Incidence of mechanical thrombectomy among stroke patients brought directly to a comprehensive stroke center versus transfer from a primary stroke center in upstate New York.

BACKGROUND: Faster time to treatment for stroke is associated with improved outcomes. In cases of large vessel occlusion (LVO), standard of care treatment with thrombectomy can only be provided at a comprehensive stroke center (CSC). We examine the outcomes of patients who are directly brought to our center, a CSC, compared to those seen at a primary stroke center (PSC) and then transferred. METHODS: Patients with LVO presenting to our center from 1/1/2019 to 12/31/2019 were included. Cohorts of patients presenting first to a PSC and presenting first to a CSC were compared. Demographics and outcome metrics (Discharge Modified Rankin Scale (mRS) and National Institute of Health Stroke Severity Scale (NIHSS) scores) were obtained for all LVO patients. Imaging was also assessed. RESULTS: Of 864 stroke admissions, 346 had LVO (40%) with 183 (53%) transferring from a PSC and 163 (47%) presenting directly. Similar percentages of each cohort were taken for thrombectomy (25.1% transfer and 31.3% direct). However, as distance between PSC and CSC increased, likelihood of thrombectomy decreased. Transfer patients were more likely to be excluded from thrombectomy secondary to a large volume of complete stroke (p = 0.0001). Direct presenters had lower discharge mRS scores than transfer patients (p < 0.01), however, severity of stroke upon admission was similar in the two groups. CONCLUSION: Patients transferred from a PSC were more likely to have a worse outcome at time of discharge than those presenting directly to our center. Large volume of completed stroke was a frequent reason for exclusion from thrombectomy. Optimizing stroke protocols to CSC in cases of LVOs may result in better outcomes.

Development of a Slow-Degrading Polymerized Curcumin Coating for Intracortical Microelectrodes.

Intracortical microelectrodes are used with brain-computer interfaces to restore lost limb function following nervous system injury. While promising, recording ability of intracortical microelectrodes diminishes over time due, in part, to neuroinflammation. As curcumin has demonstrated neuroprotection through anti-inflammatory activity, we fabricated a 300 nm-thick intracortical microelectrode coating consisting of a polyurethane copolymer of curcumin and polyethylene glycol (PEG), denoted as poly(curcumin-PEG1000 carbamate) (PCPC). The uniform PCPC coating reduced silicon wafer hardness by two orders of magnitude and readily absorbed water within minutes, demonstrating that the coating is soft and hydrophilic in nature. Using an in vitro release model, curcumin eluted from the PCPC coating into the supernatant over 1 week; the majority of the coating was intact after an 8-week incubation in buffer, demonstrating potential for longer term curcumin release and softness. Assessing the efficacy of PCPC within a rat intracortical microelectrode model in vivo, there were no significant differences in tissue inflammation, scarring, neuron viability, and myelin damage between the uncoated and PCPC-coated probes. As the first study to implant nonfunctional probes with a polymerized curcumin coating, we have demonstrated the biocompatibility of a PCPC coating and presented a starting point in the design of poly(pro-curcumin) polymers as coating materials for intracortical electrodes.

Rapidly progressive diffuse leptomeningeal glioneuronal tumor in an adult female: illustrative case.

BACKGROUND: Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare brain tumor only recently classified by the World Health Organization in 2016 and has few reports on its incidence in adults. OBSERVATIONS: The authors describe a case of DLGNT presenting in a 47-year-old female with seizures, cranial neuropathies, and communicating hydrocephalus with rapid clinical progression. Workup demonstrated progressive leptomeningeal enhancement of the skull base, cranial nerves, and spine, and communicating hydrocephalus. Elevated serum rheumatological markers and early response to systemic corticosteroids and immunosuppressant therapy complicated the diagnosis. Multiple biopsy attempts were required to obtain diagnostic tissue. Pathology demonstrated hypercellularity surrounding leptomeningeal vessels with nuclear atypia, staining positive for GFAP, Olig2, S100, and synaptophysin. Molecular pathology demonstrated loss of chromosome 1p, BRAF overexpression but no rearrangement, and H3K27 mutation. Repeat cerebrospinal fluid (CSF) diversion procedures were required for hydrocephalus management due to high CSF protein content. LESSONS: This report describes a rare, aggressive, adult presentation of DLGNT. Leptomeningeal enhancement and communicating hydrocephalus should raise suspicion for this disease process. Biopsy at early stages of disease progression is essential for early diagnosis and prompt treatment. Further study into the variable clinical presentation, histological and molecular pathology, and optimal means of diagnosis and management is needed.

