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Novel insights on regulation of gene expression mechanisms highlight the pivotal role of epitranscriptomic modifications on decision about transcript fate. These modifications include methylation of adenosine and cytosine in RNA molecules. Impairment of the normal epitranscriptome profile was observed in several pathological conditions, such as cancer and neurodegeneration. However, it is still unknown if alteration of this regulatory mechanism can be involved in cerebral cavernous malformation (CCM) development. CCM is a rare genetic condition affecting brain microvasculature, resulting from mutations in the three genes KRIT1, CCM2, and PDCD10. By data integration of association study, in silico prediction, and gene expression analysis, we evaluated role of single nucleotide polymorphisms (SNPs) highly recurrent in patients with CCM, on CCM gene expression regulation. Results showed that several of these SNPs lead to a drastic downexpression, in KRIT1 and CCM2 genes and this downregulation can be due to alteration of epitranscriptome profile, occurring these SNPs in gene regions that are subject to epitranscriptome modifications. These data suggest that this novel mechanism of gene expression regulation can be consider to further investigation on CCM pathogenesis.

Background: Rhinocerebral mucormycosis (ROCM) is an opportunistic fungal infection originating from the paranasal sinuses with extension to the brain. A delayed diagnosis can rapidly result in a poor prognosis. ROCM commonly affects patients with diabetes or immunocompromised states with a variable progression. Case Description: We report the case of a 59-year old patient with an untreated diabetes who developed a ROCM with rapidly progressive neurological symptoms. From the onset of sinus pain, nasal congestion, he rapidly developed facial swelling and masticatory dysfunction. The patient underwent sinus surgery which allowed Rhizopus oryzae to be isolated. Accordingly, a systemic therapy by intensive intravenous amphotericin B was started. Nevertheless, the infection rapidly resulted in bilateral cavernous sinuses thrombosis and occlusion of the left internal carotid artery providing the subsequent patient death. Conclusion: Mucormycosis is a life-threatening fungal infection in diabetic and/or immunosuppressed patients. Our case demonstrates the three main mechanisms for infection spreading that are direct, perineural, and perivascular diffusion. Clear identification of the main risk factors, proper assessment of clinical features, and radiological findings may improve the chance for an early diagnosis and patient survival.

Background We present an unusual but possible complication after ETV for the treatment of acute hydrocephalus due to malfunction of a previously implanted V-P shunt. Case Description A 12-year-old male patient was urgently operated upon by means of an endoscopic third-ventriculostomy and the positioning of a temporary external ventricular catheter because of the malfunction of a previously implanted V-P shunt; immediately after the operation, the tip of the external catheter caused an obstruction of the ostomy, which was resolved with the withdrawn of catheter for circa 1 cm, left closed and ultimately removed after 4 days. The patient did not present any further symptom and remained shunt-free at the last 2-year follow-up visit. Conclusions One should consider such occurrence in cases of early ETV failure when a ventricular catheter is left in situ, even though temporarily.

Cerebral cavernous malformations (CCM) are lesions affecting brain capillaries that appear with a mulberry-like morphology. This shape results from the enlarged and tangled microvessels having defective endothelial cell junctions, few surrounding pericytes and dense extracellular collagen-rich matrix. Three genes KRIT1, CCM2 and PDCD10 are linked to disease onset. However, a variable percentage of patients harbour no mutations at these loci, encouraging hypothesis of further genetic factors involved in CCM pathogenesis. Here we present data obtained by transcriptome analysis on endothelial cells isolated by CCM specimens, with the aim to identify dysregulated pathways involved in lesion onset. Lesions belonged to two patients carried neither germline nor somatic mutations at the three CCM genes. By comparison with Human brain microvascular endothelial cells (HBMECs) expression profile, we identified 1325 differentially expressed genes (Bonferroni pValue

Background: Hirayama disease (HD) is a rare, benign, and self-limiting motor neuron disorder that results in selective motor impairment of the C7-T1 myotomes. It is characterized by progressive, unilateral, or bilateral asymmetric muscle atrophy of the distal upper extremities and myelopathy. Case Description: A 23-year-old male presented with bilateral atrophy of the thenar/hypothenar eminences/ interosseous muscles, plus left-hand weakness. The cervical MRI documented subacute ischemic damage of the distal cervical cord. To rule out a tumor and reduce questionable cord compression, the patient underwent a C5–C6 anterior cervical discectomy and fusion (ACDF) immediately followed by a laminectomy with durotomy and to obtain a spinal cord biopsy. When the histology confirmed focal cord ischemia consistent with HD, it was clear that both operations were unnecessary. Conclusion: Establishing the diagnosis of HD is based on clinical findings and MRI/flexion MR features which include the demonstration of an increased T2-weighted intramedullary cord signal, enlargement of the posterior epidural space, and segmental spinal cord atrophy. The presence of HD should be recognized as a “nonsurgical entity,” and conservative nonsurgical management should be employed.

