Hemangioblastomas and Other Vascular Origating Tumors of Brain or Spinal Cord.

Hemangioblastomas (HBs) are highly vascularized, slow-growing, rare benign tumors (WHO grade I). They account for about 2% of intracranial neoplasms; however, they are the most common primary cerebellar tumors in adults. Another frequent seat is the spinal cord (2-10% of primary spinal cord tumors). HBs are constituted by stromal and capillary vascular cells; macroscopically, HBs appear as nodular tumors, with or without cystic components. Although most of the HBs are sporadic (57-75%), they represent a particular component of von Hippel-Lindau disease (VHL), an autosomal dominant syndrome with high penetrance, due to a germline pathogenic mutation in the VHL gene, which is a tumor suppressor with chromosomal location on the short arm of chromosome three. VHL disease determines a variety of malignant and benign tumors, most frequently HBs, renal cell carcinomas, pheochromocytomas/paragangliomas, pancreatic neuroendocrine tumors, and endolymphatic sac tumors. Up to 20% of cases are due to de novo pathogenic variants without a family history. Many epidemiologic details of these tumors, especially the sporadic forms, are not well known. The median age of patients with sporadic HBS is about 40 years. More than two-third of VHL patients develop one or more central nervous system HBs during their lifetime; in case of VHL, patients at first diagnosis are usually younger than the patients with sporadic tumors. The most common presenting signs and symptoms are related to increased intracranial pressure, cerebellar signs, or spinal cord alterations in case of spinal involvement. Magnetic resonance imaging is the gold standard for the diagnosis, assessment, and follow-up of HBs, both sporadic and syndrome-related; angiography is rarely performed because the diagnosis is easily obtained with magnetic resonance. However, the diagnosis of an asymptomatic lesion does not automatically result in therapeutic actions, as the risks of treatment and the onset of possible neurological deficit need to be balanced, considering that HBs may remain asymptomatic and have a static or slow-growing behavior. In such cases, regular follow-up can represent a valid therapeutic option until the patients remain asymptomatic. There are no actual pharmacological therapies that are demonstrated to be effective for HBs. Surgery represents the primary therapeutic approach for these tumors. Observation or radiotherapy also plays a role in the long-term management of patients harboring HBs, especially in VHL; in few selected cases, endovascular treatment has been suggested before surgical removal. This chapter presents a systematic overview of epidemiology, clinical appearance, histopathological and neuroradiological characteristics of central nervous system HBs. Moreover, the genetic and molecular biology of sporadic and VHL HBS deserves special attention. Furthermore, we will describe all the available therapeutic options, along with the follow-up management. Finally, we will briefly report other vascular originating tumors as hemangioendotheliomas, hemangiomas, or angiosarcomas.

The Pre-Lumbar puncture Intracranial Hypertension Scale (PLIHS): A practical scale to identify subjects with normal cerebrospinal fluid pressure in the management of idiopathic intracranial hypertension.

BACKGROUND: Idiopathic Intracranial Hypertension (IIH) diagnosis requires lumbar puncture to measure cerebrospinal fluid (CSF) pressure. The Pre-Lumbar puncture Intracranial Hypertension Scale (PLIHS) is aimed to detect cases that will show raised or normal CSF opening pressure. METHODS: Retrospective analysis of records of patients who underwent lumbar puncture for suspect IIH. The target was CSF opening pressure ≥ 250 mmH2O, whereas a set of known neurological, neuro-ophthalmological and neuro-radiological parameters, plus obesity, were used as predictors in a logistic regression model. The PLIHS was based on significant predictors and a cut-off was validated using chi-squared test around CSF opening pressure ≥ 250 and < 200 mmH2O. RESULTS: Records of 162 patients were included: CSF opening pressure was <200 mmH2O in 40 and ≥ 250 mmH2O in 95 patients; 85 fulfilled IIH diagnosis. PLIHS is based on Frisén grade 2 or higher papilledema, tinnitus, empty sella, perioptic subarachnoid space distension, and obesity. Score range is 0-7: correlation with CSF opening pressure is 0.508 (p < .001), and PLIHS score is different between subjects not diagnosed with IIH, and those diagnosed with IIH both with and without papilledema (p < .001). PLIHS score ≤ 2 identifies cerebrospinal fluid pressure < 200 mmH2O; PLIHS score ≥ 3 identifies CSF opening pressure ≥ 250 mmH2O, IIH diagnosis, visual acuity ≤0.7, and optic nerve atrophy. CONCLUSIONS: The PLIHS, can be used to identify patients who will particularly need LP, thus helping with the organization of the diagnostic work-up by optimising healthcare resources and potentially limit the likelihood to incur in LP-related adverse events.

Characteristics of Moyamoya Disease in the Older Population: Is It Possible to Define a Typical Presentation and Optimal Therapeutical Management?

