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Background: Cerebello-pontine AVMs (CPAVMs) and petrous apex dural arteriovenous fistulae (DAVFs) are rare and sometimes difficult to distinguish. We report a fatal hemorrhagic complication after coil embolization of the petrosal vein draining a trigeminal AVM misdiagnosed as a DAVF., Case Presentation: A 73-year-old woman with a petrous apex arteriovenous shunt with dual dural and pial arterial supply presented with posterior fossa hemorrhage. The draining petrosal vein was catheterized and coiled via the superior petrosal sinus. Two episodes of contrast extravasation occurred during coiling, but the lesion was completely occluded at the end of the procedure. The patient developed a fatal posterior fossa hemorrhage in the recovery room. Microscopic pathology revealed numerous dilated vessels within the trigeminal nerve., Conclusion: CPAVMs and DAVFs with pial drainage should be distinguished pre-operatively. Occlusion of a pial vein (as opposed to a sinus) in the treatment of an arteriovenous shunt carries hemorrhagic risk if a liquid embolic agent is not used to completely occlude all pathological vessels.

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006-2012 and 2013-2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006-2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

Natalizumab is used as a second-line treatment for multiple sclerosis (MS). Some reports have linked natalizumab to primary central nervous system lymphoma (PCNSL), although few have described its management. A 45-year-old woman with Balo's Concentric Sclerosis presented dizziness, vertigo accompanied by dysarthria, weakness on the left side and blurred vision to the right eye after the fourth dose of natalizumab. Magnetic resonance imaging (MRI) and a brain biopsy confirmed the diagnosis of PCNSL. The patient received modified PCNSL chemotherapy (MATRix protocol) followed by high-dose chemotherapy (HDC) supported by an autologous hematopoietic stem cell transplant (ASCT) as a consolidation therapy. Thirty months later, she is still in complete remission of her PCNSL and MS. In this case, whole brain radiotherapy was excluded because it may be associated with an increased risk of neurotoxicity in MS. ASCT was preferred because it has been shown to prevent disability progression in less advanced MS stages. Our patient is the second to receive an ASCT in this context and this option of treatment should be the preferred if the patient is eligible.

Inflammatory myofibroblastic tumors (IMT) of the central nervous system (CNS) are rare entities that have a predilection for local recurrences. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in the over-expression of the anaplastic lymphoma kinase (ALK) gene. We hereby present the case of a patient diagnosed with a left parieto-occipital IMT that recurred after multiple surgeries and radiotherapy. Immuno-histochemical examination of the tumor demonstrated ALK overexpression and the presence of an ALK rearrangement observed in lung cancers. The patient was subsequently started on an ALK inhibitor. A response evaluation criteria in solid tumors (RECIST) partial response was observed by the seventh month of ALK inhibition and the tumor remained in control for 14 months. The current case reiterates the activity of ALK inhibitors within the CNS and suggests that radiotherapy may potentiate the permeability of ALK inhibitors in CNS tumors addicted to ALK signalling., Competing Interests: The authors have declared financial relationships, which are detailed in the next section.

Innovations in endovascular tools have permitted an increasingly broad range of neurovascular lesions to be treated via minimally invasive methods. However, some device modifications may carry additional risks, not immediately apparent to operators. A patient with a symptomatic, partially thrombosed basilar apex aneurysm was allocated balloon-assisted coiling. Attempts were made to place a microwire across the basilar apex through the posterior communicating artery. Overlapping courses of the posterior cerebral and posterior choroidal arteries on the roadmap images were not recognized and a flanged-tip microwire was inadvertently advanced deep into the choroidal artery. Following the wire with a microcatheter led to binding of arterial tissue within the microcatheter. Removing the wire led to an avulsion of the choroidal artery and a severe hemorrhagic complication which proved fatal. Tissue was identified on the tip of the guidewire. Pathology showed layers of vascular tissue within the laser-cut flanges of the distal wire tip. A similar complication, also fatal, occurred during balloon angioplasty of a distal vertebral artery, when an exchange wire was accidently introduced into a perforator from a posterior cerebral artery. Ex vivo catheterization of distal mesenteric arterial branches showed that the wall of small arteries can be entrapped by laser-cut, flanged, but not by smooth guidewire tips. Microwires with a flanged instead of smooth distal tip, when placed into small caliber vessels, may cause hemorrhagic complications from avulsions*.

Haemorrhagic complications can occur following aneurysm treatment with flow diverters (FD), but the underlying mechanism remains unknown. We describe a case where deformation of the device may have contributed to the complication. A patient with a giant, previously unruptured cavernous aneurysm that extended intracranially to cause oedema of the internal capsule was treated with flow diversion. Treatment was followed by multiple episodes of peri-aneurysmal haemorrhages within eight days. A deformation of the device which occurred where it curved to cross the aneurysm neck created residual flows which, in the presence of a stent stenosis immediately beyond the neck, may have contributed to the observed ruptures. Following multiple haemorrhages the patient subsequently died. Autopsy demonstrated early red thrombus partially bridging the struts of the flow diverter, and intra-aneurysmal thrombus of various ages. Microscopic pathology showed an aneurysm wall consisting of collagen infiltrated with neutrophils, but the wall was absent near the cerebral peduncle, adjacent to the brain haemorrhage. Radiographs of the extracted specimen confirmed deformation of the FD construct, located at the transition zone of the stent, leading to increased pore size and porosity. The site of the deformation correlated with the angiographic presence of a continued blood inflow jet into the aneurysm. Stent deformation at the transition zone may promote persistent blood entry into the aneurysm, and in turn potentially contribute to haemorrhagic complications.