Brain edema after severe traumatic brain injury (TBI) plays an important role in the outcome and survival of injured patients. It is also one of the main targets in the therapeutic approach in the current clinical practice. To date, the pathophysiology of traumatic brain swelling is complex and, being that it is thought to be mainly cytotoxic and vasogenic in origin, not yet entirely understood. However, based on new understandings of the hydrodynamic aspects of cerebrospinal fluid (CSF), an additional mechanism of brain swelling can be considered. An increase in pressure into the subarachnoid space, secondary to traumatic subarachnoid hemorrhage, would result in a rapid shift of CSF from the cisterns, through the paravascular spaces, into the brain, resulting in an increase of brain water content. This mechanism of brain swelling would be termed as “CSF-shift edema.”. This “CSF-shift,” promoted by a pressure gradient, leads to increased pressure inside the paravascular spaces and the interstitium of the brain, disturbing the functions of the paravascular system, with implications of secondary brain injury. Cisternostomy, an emerging surgical treatment, would reverse the direction of the CSF-shift, allowing for a decrease in brain swelling. In addition, this technique would reduce the pressure in the paravascular spaces and interstitium, leading to a recovery of the functionality of the paravascular system. © 2017 Wiley Periodicals, Inc.

Background The differential diagnosis between radiation necrosis, tumor recurrence and tumor progression is crucial for the evaluation of treatment response and treatment planning. The appearance of treatment-induced tissue necrosis on conventional Magnetic Resonance Imaging (MRI) is similar to brain tumor recurrence and it could be difficult to differentiate the two entities on follow-up MRI examinations. Dynamic Susceptibility Contrast-enhanced (DSC) and Dynamic Contrast-Enhanced (DCE) are MRI perfusion techniques that use an exogenous, intravascular, non-diffusible gadolinium-based contrast agent. The aim of this study was to compare the diagnostic accuracy of DSC and DCE perfusion MRI in the differential diagnosis between radiation necrosis and tumor recurrence, in the follow-up of primary and metastatic intra-axial brain tumors after Stereotactic RadioSurgery (SRS) performed with CyberKnife. Methods A total of 72 enhancing lesions (57 brain metastases and 15 primary brain tumors) were analyzed with DCE and DSC, by means of MRI acquisition performed by 1,5 Tesla MR scanner. The statistical relationship between the diagnosis of tumor recurrence or radiation necrosis, decided according to clinicoradiologically criteria, rCBV and Ktrans was evaluated by the point-biserial correlation coefficient respectively. Results The statistical analysis showed a correlation between the diagnosis of radiation necrosis or recurrent tumor with Ktrans (rpb = 0.54, p

Cerebrovascular malformations include a wide range of blood vessel disorders affecting brain vasculature. Neuroimaging differential diagnosis can result unspecific due to similar phenotypes of lesions and their deep localization. Next-generation sequencing (NGS) platforms simultaneously analyze several hundreds of genes and can be applied for molecular distinction of different phenotypes within the same disorder's macro-area. We discuss about the main criticisms regarding molecular bases of cerebral cavernous malformations (CCM) and brain arteriovenous malformations (AVM), highlighting both common pathogenic aspects and genetic differences leading to lesion development. Many recent studies performed on human CCM and AVM tissues aim to detect genetic markers to better understand molecular bases and pathogenic mechanism, particularly for sporadic cases. Several genes involved in angiogenesis show different expression patterns between CCM and AVM, and these could represent a valid starting point to project a NGS panel to apply for differential cerebrovascular malformation diagnosis.

Background: Osteomyelitis is a progressive infection of bone and bone marrow by microorganisms, resulting in inflammatory destruction of bone, bone necrosis, and new bone formation. Skull involvement is a rare occurrence which mainly affects children with chronic inflammatory diseases of paranasal sinusitis, or malignant otitis. In adults, cranial vault osteomyelitis can occur after cranial surgery or head trauma. Case Description: We describe an unusual case of chronic cranial osteomyelitis occurred 3 months following a mild traumatic brain injury. The causative mechanisms along with the diagnostic modalities are discussed. Conclusion: Focal cranial vault osteomyelitis, in the absence of severe trauma, can be challenging to diagnose. Imaging findings and patient history should be carefully investigated to make a correct diagnosis.