Whereas several studies have been so far presented about the surgical outcomes in terms of mortality and perioperative complications for elderly patients submitted to neurosurgical treatments, the management of elderly moyamoya patients is unclear. This review aims to explore the available data about the clinical manifestation, characteristics, and outcome after surgery of older patients with moyamoya arteriopathy (MA). We found only two articles strictly concerning elderly patients with MA. We have also evaluated other reported adult series of moyamoya patients, including elderly cases in their analysis. Patients with MA above 50 years old may be considered a peculiar subset in which patients are often presenting with ischemic symptoms and a higher Suzuki grade. Conservative treatment may be proposed in asymptomatic or stable cases due to their fragility and possible increase of post-operative complications, while the best surgical options in symptomatic cases are still under investigation, although we believe that a minimal invasive superficial temporal artery-middle cerebral artery bypass could be considered the treatment of choice for the immediate effect on brain perfusion with a limited rate of post-operative complications.

Additive Fabrication of a Vascular 3D Phantom for Stereotactic Radiosurgery of Arteriovenous Malformations.

In this study, an efficient methodology for manufacturing a realistic three-dimensional (3D) cerebrovascular phantom resembling a brain arteriovenous malformation (AVM) for applications in stereotactic radiosurgery is presented. The AVM vascular structure was 3D reconstructed from brain computed tomography (CT) data acquired from a patient. For the phantom fabrication, stereolithography was used to produce the AVM model and combined with silicone casting to mimic the brain parenchyma surrounding the vascular structure. This model was made with tissues-equivalent materials for radiology. The hollow vascular system of the phantom was filled with a contrast agent usually employed on patients for CT scans. The radiological response of the phantom was tested and compared with the one of the clinical case. The constructed model demonstrated to be a very accurate physical representation of the AVM and its vasculature and good morphological consistency was observed between the model and the patient-specific source anatomy. These results suggest that the proposed method has potential to be used to fabricate patient-specific phantoms for neurovascular radiosurgery applications and medical research.

Headache in spontaneous intracranial hypotension: an overview with indications for differential diagnosis in the clinical practice.

Headache is the most common symptom of spontaneous intracranial hypotension (SIH). The present review focuses on data regarding headache features reported in the most relevant published articles and summarizes the main SIH headache features, namely, orthostatic headache, headache triggered by Valsalva maneuver, pattern of onset of headache, and location and quality of headache. Published data indicate that the clinical suspect of this disorder may be challenging, due to its protean presentation. Among the main implications for clinical practice, we suggest to suspect SIH in all patients with a new onset headache, as different forms of primary and secondary headache should be considered in the differential diagnosis of SIH, particularly cervicogenic headache, new daily persistent headache, and headaches precipitated by Valsalva maneuver. The clinical interview must include specific questions on the possible orthostatic feature of headache, although its absence should not make clinicians to reject the SIH hypothesis as headache cannot be orthostatic in each patient and in all periods of the natural history of the disease. Other disorders with orthostatic symptoms, such as in postural tachycardia syndrome (POTS) and persistent postural-perceptual dizziness (PPPD), should be considered in the differential diagnosis. Awareness that SIH can present with acute, sudden onset requires that clinicians working in the emergency settings should consider SIH in the range of diagnoses of thunderclap headache.

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

In Situ Side-to-Side Pericallosal-Pericallosal Artery and Callosomarginal-Callosomarginal Artery Bypasses for Complex Distal Anterior Cerebral Artery Aneurysms: A Technical Note.

BACKGROUND: Despite surgical and endovascular technical improvements over the last decades, the treatment of complex aneurysms of the distal anterior cerebral artery (ACA) is very challenging for both vascular neurosurgeons and interventional neuroradiologists. Furthermore, the interpersonal anatomic variability requires, most of the time, a tailored planning. OBJECTIVE: To describe a novel technique of bypasses in the territory of ACA to protect the brain territory distal to the aneurysm. METHODS: A 53-yr-old male with a large complex fusiform aneurysm of the left distal A2 segment of the ACA, involving the origin of the callosomarginal and pericallosal arteries, was judged not suitable for a single procedure (endovascular or neurosurgical). Two side-to-side bypasses were performed in a single surgery to connect the pericallosal and callosomarginal arteries of both sides, distally to the aneurysm. Subsequently, an endovascular embolization of the aneurysm was achieved with coils. RESULTS: The patency of the microanastomoses, performed in the anterior interhemispheric fissure, was positively evaluated intraoperatively with indocyanine green and fluorescein videoangiography. The aneurysm sac, together with proximal A2 segment, was completely occluded with platinum coils. At the last follow-up, computed tomography angiography confirmed the patency of both bypasses, without any sign of aneurysm recanalization. The patients never complained of any focal neurological deficits or worsening of clinical status. CONCLUSION: We present an elegant and innovative solution to completely protect the distal ACA territory in cases of complex aneurysm involving the origin of both callosomarginal and pericallosal arteries.

Correction: Sciacca, F. L., et al. Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. Int. J. Mol. Sci. 2018, 19, 3675.

The authors wish to make the corrections to this paper [...].

