Pipeline Embolization Device for the Treatment of Intracranial Pseudoaneurysms.

BACKGROUND: Intracranial pseudoaneurysms (PSAs) are associated with high rupture and mortality rates and have traditionally been treated by parent vessel sacrifice. There has been recent interest in using flow-diverting devices for treatment of these complex lesions while preserving flow through the parent artery. The objective of this study is to examine the safety and efficacy of these devices in the treatment of intracranial PSA. METHODS: We performed a multi-institutional retrospective study of intracranial PSAs treated with the Pipeline Embolization Device (PED) between 2014 and 2017 at 7 institutions. Complications and clinical and radiographic outcomes were reviewed. RESULTS: A total of 19 patients underwent PED placement for intracranial PSA. Iatrogenic injury and trauma comprised most etiologies in our series. The mean pseudoaneurysm diameter was 8.8 mm, and 18 of 19 PSAs (95%) involved the internal carotid artery (ICA). Multiple PEDs were deployed in a telescoping fashion in 7 patients (37%). Of the 18 patients with follow up imaging, 14 (78%) achieved complete pseudoaneurysm obliteration and 2 achieved near-complete obliteration (11%). Two patients (11%) were found to have significant pseudoaneurysm progression on short-term follow-up and required ICA sacrifice. No patients experienced new neurologic deficits or deterioration secondary to PED placement. No patients experienced bleeding or rebleeding from PSA. CONCLUSIONS: In well-selected patients, the use of flow-diverting stents may be a feasible alternative to parent vessel sacrifice. Given the high morbidity and mortality associated with PSA, we recommend short- and long-term radiographic follow-up for patients treated with flow-diverting stents.

Daam2 driven degradation of VHL promotes gliomagenesis.

Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.

Aneurysms with persistent patency after treatment with the Pipeline Embolization Device.

The Pipeline Embolization Device (PED) was approved for the treatment of intracranial aneurysms from the petrous to the superior hypophyseal segment of the internal carotid artery. However, since its approval, its use for treatment of intracranial aneurysms in other locations and non-sidewall aneurysms has grown tremendously. The authors report on a cohort of 15 patients with 16 cerebral aneurysms that incorporated an end vessel with no significant distal collaterals, which were treated with the PED. The cohort includes 7 posterior communicating artery aneurysms, 5 ophthalmic artery aneurysms, 1 superior cerebellar artery aneurysm, 1 anterior inferior cerebellar artery aneurysm, and 2 middle cerebral artery aneurysms. None of the aneurysms achieved significant occlusion at the last follow-up evaluation (mean 24 months). Based on these observations, the authors do not recommend the use of flow diverters for the treatment of this subset of cerebral aneurysms.

Reliable Intraoperative Repair Nuances of Cerebrospinal Fluid Leak in Anterior Cervical Spine Surgery and Review of the Literature.

BACKGROUND: Cerebrospinal fluid (CSF) leak during anterior cervical spine surgery can lead to complications, including wound breakdown, meningitis, headaches, need for lumbar drain, or additional surgery. These leaks can be difficult to manage given the limited field of view and lack of deep access. Herein, we describe 8 consecutive patients who underwent intraoperative repair of CSF leak, with no postoperative evidence of wound dehiscence or drainage. METHODS: A retrospective review was performed on 8 cases where CSF leak was encountered during an anterior cervical spine surgery. Patients had ossification of the posterior longitudinal ligament, intradural disk herniation, or dural ectasia. Intraoperative repair was as follows. First, CSF was drained to low pressure, and durotomy was covered by dural substitute and sealant agent. Then the interbody graft used was manually undersized in the anteroposterior dimension to allow for expansion of the agents used. Anterior instrumentation was then performed. Finally, a wound drain was anchored to a biologic bag for shoulder level passive drainage. RESULTS: In all 8 cases, there were no cases of wound dehiscence or CSF leak using this strategy. Likewise, there was no evidence of cord compression or neurologic deficits. No meningitis or persistent headaches were reported, and there was no need for lumbar drain placement at any time postoperatively. CONCLUSIONS: Once durotomy is encountered during anterior spine surgery, draining the CSF to a low pressure followed by dural substitute with a sealing agent, followed by a smaller anteroposterior size graft is an effective strategy of preventing complications in an inescapable problem.

Vacuum-assisted en bloc resection of large convexity meningiomas. Technical note.

Convexity meningiomas are common tumors encountered by neurosurgeons. Retracting, grasping, and mobilizing large convexity meningiomas can be difficult and awkward as well as place unwanted forces on surrounding neurovascular structures. The authors present a safe alternative to traditional retraction and manipulation methods by using a modified bulb syringe connected to standard surgical suction to function as a vacuum retractor. This technique allows for rapid, safe, en bloc resection of large convexity meningiomas with little to no pressure on the surrounding brain. The authors present an illustrative case and describe and discuss the technique.

Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells.

Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between 'neurogenic' and 'non-neurogenic' regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursors in vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.

Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo.

Neurogenesis continues throughout adulthood in the mammalian olfactory bulb and hippocampal dentate gyrus, suggesting the hypothesis that recently generated, adult-born neurons contribute to neural plasticity and learning. To explore this hypothesis, we examined whether olfactory experience modifies the responses of adult-born neurons to odorants, using immediate early genes (IEGs) to assay the response of olfactory granule neurons. We find that, shortly after they differentiate and synaptically integrate, the population of adult-born olfactory granule neurons has a greater population IEG response to novel odors than mature, preexisting neurons. Familiarizing mice with test odors increases the response of the recently incorporated adult-born neuron population to the test odors, and this increased responsiveness is long lasting, demonstrating that the response of the adult-born neuron population is altered by experience. In contrast, familiarizing mice with test odors decreases the IEG response of developmentally generated neurons, suggesting that recently generated adult-born neurons play a distinct role in olfactory processing. The increased IEG response is stimulus specific; familiarizing mice with a set of different, "distractor" odors does not increase the adult-born neuron population response to the test odors. Odor familiarization does not influence the survival of adult-born neurons, indicating that the changes in the population response of adult-born neurons are not attributable to increased survival of odor-stimulated neurons. These results demonstrate that recently generated adult-born olfactory granule neurons and older, preexisting granule neurons undergo contrasting experience-dependent modifications in vivo and support the hypothesis that adult-born neurons are involved in olfactory learning.

Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells.

Recent work in neuroscience has shown that the adult central nervous system contains neural progenitors, precursors, and stem cells that are capable of generating new neurons, astrocytes, and oligodendrocytes. While challenging previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them future possibilities for the development of novel neural repair strategies. The purpose of this review is to present current knowledge about constitutively occurring adult mammalian neurogenesis, to highlight the critical differences between "neurogenic" and "non-neurogenic" regions in the adult brain, and to describe the cardinal features of two well-described neurogenic regions-the subventricular zone/olfactory bulb system, and the dentate gyrus of the hippocampus. We also provide an overview of currently used models for studying neural precursors in vitro, mention some precursor transplantation models, and emphasize that, in this rapidly growing field of neuroscience, one must take caution with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims toward molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what the function might be of newly generated neurons in the adult brain and provide a summary of current thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.

Large-scale maintenance of dual projections by callosal and frontal cortical projection neurons in adult mice.

Integration of sensory-motor information in premotor cortex of rodents occurs largely through callosal and frontal cortical association projections directed in a hierarchically organized manner. Although most anatomical studies in rodents have been performed in rats, mammalian genetic models have focused on mice, because of their successful manipulation on the genetic and cell biological levels. It is therefore important to establish the normal patterns of anatomical connectivity in mice, which potentially differ from those in rats. The goal of this study is to investigate the anatomical development of callosal and frontal premotor projection neurons (CPN and FPN, respectively) in mouse sensory-motor and premotor cortex and to investigate quantitatively the potential laminar differences between these neurons with simultaneous callosal and frontal projections during development. The retrograde tracers Fluoro-Gold and DiI were injected into sensory-motor and premotor cortices, respectively, C57Bl/6 mice at different developmental times (P2, P8, P21, adult). We found that, in contrast to the case in primate and cat, there is widespread overlap in populations of long-distance projection neurons in mice; many projection neurons have simultaneous projections to both contralateral somatosensory cortex and ipsilateral frontal cortex, and a considerable number of these dual projections persist into adulthood. In addition, there are significant laminar differences in the percentage of neurons with simultaneous callosal and frontal projections, and an isolated population of layer V FPN has bilateral projections to both premotor cortical hemispheres. Taken together, our results indicate that a large proportion of individual projection neurons maintains simultaneous callosal and frontal projections in adult mice, suggesting that these dual projections might serve the critical function of integrating motor coordination information with multimodal association areas.

The repair of complex neuronal circuitry by transplanted and endogenous precursors.

During the past three decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of novel approaches has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain, and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis, and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops, as well as to approaches by which transplanted or endogenous precursors might be used to repair the adult brain. For example, recruitment of new neurons can be induced in a region-specific, layer-specific, and neuronal type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow for the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that might not require transplantation of exogenous cells.

Constitutive and induced neurogenesis in the adult mammalian brain: manipulation of endogenous precursors toward CNS repair.

Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. During the past 3 decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops as well as to approaches by which endogenous precursors might be recruited to repair the adult brain. Recruitment of new neurons can be induced in a region-specific, layer-specific and neuronal-type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that do not require transplantation of exogenous cells.