The need to improve surgical efficacy in patients affected by high-grade gliomas has led to development of advanced pre-surgical MRI-based techniques such as tractography. This study investigates pre-surgical planning of optic radiations (ORs) in patients affected by occipito-temporo-parietal high-grade gliomas, by means of constrained spherical deconvolution (CSD) and diffusion tensor imaging (DTI) tractography. Twelve patients with occipito-temporo-parietal high-grade gliomas were recruited and analyzed using a 3 T MRI scanner. Diffusion-weighted imaging (DWI) was conducted with 64 gradient diffusion directions. OR alterations were assessed qualitatively and quantitatively to evaluate the effectiveness of CSD- and DTI-based pre-surgical planning. CSD-based tractography provided better qualitative evaluation of affected white matter tracts when compared to DTI; by thresholding tractographic probabilistic maps coming from all reconstructions, we detected, at the highest cutoff level, OR involvement in 75 % of patients (vs 41.67 % of patients with probabilistic DTI). Quantitative analysis of diffusion parameters revealed a statistically significant decrease in fractional anisotropy (FA) in the affected side following CSD-based reconstructions; on the contrary, DTI-based reconstructions did not show any significant quantitative alteration. Our results showed improvement in pre-surgical planning of high-grade gliomas involving ORs with use of CSD-based tractography. This technique provided more useful information regarding the white matter spatial relationship with brain neoplasm and its involvement in the glioma, when compared to DTI. Using CSD model for OR evaluation may optimize safe surgical resection margins, helping to reduce risk of post-operative visual deficits.

Purpose The aim of this work was to investigate the diagnostic value of the DIR sequence at 3T MR imaging operating in the evaluation of cortical development anomalies. Methods We studied 40 patients, with a previous diagnosis of cortical dysplasia, by FLAIR-3D, DIR, FSE T2 and MPR-GE T1 sequences at 3T MRI. Two independent observers evaluated, for each sequence and lesion, some semiological aspects (cortical thickness, cortical signal intensity, white-gray matter blurring, subcortical white matter intensity). We made also a quantitative evaluation of the cortical signal intensity in lesion site, drawing a ROI on each MRI sequences and comparing them to the correspondent normal contralateral cortical area. Results We identified 44 cortical development anomalies. Qualitative analyses showed a high level of agreement between the observers concerning DIR potentialities in detecting and characterizing the cortical development disorders. Particularly DIR sequence was able to demonstrate the blurring and the subcortical white matter anomalies. The quantitative analyses didn’t show a significant difference between DIR and traditional sequences in the evaluation of the cortical signal intensity. Conclusion 3T MRI-DIR sequence is a useful and better suitable sequence compared to the traditional sequences in the characterization of some semiological aspects of the cortical development disorders, particularly blurring and subcortical white matter hyperintensity.

Background Unruptured intracranial aneurysms (UIAs) are increasingly identified and are an important health-care burden; in the past they were commonly treated by surgical clipping, but nowadays endovascular coil embolization is increasingly employed as an alternative. Methods The Unruptured Aneurysms Italian Study (UAIS) is a multicentric cooperative prospective study aimed to delineate the "State of the Art" of UIAs treatment in Italy. 51 Italian Neurosurgical and Neuroradiological Units, representatives of all 20 Italian regions are involved in the Study. Results UAIS started on June 2003 and ended on July 2007. 1138 patients were collected by that date, but 181 were ruled-out due to severe violation of the protocol; 957 had complete data and could be statistically evaluated. Conclusions UAIS demonstrates that the treatment of UAs, as performed in Italy as a Nation, is effective in improving long-term outcome vs. natural history, particularly in aneurysms larger than 7 mm.

Background: The most common etiology of classic trigeminal neuralgia (TN) is vascular compression. However, other causes must be considered. Among these, spontaneous hematoma of the Meckel′s cave (MC) causing symptomatic TN is very rare. Case Description: We present the case of a 60-year-old woman with a 2-month history of left TN and diplopia. Neuroradiological examinations revealed a well-defined hematoma in the left MC. The patient underwent surgical decompression with a progressive neurological improvement. Conclusion: Despite the number of lesions potentially affecting the MC, spontaneous hemorrhage is rare but should be taken into account in the differential diagnosis.

Background An understanding of the natural history of unruptured intracranial aneurysms (IAs) has always played a critical role in presurgical or endovascular planning, to avoid possibly fatal events. Size, shape, morphology, and location are known risk factors for rupture of an aneurysm, but morphologic parameters alone may not be sufficient to perform proper rupture risk stratification. Methods We performed a systematic PubMed search and focused on hemodynamics forces that may influence aneurysmal initiation, growth, and rupture. Results We included 223 studies describing several hemodynamic parameters related to aneurysm natural history. In these studies, different modalities of aneurysm model creation have been used to evaluate flow and to comprehensively analyze the evolution of IAs. Controversy exists about the correlation between these parameters and initiation, growth, rupture risk, or stabilization of the aneurysmal sac. Recent findings have also shown the importance of flow patterns in this process and the relationship between unruptured IA geometry and hemodynamic parameters. Conclusions The role of hemodynamic forces in evaluation of the natural history of unruptured IAs presents is inherently complex and is still not completely understood. In this complex scenario, although several attempts have been described in the literature, a proper risk rupture stratification and treatment strategy selection based on hemodynamic forces has not yet been created. Further efforts should be made to accomplish this important goal. © 2017 Elsevier Inc.

A 42-year-old woman presented with progressive blurred vision, vertigo, and headache. MRI showed bilateral intraocular protrusion of the optic nerve head and right transverse sinus thrombosis . Low-molecular-weight heparin was administered without symptom relief. Additional MRI showed left frontoparietal arachnoid space obliteration by pathological tissue, and infiltration of the sagittal and right transverse sinuses. After Gd administration, we observed diffuse enhancement of the dura in the left cerebral hemisphere and subdural and epicranial soft-tissue infiltration . A biopsy of the extra-axial tissue was performed. Histological examination showed a neoplasm composed of large cells with ovoid nuclei associated with non-neoplastic lymphocytes. Frequent mitotic figures were observed in the large cells. The large neoplastic cells were positive for CD20, bcl-2, bcl-6, and MUM1 and negative for CD10 and CD30. Accordingly, a diffuse infiltrative form of Bing-Neel syndrome was diagnosed. The patient was treated with 3 cycles of rituximab, dexamethasone, methotrexate HD, and cytarabine. Osmotic and steroid therapies were undertaken.

Background: Intramedullary spinal ependymoma is a tumor, hardly characterizable with conventional magnetic resonance (MR) imaging only. MR diffusion tensor imaging (DTI) with three dimensional fiber tracking reconstructions allows the evaluation of the relationship between neoplasm and white matter fiber tracts, being a powerful tool in presurgical planning. We present DTI findings in a case of a young female with an extensive cervicothoracic spinal ependymoma. Case Description: The patient complained of a 2 month history of acute urinary retention, weakness and numbness on the lower limbs and the upper left limb. She underwent MR imaging that showed an extensive cervicothoracic spinal mass, difficult to characterize with conventional MR sequences. DTI showed peripherally displacement of fibers, without involvement of the spinal cord, findings consistent with an ependymoma. The patient underwent surgery with a complete resection "en bloc" of the lesion, which showed clear cleavage planes, as detected by DTI. Histopathological findings confirmed the diagnosis of ependymoma. Conclusions: DTI is a useful tool in presurgical planning, helping in differentiating not infiltrating neoplasms, such as spinal ependymomas, from other infiltrative and more aggressive neoplasms, which are considered not resectable. © 2017 Surgical Neurology International | Published by Wolters Kluwer - Medknow.

Following aneurysmal subarachnoid hemorrhage, the primary goal of treatment is to exclude the vascular malformation from the intracranial circulation, while preserving the parent artery. In unruptured aneurysms, the decision whether to treat or observe the malformation is made on a case-by-case basis. In this regard, the ISUIA (International Study of Unruptured Intracranial Aneurysms) investigators suggested that aneurysm size and location were independent predictors for aneurysm rupture.1 ISUIA examined 1692 patients with cerebral aneurysms with a mean follow-up time of 4.1 years. Rupture rates differed depending on size and location, ranging from 0% in aneurysms 25 mm located in the posterior circulation. More recently, UCAS (Unruptured Cerebral Aneurysm Study) reported results similar to ISUIA. However, other evidence has contradicted these studies, with a higher percentage of small aneurysms reported among case series of ruptured intracranial aneurysms. This indicates a discrepancy between the ISUIA and UCAS data and the size of ruptured aneurysms seen in routine clinical practice.

Cerebral cavernous malformations (CCMs) are clusters of capillaries in the brain that may cause focal deficits or seizures in affected patients. They occur in both sporadic and inherited autosomal dominant form. Germline mutations in CCM1, CCM2 and CCM3 were identified in familial cases. Over the past 13 years we performed sequencing and MLPA of the CCM genes in all sporadic and familial CCM cases coming from some hospital clinics of Neurology and Neurosurgery of Messina and other Italian cities. Our results showed that CCM sporadic patients, negative for previously reported CCM gene causative mutations, always carried known CCM polymorphisms. Previously, we reported polymorphisms in CCM2 gene associated with an increase in risk for CCM. Here, we undertook a case-control study to investigate the possible association of others polymorphisms (c.485 + 65 C/G, c.989 + 63 C/G, c.1980 A/G in CCM1 gene, c.472 + 127 C/T in CCM2 and c.150 G/A in CCM3) with CCMs. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Statistically significant differences in frequencies between patients and controls were found for c.485 + 65C/G, c.1980 A/G and c.472 + 127C/T polymorphisms. For c.485 + 65C/G polymorphism, a higher frequency of mutated allele (G) was found in patients group (9%) than in controls (2%) (p = 0.0041); for c.1980 A/G polymorphism, we found a frequency of mutated allele (G) higher in the control group (25%) compared to that of patients (8%) (p = 0.0396). Same trend was observed for c.472 + 127C/T polymorphism (T allele frequency = 34% and 6% in control group and patients, respectively; p = 0.0001). Polymorphisms c.485 + 65C/G, c.1980 A/G and c.472 + 127C/T were associated with an increased risk of CCM as indicated by odds ratio values. Furthermore, c.1980 A/G and c.472 + 127C/T polymorphisms were associated with less severe CCM symptomatology. Identification of these polymorphisms in CCM sporadic patient may represent a useful tool for clinicians to determine prognosis, scheduled periodic checks and appropriate treatment strategy.