Advanced MRI Assessment during Dendritic Cell Immunotherapy Added to Standard Treatment Against Glioblastoma.

Evaluating changes induced by immunotherapies (IT) on conventional magnetic resonance imaging (MRI) is difficult because those treatments may produce inflammatory responses. To explore the potential contribution of advanced MRI to distinguish pseudoprogression (PsP) and true tumor progression (TTP), and to identify patients obtaining therapeutic benefit from IT, we examined aMRI findings in newly diagnosed glioblastoma treated with dendritic cell IT added to standard treatment. We analyzed longitudinal MRIs obtained in 22 patients enrolled in the EUDRACT N° 2008-005035-15 trial. According to RANO criteria, we observed 18 TTP and 8 PsP. Comparing MRI performed at the time of TTP/PsP with the previous exam performed two months before, a difference in cerebral blood volume ΔrCBVmax ≥ 0.47 distinguished TTP from PsP with a sensitivity of 67% and specificity of 75% (p = 0.004). A decrease in minimal apparent diffusion coefficient rADCmin (1.15 vs. 1.01, p = 0.003) was observed after four vaccinations only in patients with a persistent increase of natural killer cells (response effectors during IT) in peripheral blood. Basal rADCmin > 1 was independent predictor of longer progression free (16.1 vs. 9 months, p = 0.0001) and overall survival (32.8 vs. 17.5 months, p = 0.0005). In conclusion, rADC predicted response to immunotherapy and survival; Apparent Diffusion Coefficient (ADC) and Cerebral Blood Volume (CBV) modifications over time help differentiating PsP from TTP at onset.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome.

Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal "moyamoya" vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors.

Sacral dural arteriovenous fistulas: a diagnostic and therapeutic challenge - single-centre experience of 13 cases and review of the literature.

BACKGROUND: Sacral dural arteriovenous fistulas (DAVFs) are rare vascular abnormalities of the spine characterised by slowly progressive symptoms that can mimic different myelopathy disorders. OBJECT: To report our single Institution experience with sacral DAVFs. METHODS: We retrospectively reviewed the clinical records of patients admitted from 1 January 2006 to 31 December 2016 with a diagnosis of sacral DAVFs, treated by endovascular embolisation or surgical clipping. Clinical presentation, imaging characteristics, treatment results and follow-up were analysed. RESULTS: We identify 13 patients with sacral DAVFs supplied by lateral sacral arteries. Clinical presentation was characterised by different degrees of motor weakness and sphincter disturbances. In all patients, spinal MRI showed spinal cord hyperintensities with enhancement and prominent perimedullary vessels. Selective internal iliac angiography was mandatory to identify the exact location of the fistula. A complete embolisation was achieved in eight patients performing a single endovascular embolisation and in three patients performing a single surgical disconnection: two patients required combined procedures. Follow-up imaging showed a complete resolution of the spinal cord hyperintensities in 81% of patients and a reduction of the intramedullary enhancement in 91%. Gait improvement was observed in 73% of patients, while remaining stable in 27%. Sphincter disturbances improved in 36% of patients and remained stable in 64%. CONCLUSION: Awareness of sacral location of DAVFs is critical because standard spinal angiography will not identify sacral supplies, unless internal iliac arteries are properly examined. In our experience, the endovascular treatment show results comparable to surgery when the fistula point is correctly disconnected.

Medial Tentorial Dural Arteriovenous Fistula Embolization: Single Experience with Embolic Liquid Polymer SQUID and Review of the Literature.

BACKGROUND: Tentorial dural arteriovenous fistulas (DAVFs) are uncommon, complex fistulas located between the leaves of the tentorium cerebelli with a specific anatomic and clinical presentation characterized by high hemorrhagic risk. We present a rare case of a medial tentorial DAVF successfully managed via transarterial embolization using SQUID liquid polymer. CASE DESCRIPTION: A 60-year-old woman presented with a history of left progressive hearing loss and tinnitus for >1 year. Cerebral angiography demonstrated the presence of a medial tentorial DAVF with multiple arterial feeders, including the artery of Davidoff and Schechter; reverse venous outflow was observed in the inferior sagittal sinus and in multiple cortical veins. The patient underwent transarterial embolization with SQUID liquid polymer, an embolic agent that provides 2 different viscous formulations to cast the DAVF. The procedure went well without any complication, and the patient regained her preoperative status. In the postprocedural period, the patient experienced complete resolution of tinnitus. At 6 months, she remained asymptomatic, and cerebral angiography confirmed complete, stable occlusion of the fistula and normalization of cerebral deep venous outflow. CONCLUSIONS: Medial tentorial DAVFs are considered the most complex DAVFs because of their location and extensive vascular supply. Our literature review focused on endovascular treatment of tentorial DAVFs to highlight the usefulness of new embolic agents in management of these diseases. To our knowledge, we report the first successful use of SQUID liquid polymer in management of a tentorial DAVF.

MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives.

Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology) criteria, including conventional MRI (cMRI), addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM) and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI) may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions.