drug-loaded material to specifically target the tumor cells. In this chapter, various preclinical and/or clinical studies in treatment of spinal cord tumors are discussed.

Treatment of Chiari III Malformation in Infant with 4K 3D ORBEYE Exoscope.

Chiari malformation (CM)-III is the rarest anomaly among CMs.1 Treatment of choice is surgical repair,2 although poor outcome and postoperative mortality has been reported.3 Surgical timing is still debated.4,5 We present the case of a male infant with a prenatal diagnosis of encephalocele. Presentation was characterized by hemodynamic instability, horizontal nystagmus, and left shoulder dystocia due to caesarean section, with a 64 mm × 49 mm × 76 mm soft, fluctuant, and translucent suboccipital-cervical sac. Magnetic resonance imaging revealed a median occipital bone defect with the meningoencephalic sac communicating with the vermian cistern and the fourth ventricle, moderate hydrocephalus, reduction of the posterior cranial fossa volume, hypoplasia of cerebellar hemispheric, vermian structures, and corpus callosum hypoplasia. The patient underwent surgery on day 4 with the use of a 4K 3D ORBEYE exoscope (Video 1). Surgery consisted of disengagement of nervous structures and repair of the neurocutaneous defect, followed on day 12 by a ventriculoperitoneal shunt with a programmable valve. The procedures were well tolerated. At the 14-month follow-up visit he was in range with growth charts (weight, height, and cranic circumference) and gained the physiologic stages of growth. He had no motor impairment but still present were convergent strabismus and mild left C5-C6 radiculopathy, secondary to shoulder dystocia. This is the first case reported in the literature of CM-III treated with the 4K 3D ORBEYE exoscope. Advantages of the exoscope were ergonomic positions for operative staff, possibility for the team to assist in the 4K 3D view, especially in cases with a narrow operative field, with a clear and detailed vision, although a learning curve is required6 to become a valid alternative in pediatric neurosurgery.

The "Combo" radiotherapy treatment for high-risk grade 2 meningiomas: dose escalation and initial safety and efficacy analysis.

PURPOSE: The subgroup "high-risk" WHO grade 2 (hRG2) meningiomas may benefit from adjuvant radiation therapy (RT), but results are still suboptimal with high rates of local progression. A dose escalation using high-conformal RT techniques needs to be evaluated in terms of efficacy and safety. We report the results of a dose-escalation study, named "Combo-RT", combining Intensity Modulated Radiotherapy (IMRT) or Volumetric Arc Therapy (VMAT) with Hypofractionated Stereotactic Radiotherapy (hSRT) boost. PATIENTS AND METHODS: From November 2015 to January 2019, we prospectively enrolled 16 patients with hRG2. Seven patients had subtotal resection (STR) and 9 patients had a recurrent tumor. All patients received Combo-RT: LINAC-IMRT/ VMAT on the surgical bed and CyberKnife-hSRT boost on residual/recurrent meningioma Toxicity and initial efficacy were evaluated. RESULTS: The median age was 62 years (range, 31-80 years). The median cumulative dose delivered was 46 Gy For IMRT or VMAT and 15 Gy in 3 fractions at a median isodose line of 77% for hSRT. The median cumulative BED and EQD2 were 108.75 Gy and 72.5 Gy respectively. 3-year-PFS was 75% for the whole cohort,100% for patients with STR, and 55.5% for recurrent patients. Negligible toxicities, and stable or improved symptoms during long-term follow-up were observed. Salvage treatment for recurrence was an independent predictor of treatment failure (P = 0.025). CONCLUSIONS: With the limitation of a small series of patients, our results suggest that a dose escalation for hRG2 meningiomas, using a Combo-RT approach, is safe and particularly effective in the subgroup of patients with STR. Further studies are warranted.

Fluorescein-guided surgery for intradural spinal tumors: A single-center experience.

•Gross total removal has a pivotal role in surgical treatment of intradural spinal tumors.•Sodium fluorescein prevents vascular injuries also preserving pial vessels in posterior myelotomy.•Fluorescence before the durotomy helps to distinguishing tumor from healthy tissue in intradural lesions.•Intraoperative fluorescence is safe and effective, also preserving functional anatomy in tumor removal.