External hydrocephalus (EH) is a benign clinical entity in which macrocephaly is associated with an increase in volume of the subarachnoid space, especially overlying both frontal lobes, and a normal or only slight increase in volume of the lateral ventricles. Several pathogenic hypotheses have been proposed but the most accredited theory seems to be delayed maturation of the arachnoid villi. There is a consensus that this is a benign entity, correlated to a familial predisposition and, in some cases, inheritance. CT and MRI are very important to make a diagnosis but also to establish the prognosis in patients who encounter the rare complications such as subdural haematomas. In conclusion, CT and MRI can provide a highly accurate diagnosis in these patients, allowing a preliminary assessment of the prognosis, particularly regarding the enlarged subarachnoid space limits and the “cortical vein” sign which can predict a further complication. These results are obtained with the same examination performed in a standard CT or MRI study of the brain and no injection of contrast medium is needed.

Background Cerebral cavernous malformations (CCMs) are vascular anomalies of the nervous system mostly located in the brain presenting sporadically or familial. Causes of familial forms are mutations in CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10) genes. Sporadic forms with no affected relative most often have only one lesion and no germ line mutations. However, a number of sporadic cases with multiple lesions have been reported and are indeed genetic cases with a de novo mutation or a mutation inherited from an asymptomatic parent. Methods Here, we performed an analysis of regulatory region of CCM genes in 60 sporadic patients, negative for mutations in coding region and intron-exon boundaries and large deletion/duplications in CCM genes by direct sequencing and MLPA. Among 5 variants identified in 851-bp region shared by CCM3 and SERPINI1 genes and acting as asymmetric bidirectional promoter, two polymorphisms c.-639 T > C/rs9853967 and c.-591 T > C/rs11714980 were selected. A case-control study was performed to analyze their possible relationships with sporadic CCMs. Promoter haplotypes activities on CCM3/SERPINI1 genes expression were tested by dual-luciferase assay. Results No variants were identified in CCM1 and CCM2 regulatory regions. In CCM3/SERPINI1 asymmetric bidirectional promoter 5 variants, 2 of them unknown and 3 corresponding to polymorphisms c.-639 T > C/rs9853967, c.-591 T > C/rs11714980 and c.-359G > A/rs9834676 were detected. While rs9853967 and rs11714980 polymorphisms fall in a critical regulatory fragment outside the minimal promoter in intergenic region, other variants had no effects on transcription factor binding according to RegRNA tool. Case-control study performed on 60 patients and 350 healthy controls showed frequencies of the mutated alleles significantly higher in the control group than in patients. Furthermore, the functional assay showed a significant reduction of CCM3 expression for C-C haplotype even more than for T-C and C-T haplotypes. In SERPINI1 direction, the reduction was not statistically significant. Conclusions Our data indicated that rs9853967 and rs11714980 polymorphisms could be associated with a protective role in CCM disease.

Background: Eagle syndrome (ES) is a rare symptomatic condition generally caused by an elongated styloid process (SP) or calcification of the stylohyoid complex. On the diagnosis is made, its treatment remains subjective since the indications for surgical intervention are still not standardized. Although styloidectomy is the surgical treatment of choice, no consensus exists regarding the transcervical or/and transoral route. Here, we report our experience in a patient with bilateral internal carotid artery (ICA) dissection caused by ES, who underwent innovative surgical technique. Case Description: A 53-year-old man, with the right-sided middle cerebral artery acute stroke, underwent computed tomography angiography 3 days after a successful endovascular treatment. The study showed a bilateral ICA dissection with bilateral hypertrophic SPs and a close relationship of ICAs with both SPs anteriorly and C1 transverse process posteriorly. Considering the occurrence of ICA compression by a styloid/C1 transverse process juxtaposition, the patient underwent the left partial C1 transversectomy by an extraoral approach. A temporary paresis of the ipsilateral lower lip lasted 1 month, with a partial remission after 3 months. The patient reported significant improvement of symptoms with a good esthetics and functional outcome. Conclusion: A styloid/C1 transverse process juxtaposition should be considered as an alternative pathogenetic mechanism in vascular ES. When a posterior ICA compression by C1 transverse process is present, a bone reshaping of C1 rather than a conventional styloidectomy can be considered an efficacious treatment which allows a good preservation of the styloid muscles and ligaments.

