Qualitative head-to-head comparison of headlamp and microscope for visualizing 5-ALA fluorescence during resection of glioblastoma.

Fluorescence-guided surgery (FGS) for high-grade gliomas using 5-aminolevulinic acid has become a new standard of care for neurosurgeons in several countries. In this video the authors present the case of a man with glioblastoma who underwent FGS in which similar images of the operative field were acquired alternating between the microscope and a new commercially available headlight, facilitating the comparison of visualization quality between the two devices. The authors also review some of the principles of fluorescence-guidance surgery that may explain the improved brightness and contrast that they observed when using the headlamp versus the microscope. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21181.

Characterization of Hemorrhagic and Ischemic Stroke in a Diverse Cohort of COVID-19 Patients.

BACKGROUND AND PURPOSE: COVID-19 is a known risk factor for stroke. There is limited data on the influence of demographics, risk factors, and hematologic function on outcomes in COVID-19 stroke patients. METHODS: All patients with acute ischemic or hemorrhagic stroke tested for COVID-19 and treated from March 13 through May 19, 2020 were retrospectively analyzed. COVID+ patients were compared to COVID- patients and a historical cohort from 2019. RESULTS: 84 patients with radiographic acute stroke from the 2020 study period and 152 patients in the historical cohort were included. Stroke incidence in COVID+ patients was 1.5%, with a significant decline in total stroke presentations during this period compared to 2019. 37 patients were COVID+ and 47 patients were COVID-. 32% of COVID+ stroke patients were Hispanic compared to 15% and 18% in the COVID- and 2019 cohorts respectively (p = 0.069 and 0.07). COVID+ stroke patients were younger, had higher rates of hemorrhagic conversion (p = 0.034), higher initial NIHSS (p < 0.001), increased cryptogenic stroke mechanism (p = 0.02), and higher mortality independent of COVID-19 severity. COVID+ patients had higher rates of thrombocytopenia (p = 0.02), and were less likely to be on antiplatelet therapy (p = 0.025). In multivariable analysis, only COVID-19 status independently predicted mortality. CONCLUSIONS: COVID status, independent of severity, was significantly associated with higher mortality in stroke patients. COVID+ stroke patients were younger and less likely to be on antiplatelets, with higher rates of thrombocytopenia, suggesting a possible role for antiplatelet use in this population.

Perioperative prophylactic middle meningeal artery embolization for chronic subdural hematoma: a series of 44 cases.

OBJECTIVE: Chronic subdural hematoma (cSDH) is a common and challenging pathology to treat due to both the historically high recurrence rate following surgical evacuation and the medical comorbidities inherent in the aging patient population that it primarily affects. Middle meningeal artery (MMA) embolization has shown promise in the treatment of cSDHs, most convincingly to avoid surgical evacuation in relatively asymptomatic patients. Symptomatic patients requiring surgical evacuation may also benefit from perioperative MMA embolization to prevent cSDH recurrence. The goal of this study was to determine the utility of perioperative MMA embolization for symptomatic cSDH requiring surgical evacuation and to assess if there is a decrease in the cSDH recurrence rate compared to historical recurrence rates following surgical evacuation alone. METHODS: Symptomatic cSDHs were evacuated using a subdural evacuating port system (SEPS) with 5-mm twist-drill craniostomy in an intensive care unit or by performing a craniotomy in the operating room, using either a small (silver dollar, < 4 cm) or large (≥ 4 cm) craniotomy. MMA embolization was performed perioperatively using angiography, selective catheterization of the MMA, and infusion of polyvinyl particles. Outcomes were assessed clinically and radiographically with interval head CT imaging. RESULTS: There were 44 symptomatic cSDHs in 41 patients, with 3 patients presenting with bilateral symptomatic cSDH. All cSDHs were evacuated using an SEPS (n = 18), a silver-dollar craniotomy (n = 16), or a large craniotomy (n = 10). Prophylactic MMA embolization was performed successfully in all cSDHs soon after surgical evacuation. There were no deaths and no procedural complications. There was an overall reduction of greater than 50% or resolution of cSDH in 40/44 (90.9%) cases, regardless of the evacuation procedure used. Of the 44 prophylactic cases, there were 2 (4.5%) cases of cSDH recurrence that required repeat surgical evacuation at the 1-year follow-up. These 2 cSDHs were initially evacuated using an SEPS and subsequently required a craniotomy, thereby representing an overall 4.5% recurrence rate of treated cSDH requiring repeat evacuation. Most notably, of the 26 patients who underwent surgical evacuation with a craniotomy followed by MMA embolization, none had cSDH recurrence requiring repeat intervention. CONCLUSIONS: Perioperative prophylactic MMA embolization in the setting of surgical evacuation, via either craniotomy or SEPS, may help to lower the recurrence rate of cSDH.

Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma.

OBJECTIVE: While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. METHODS: Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. RESULTS: Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). CONCLUSIONS: This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.

Single arm access venous sinus stenting (SAVeS) technique: Technical note.

Intracranial venous sinus stenting is gaining acceptance as an effective treatment for idiopathic intracranial hypertension (IIH). The typical approach is via femoral venous and arterial access for transvenous stenting with simultaneous angiography. These patients are at an above average risk for groin complications considering obesity is typically associated with IIH and the need for heparinization and dual antiplatelet therapy. Here, we describe cerebral venography, angiography, and venous sinus stenting via a single upper extremity. We utilize a transradial approach for angiography and a venous access via the brachial or basilic vein. Over a series of 28 consecutive procedures, we were able to successfully access the intracranial venous sinuses via the arm without access site complications. This method offers the advantages of immediate patient mobilization after the procedure and more easily monitored and compressible access sites for easier post-procedural care.

The Long Noncoding RNA Pnky Is a Trans-acting Regulator of Cortical Development In Vivo.

While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. Here, we show that conditional deletion of Pnky from the developing cortex regulates the production of projection neurons from neural stem cells (NSCs) in a cell-autonomous manner, altering postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a BAC transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates development in trans.

Molecular Pathogenesis and Emerging Treatment for Glioblastoma.

Glioblastoma is the most common primary malignant brain tumor, with more than10,000 new cases each year in the United States. Significant basic science and clinical research has been devoted to understanding this disease, yet median survival with standard of care treatment remains approximately 15 months. Over the past decade, advances in genomic sequencing technology, biostatistics, and computing have allowed for an unprecedented ability to profile the gene expression patterns and mutations driving the formation of tumors. These advances have generated both prognostic information as well as a multitude of treatment targets that are just now coming into clinical practice. This article aims to provide a comprehensive update on the recent use of genetic profiling to identify the molecular pathways altered in glioblastoma and to describe ongoing clinical trials to exploit these pathways for treatment.

Spinal Subdural Abscess Following Laminectomy for Symptomatic Stenosis: A Report of 2 Cases and Review of the Literature.

BACKGROUND Spinal subdural abscesses, also known as empyemas, are rare infectious lesions, the exact incidence of which is unknown. Presentation is typically dramatic, with back pain, fever, motor, and sensory deficits. Rapid identification and surgical intervention with laminectomy, durotomy, and washout provides the best outcomes. While hematogenous spread of an extra-spinal infection is the most common cause of this condition, a significant number of cases result from iatrogenic mechanisms, including lumbar punctures, epidural injections, and surgery. CASE REPORT Here we present 2 cases: 1) an 87-year-old man with type 2 diabetes, schizophrenia, mild cognitive impairment, and symptomatic lumbar spinal stenosis and 2) a 62-year-old man with a prior L3-4 spinal fusion with symptomatic lumbar spinal stenosis. In both cases, patients underwent laminectomy for spinal stenosis and developed epidural abscess. Following successful drainage of the epidural abscess, they continued to be symptomatic, and repeat imaging revealed the presence of a subdural abscess that was subsequently evacuated. Case 1 had significant improvement with residual lower-extremity weakness, while Case 2 made a complete neurological recovery. CONCLUSIONS These cases illustrate patients at increased risk for developing this rare spinal infection, and demonstrate that rapid recognition and surgical treatment is key to cure and recovery. Review of the literature highlights pertinent risk factors and demonstrates nearly one-third of reported cases have an iatrogenic etiology. The cases presented here demonstrate that a subdural process should be suspected in any patient with intractable pain following treatment of an epidural abscess.

Uncovering the roles of long noncoding RNAs in neural development and glioma progression.

In the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, and emerging data indicate that lncRNAs can have important biological functions and roles in human diseases including cancer. Many lncRNAs appear to be expressed specifically in the brain, and the roles of lncRNAs in neural stem cells (NSCs) and brain development are now beginning to be discovered. Here we review recent advances in understanding the diversity of lncRNA structure and functions in NSCs and brain development. NSCs in the adult mouse ventricular-subventricular zone (V-SVZ) generate new neurons throughout life, and we discuss how key elements of this adult neurogenic system have facilitated the discovery and functional characterization of known and novel lncRNAs. A review of lncRNAs described in other NSC systems reveals a variety of molecular mechanisms, including binding and recruitment of transcription factors, epigenetic modifiers, and RNA-splicing factors. Finally, we review emerging evidence indicating that specific lncRNAs can be key drivers of glial tumors, and discuss next steps towards an in vivo understanding of lncRNA function in development and disease.

Thalamotomy-Like Effects From Partial Removal of a Ventral Intermediate Nucleus Deep Brain Stimulator Lead in a Patient With Essential Tremor: Case Report.

BACKGROUND AND IMPORTANCE: The ventral intermediate nucleus of the thalamus is a primary target of deep brain stimulation (DBS) in patients with essential tremor. Despite reliable control of contralateral tremor, there is sometimes a need for lead revision in cases of infection, hardware malfunction, or failure to relieve symptoms. Here, we present the case of a patient undergoing revision after ventral intermediate nucleus (Vim) DBS failed to control his tremor. During the electrode removal, the distal portion of the lead was found to be tightly adherent to tissue within the deep brain. Partial removal of the electrode in turn caused weakness, paresthesias, and tremor control similar to the effects produced by thalamotomy or thalamic injury. CLINICAL PRESENTATION: A 48-year-old man with essential tremor had bilateral Vim DBS leads implanted 10 years earlier but had poor control of his tremor and ultimately opted for surgical revision with lead placement in the zona incerta. During attempted removal of his right lead, the patient became somnolent with contralateral weakness and paresthesias. The procedure was aborted, and postoperative neuroimaging was immediately obtained, showing no signs of stroke or hemorrhage. The patient had almost complete control of his left arm tremor postoperatively, and his weakness soon resolved. CONCLUSION: To the best of our knowledge, this is the first reported case of cerebral injury after DBS revision and offers insights into the mechanism of high-frequency electric stimulation compared with lesions. That is, although high-frequency stimulation failed to control this patient's tremor, thalamotomy-like injury was completely effective.

The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells.

While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations.

Analysis of Mll1 deficiency identifies neurogenic transcriptional modules and Brn4 as a factor for direct astrocyte-to-neuron reprogramming.

BACKGROUND: Mixed lineage leukemia-1 (Mll1) epigenetically regulates gene expression patterns that specify cellular identity in both embryonic development and adult stem cell populations. In the adult mouse brain, multipotent neural stem cells (NSCs) in the subventricular zone generate new neurons throughout life, and Mll1 is required for this postnatal neurogenesis but not for glial cell differentiation. Analysis of Mll1-dependent transcription may identify neurogenic genes useful for the direct reprogramming of astrocytes into neurons. OBJECTIVE: To identify Mll1-dependent transcriptional modules and to determine whether genes in the neurogenic modules can be used to directly reprogram astrocytes into neurons. METHODS: We performed gene coexpression module analysis on microarray data from differentiating wild-type and Mll1-deleted subventricular zone NSCs. Key developmental regulators belonging to the neurogenic modules were overexpressed in Mll1-deleted cells and cultured cortical astrocytes, and cell phenotypes were analyzed by immunocytochemistry and electrophysiology. RESULTS: Transcriptional modules that correspond to neurogenesis were identified in wild-type NSCs. Modules related to astrocytes and oligodendrocytes were enriched in Mll1-deleted NSCs, consistent with their gliogenic potential. Overexpression of genes selected from the neurogenic modules enhanced the production of neurons from Mll1-deleted cells, and overexpression of Brn4 (Pou3f4) in nonneurogenic cortical astroglia induced their transdifferentiation into electrophysiologically active neurons. CONCLUSION: Our results demonstrate that Mll1 is required for the expression of neurogenic but not gliogenic transcriptional modules in a multipotent NSC population and further indicate that specific Mll1-dependent genes may be useful for direct reprogramming strategies.

Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo.

Long noncoding RNAs (lncRNAs) have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression for the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone lineage, we stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Our data and workflow thus provide a uniquely coherent in vivo lncRNA analysis and form the foundation of a user-friendly online resource for the study of lncRNAs in development and disease.

Design, syntheses, and evaluation of Taspase1 inhibitors.

Taspase1 is a threonine protease responsible for cleaving MLL (Mixed-Lineage Leukemia) to achieve proper HOX gene expression. Subsequent studies identified additional Taspase1 substrates including Transcription Factor IIA (TFIIA) and Drosophila HCF. Taspase1 is essential for cell proliferation and is overexpressed in many cancer cell lines. Currently no small molecule inhibitors of this enzyme have been described. Here, we report the synthesis and evaluation of vinyl sulfone, vinyl ketone, epoxy ketone, and boronic acid inhibitors designed based on the preferred Taspase1 cleavage site (Ac-Ile-Ser-Gln-Leu-Asp). Specifically, we evaluated compounds in which the reactive warhead is positioned in place of the P1 aspartic acid side chain as well as at the C-terminus of the peptide. Interestingly, both classes of inhibitors were effective and vinyl ketones and vinyl sulfones showed the greatest potency for the target protease. These results suggest that Taspase1 has unique substrate recognition properties that could potentially be exploited in the design of potent and selective inhibitors of this enzyme.