Background: Inflammatory myofibroblastic tumors (IMTs) of the central nervous system (CNS) are rare entities with diverse histopathological features and varying propensities to recur., Case Description: A 26 year-old male with an IMT of the CNS of the left tentorium had tumor progression 2 months after partial surgical resection. Histopathological studies confirmed expression of ALK. Macroscopic total resection was performed followed by radiotherapy. A recurrence occurred 20 months after the second surgery that necessitate reoperation. Including the present case, we identified 30 cases of IMT of the CNS corresponding to our search criteria in the literature. The extent of resection was reported in 26 of these cases. Gross total resection was done in 75% of ALK-positive and in 61% of ALK-negative cases. Recurrence rate after gross total resection for ALK-positive and ALK-negative cases was 33% and 9%, respectively. Every recurrence in ALK-positive patients occurred within 2 years after surgery., Conclusion: IMT of the CNS are a heterogeneous group of tumors and the treatment of choice is complete surgical resection. Because of the high recurrence rate reported for IMT of the CNS expressing ALK, a closed follow-up is recommended. When faced with an early recurrence, a surgical resection followed by radiotherapy may be advised.

Background and Purpose: The relationship between aneurysm dimensions, flow, thrombosis, and rupture remains poorly understood. We attempted to clarify this relationship by exploring various swine aneurysm models., Materials and Methods: Bilateral carotid aneurysms were constructed according to 3 protocols in 24 animals: small aneurysms with wide necks (group 1; n = 6 animals); small aneurysms with small necks (group 2; n = 4 animals), and giant aneurysms with large necks (group 3; n = 14 animals). Group 3 included 3 subgroups, related to testing the model in various experimental conditions: The neck was clipped in 3 animals; venous pouches lacked an endothelial lining in 4 animals; and 7 were control animals. Animals were followed until rupture, or for 1-4 weeks. Angiography was performed postoperatively and before euthanasia. We studied lesion pathology, paying attention to thrombosis, recanalization, wall composition, and perianeurysmal hemorrhage., Results: Groups differed significantly in aneurysm dimensions and aspect ratio (P = .002). Ruptures occurred more frequently in animals with untreated giant aneurysms (7/7) than in animals with small wide-neck (0/6) or small-neck (2/4) aneurysms (P = .002). Ruptures occurred only in animals with thrombosed aneurysms. Lesions lacking an endothelial lining and 5 of 6 clipped venous pouches thrombosed but did not rupture. One giant lesion ruptured despite complete clipping. The wall was deficient in α-actin and was infiltrated with inflammatory cells and erythrocytes in all thrombosed cases, ruptured or not. Ruptures were associated with recanalizing channels in 9 of 10 cases., Conclusions: Thrombosis, inflammation, and recanalization may precipitate aneurysmal ruptures in a swine model.

Cushing's disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27(Kip1) expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27(Kip1) knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27(Kip1) loss-of-function act cooperatively on pituitary adenoma development.

The blood-brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT1) expressed by BBB endothelial cells (ECs). Activation of AT1 restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent, in vitro, on the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions.

Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo-pituitary-adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that approximately 50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process.

Background and Purpose: Cyanoacrylates are effective occlusive agents in neurovascular interventions. To study their potential to improve long-term results of endovascular treatment of aneurysms, we conducted experimental studies in canine aneurysm models., Methods: Venous pouch carotid aneurysms were constructed in dogs. Results of coil embolization of lateral wall and bifurcation aneurysms were compared. A lateral wall model of embolization with gelatin sponges was used to study the effects of coating sponges with cyanoacrylate on angiographic results and neointima thickness at 3 and 12 weeks. These models were also used to investigate the control of endovascular cyanoacrylate deposition, alone or over a coil placed at the neck of the treated lesions. The results of endovascular cyanoacrylate embolization of bifurcation aneurysms were compared with those of coil embolization at 3 months., Results: Bifurcation aneurysms treated with coils showed more frequent recurrences (P <.01) and thinner neointimas (P <.01) at 3 months than did lateral wall aneurysms. Cyanoacrylate-coated sponges improved angiographic results (P <.05) and led to thicker neointimas at 3 and 12 weeks (P <.05) as compared with uncoated sponges. Endovascular cyanoacrylate deposition with microcatheters led to stray emboli in all cases. Cyanoacrylate delivery was improved by a single coil positioned at the neck of the aneurysm, but parent vessel embolization still occurred in 25% of the animals. Cyanoacrylate embolization of bifurcation aneurysms improved angiographic results at 3 months as compared with coil embolization (P <.01)., Conclusion: Cyanoacrylate embolization is currently difficult to control. It has the potential to decrease recurrences after endovacular treatment of aneurysms, but a safe method for endovascular delivery has yet to be developed.