Tumors of the spine with an intradural location have an incidence ranging from 3 to 10 per 100,000 persons per year, and intradural extramedullary tumors account for two thirds of all intraspinal neoplasms. Among these, spinal meningiomas account for 25%–46% of all spinal cord tumors. They develop from the arachnoid cells that differentiate from neural crest cells and, like cerebral meningioma, they have a slow-growing behavior. Although spinal meningiomas are not uncommon, calcified spinal meningioma is rare in spinal location. Calcified meningioma manifests with extensive matrix and tends to infiltrate the surrounding structures. It exhibits a growth pattern limited by an incompletely developed intermediate leptomeningeal layer. This pattern makes such a tumor different from the commonly encountered meningioma that develops into a variable interface in the small space confined between the arachnoid and the intermediate leptomeningeal spaces. Because the intraspinal spaces are much smaller than intracranial spaces, symptoms usually appear rapidly compared with intracranial tumors.

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

Object Meningiomas constitute 25% of primary spinal tumors and predominantly involve the thoracic spinal cord. Although calcifications are commonly seen in intracranial meningiomas, gross calcifications are observed in only 1–5% of all spinal meningiomas. We report the clinical findings, surgical strategy and histological features of 9 patients with ossified spinal meningiomas (OSMs). Patients and methods Clinical and surgical features of 9 patients with ossified spinal meningiomas were retrospectively reviewed. Results There were 8 women and 1 man with a mean age of 59 years. In 7 patients, the lesions were localized in the thoracic segment of the spine while in 2 patients in the lower cervical segment. All patients presented with weakness of the lower limbs and hypoesthesia below the site level of the lesion. Only 2 patients presented with urinary incontinence. Gross-total resection of the tumor was achieved in 6 patients while in 3 a subtotal removal of the meningioma was obtained. In all patients the postoperative course was uneventful. Six patients presented with a significant neurological improvement while in 3 patients a mild improvement was observed. Microscopically, all tumors showed typical histological pattern of ossified meningioma. Conclusions OSMs are amenable to surgery if the complete removal can be achieved. Because of their hard-rock consistency complete resection can be challenging. In difficult cases, subtotal removal can be advised and follow-up imaging is mandatory. Overall, the risk of long-term recurrence of the lesions is low, and a good clinical outcome after total or subtotal removal can be expected.

The transformation of normal cells into neoplastic cells is based on a series of gradual and progressive processes . One of the most important aspects underlying the tumorigenesis ist hat neoplastic proliferation needs mechanisms to ensure cancer development, bypass the body's protective strategies, and survive the apoptotic mechanisms. Subsequently, measures to promote replicative immortality and vascular support will be required. If cancer develops in an area offering excellent vascularization, pre-existing vascular circuits can supporti ts growth .Otherwise,tumor angiogenetic mechanisms will trigger new vascular networks, which will be necessary for tumor survival and expansion. The latter occurrence is what takes place in most of the neoplasms characterized by high growth pattern: proangiogenic factors secreted by the tumor, the most important being the vascular endothelial growth factor (VEGF), create a chemotactic gradient able to recruit endothelial cells and pericytes from the existing vascular system .

Chordomas are midline tumors that arise from embryonic remnants of the notochord and are considered to be malignant tumors because of their tendency to invade and destroy the involved bone. Cases of intradural chordomas without bone involvement have been rarely described with a predilection for prepontine location. The absence of bony invasion renders the complete excision of these tumors more feasible and is related to their better prognosis in comparison to conventional chordomas. Herein we report the first intradural chordoma arising in the Meckel's cave. The intradural location of the lesion, outside midline structures, in the absence of bone infiltration, made the differential diagnosis versus other meningeal lesions such as chordoid meningioma challenging. The intense and strong immunohistochemical expression of pan-cytokeratins, S100, cytokeratin-19 and of the notochordal marker brachyury allowed differential diagnosis toward other tumors showing chordoid morphology. The expression of brachyury, which had not been previously analyzed in intradural chordoma, definitely links the histogenesis of this neoplasia to the notochord, similar to that of conventional chordoma. We also show that, different from conventional chordoma, intradural chordoma does not express the metallo-proteinases (MMPs) -2 and -9, which may account for its indolent biological behavior.

Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. From the Clinical Editor In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.

The efficacy of current anti-cancer multimodal therapeutic strategies in gliomas is limited by the lack of specific therapies against malignant cells and the prognosis in patients affected by cerebral gliomas remains very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of neoplastic cells when they combine with the extracellular matrix through the up-regulation of crucial pathways such as angiogenesis and invasion. The major problem in brain drug delivery is the presence of the blood brain barrier which limits the delivery of many chemotherapeutic agents and other kinds of therapeutic molecules. This event often contributes to the failure of the treatment. Nanoparticle systems can represent ideal devices for delivery of specific compounds to brain tumors across the blood brain barrier. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of angiogenesis into gliomas, their importance into tumor progression and the possibilities to block these mechanisms with new nanoparticle-based therapeutic strategies. We will also report the results of preclinical and/or clinical studies that adopt nanoparticle-based antiangiogenic therapeutic approach in cerebral gliomas, considering also some patents deal with antiangiogenic strategy.

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three-gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at-risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified,nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255-4delGTA; c.1682-1683 delTA in CCM1; c.48A > G; c.82-83dupAG in CCM2; and c.395 + 1G > A in CCM3 genes [corrected].The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at-risk relatives.

We read with great interest the article by Gazzeri et al1 focusing on tissue-glue–coated collagen sponge (TachoSil) application to repair minor cerebral dural sinus lacerations. In their series, 57 consecutive patients were prospectively enrolled, and tears of the cerebral venous sinus were treated by TachoSil application directly to the site of the bleeding. In all patients, venous bleeding was managed initially by standard techniques for hemostasis such as compression, application of oxidized cellulose, or gelatin sponge. TachoSil application was used when standard measures failed to be effective, were excessively time- consuming or inadequate, or were considered risky. No complications related to the use of the hemostatic device were observed, and the authors concluded that the use of such an agent may shorten the surgical procedure and achieve hemostasis in potentially hazardous bleeding from minor tears of the cerebral venous sinus.

Background A noninvasive method to predict the grade of a meningioma would be desirable since it would anticipate information about tumour nature, recurrence and improve tumour management and outcomes. The aim of the present study was to assess the ability of perfusion computed tomography (PCT) technique in predicting the meningioma grade before surgery. Data from PCT, such as cerebral blood volume (CBV) and permeability surface (PS), were correlated with immunohistolopathological information. Methods Twenty-three patients with a diagnosis of intracranial meningioma underwent PCT for pre-surgical evaluation of CBV and PS. During surgery, samples from the centre and periphery of the tumour were obtained. Two correspondent regions of interest (ROIs) were drawn on CBV and PS maps. Central and peripheral CBV and PS mean values were calculated. PCT parameters were correlated to CD-34 and endoglin. Results There was a positive correlation between PS and CD-34. No correlation was found between PS values and endoglin, CBV values and CD-34 and endoglin values. Conclusion Our findings suggest that PCT may support conventional morphological imaging in predicting meningioma grading before surgery.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. It is estimated that each year TBIs are associated with 1.1 million emergency department visits, 235,000 hospitalizations, and 50,000 deaths (1). Despite improvements in medical interventions, there are still no neuroprotective agents available to counteract secondary or delayed damage to the traumatically injured human brain or to promote its repair. TBI encompasses heterogeneous etiologic, anatomical, and molecular patterns of injury that exhibit different propensities to cause cerebral damage. Without careful consideration of individual injuries, the results of therapeutic trials remain difficult to interpret.

Rare Neural Tube Defect: Type I Split Cord Malformation and Spinal Neurenteric Cyst in an Adult Objective: Split cord malformation (SCM) is a rare form of closed neural tube defect characterized by a sagittal splitting of the spinal cord. Pang’s classification distinguishes a type I SCM (diastematomyelia with septum) and a type II SCM (true diplomyelia). SCM typically presents in childhood and, rarely, in aduls. Neurenteric cysts are composed of heterotopic endodermal tissue. They usually have an intradural extramedullary location, ventrally or ventrolaterally to the spinal cord. Less frequently, the cyst may be located posteriorly to the spinal cord, within the cord, or within the cleft of a diastematomyelia. Methods: We reported a 56-year-old woman with a 4-month history of severe back pain and paresthesia on the right flank. MRI revealed, at T9-T11 level, the coexistence of a type 1 SCM and an intradural extramedullary neurenteric cyst. The patient underwent surgery. Results: Following a T9-T11 laminectomy, a posterior median incision of the dura was performed to expose the cystic thin-walled translucent membrane. The wall was opened with drainage of a whitish fluid and the cyst membrane was totally removed “en-bloc”. After the operation, the patient referred complete disappearance of the dorsolumbar pain. There was no deterioration of neurological status. The patient was discharged on 7th day post-operatively. Conclusion: The association between diastematomyelia and neurenteric cyst represents a very rare condition, especially in adulthood, in spite of their possible common embryological origin. The symptoms are usually related to the spinal cord compression caused by the cyst; therefore, the surgical excision of the cyst is effective.

BACKGROUND: Glossopharyngeal neuralgia (GN) is a rare condition characterized by severe, paroxysmal episodes of pain mainly localized to the external ear canal, pharynx, and tongue, usually caused by a neurovascular conflict between postero-inferior cerebellar artery (PICA) and IX cranial nerve. Sometimes there is also a compression of X c.n. CASE DESCRIPTION: We present a case of a 71-year-old female with a 3-year history of intense pain localized in the pharynx and posterior portion of the tongue. Preoperative magnetic resonance imaging (MRI) documented a neurovascular conflict between a loop of PICA and IX left c.n. Surgery was performed through a retrosigmoid craniectomy. The intraoperative findings documented a loop of PICA compressing IX, X, and XI c.n. Microvascular decompression (MVD) of IX c.n. was performed using the interposing technique. No rhizotomy and MVD of the X c.n. was performed. Postoperative course showed the regression of all symptoms. CONCLUSIONS: The surgical treatment of patients with GN caused by complex neurovascular conflicts can be safely performed with the classical MVD of IX c.n. A double MVD of both IX and X c.n. has a role only in patients presenting symptoms from both nerves. Rhizotomy, in our opinion, has to be avoided in all cases. The authors review the literature concerning GN caused by complex neurovascular conflicts.

Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage.

Introduction: Klippel-Feil syndrome is characterized by a congenital fusion of cervical vertebrae. Intracranial teratomas are nongerminomatous germ cell tumors and they account for 0.3 to 0.9% of all intracranial tumors. Teratomas with malignant transformation refer to lesions which give rise to malignant cancer of somatic type. The association between tumors of dermoid origin and Klippel-Feil malformation is extremely rare. Only 23 other cases have so far been reported, and only one case of dermoid tumor with areas of dedifferentiation on squamous cell carcinoma has been described. Case presentation: We report the case of a 72-year-old white man with a 2-year history of gait and balance disturbances. A brain magnetic resonance imaging revealed a fourth ventricle neoplastic process with infiltrative features. He was operated through a suboccipital craniectomy with a C1 laminotomy and bilateral vertebral artery transposition. At 6-months follow-up, magnetic resonance imaging showed an early regrowth of the fourth ventricle tumor, with the same radiological features. Conclusions: Patients with Klippel-Feil malformation could develop posterior fossa dermoid tumors. The malignant potential of such tumors must be considered and surgery is recommended. Particular attention must be focused on the histopathological analysis in order to identify possible foci of malignant transformation.

BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy ( z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient ( z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient ( z = −2.51, n = 20, P = .006; z = −2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract ( z = −2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.

OBJECTIVE Total brain water content changes in several cerebral pathological conditions and the measurement of brain water content are important for the selection of appropriate therapeutic procedures. We present a quantitative, in vivo, bioelectrical impedance analysis (BIA) method and propose its use for the accurate assessment of brain water content among human subjects. METHODS Cerebral BIA is based on the conduction of an applied current in the brain parenchyma. Application of an excitatory current of 800 microA at 50 kHz, via two electrodes placed on the eyelids with the eyes closed, and detection of the voltage drop with two electrodes placed in the suboccipital region allow brain resistance and reactance to be measured. By means of an equation that considers cranial circumference and resistance, it is possible to quantify the total brain water content, expressed as the bioelectrical volume. Cerebral BIA was performed with a series of healthy volunteers (n = 100), for determination of average brain water content values. The method was then applied to 50 patients with brain tumors (n = 20), intracranial hemorrhage (n = 16), or hydrocephalus (n = 14), for assessment of changes in global brain water contents. Data were compared with those obtained for healthy volunteers. RESULTS Statistically significant differences (P < 0.001) were observed between the two groups. Mean brain water content values (expressed as bioelectrical volume values) were 38.2 +/- 3.9 cm2/Omega for healthy volunteers and 67.7 +/- 13.1 cm2/Omega for patients with cerebral pathological conditions. Statistically significant differences (P < 0.05) were also observed among patients with cerebral pathological conditions. CONCLUSION The results of this study suggest that BIA, applied to the cerebral parenchyma, is a valid method for the prediction of brain water contents under both normal and pathological conditions. However, further studies are needed to establish whether it is sensitive and reliable enough for future clinical applications.

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 ( n = 8), control; group 2 ( n = 8), control plus placebo; group 3 ( n = 8), control plus r-Hu-EPO; group 4 ( n = 8), SAH; group 5 ( n = 8), SAH plus placebo; group 6 ( n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations ( P < 0.001), and reduced vasoconstriction of the basilar artery ( P < 0.05), ischemic neuronal damage ( P < 0.001), and subsequent neurological deterioration ( P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.