The ganglioside GM1a functions as a coreceptor/attachment factor for dengue virus during infection.

Dengue virus (DENV) is a flavivirus causing an estimated 390 million infections per year around the world. Despite the immense global health and economic impact of this virus, its true receptor(s) for internalization into live cells has not yet been identified, and no successful antivirals or treatments have been isolated to this date. This study aims to improve our understanding of virus entry routes by exploring the sialic acid-based cell surface molecule GM1a and its role in DENV infection. We studied the interaction of the virus with GM1a using fluorescence correlation spectroscopy, fluorescence crosscorrelation spectroscopy, imaging fluorescence correlation spectroscopy, amide hydrogen/deuterium exchange mass spectrometry, and isothermal titration calorimetry. Additionally, we explored the effect of this interaction on infectivity and movement of the virus during infection was explored using plaque assay and fluorescence-based imaging and single particle tracking. GM1a was deemed to interact with DENV at domain I (DI) and domain II (DII) of the E protein of the protein coat at quaternary contacts of a fully assembled virus, leading to a 10-fold and 7-fold increase in infectivity for DENV1 and DENV2 in mammalian cell systems, respectively. We determined that the interaction of the virus with GM1a triggers a speeding up of virus movement on live cell surfaces, possibly resulting from a reduction in rigidity of cellular rafts during infection. Collectively, our results suggest that GM1a functions as a coreceptor/attachment factor for DENV during infection in mammalian systems.

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury.

BACKGROUND: Non-invasive, external low intensity focused ultrasound (liFUS) offers promise for treating neuropathic pain when applied to the dorsal root ganglion (DRG). OBJECTIVE: We examine how external liFUS treatment applied to the L5 DRG affects neuronal changes in single-unit activity from the primary somatosensory cortex (SI) and anterior cingulate cortex (ACC) in a common peroneal nerve injury (CPNI) rodent model. METHODS: Male Sprague Dawley rats were divided into two cohorts: CPNI liFUS and CPNI sham liFUS. Baseline single-unit activity (SUA) recordings were taken 20 min prior to treatment and for 4 h post treatment in 20 min intervals, then analyzed for frequency and compared to baseline. Recordings from the SI and ACC were separated into pyramidal and interneurons based on waveform and principal component analysis. RESULTS: Following CPNI surgery, all rats (n = 30) displayed a significant increase in mechanical sensitivity. In CPNI liFUS rats, there was a significant increase in pyramidal neuron spike frequency in the SI region compared to the CPNI sham liFUS animals beginning at 120 min following liFUS treatment (p < 0.05). In the ACC, liFUS significantly attenuated interneuron firing beginning at 80 min after liFUS treatment (p < 0.05). CONCLUSION: We demonstrate that liFUS changed neuronal spiking in the SI and ACC regions 80 and 120 min after treatment, respectively, which may in part correlate with improved sensory thresholds. This may represent a mechanism of action how liFUS attenuates neuropathic pain. Understanding the impact of liFUS on pain circuits will help advance the use of liFUS as a non-invasive neuromodulation option.

Focused Ultrasound for Chronic Pain.

Chronic pain affects millions of Americans and is one of the leading reasons for individuals to seek medical attention. Focused ultrasound has been studied as a noninvasive treatment option for various pain disorders. Current studies have used focused ultrasound for ablation, neuromodulation, and opening of the blood-brain barrier for drug and therapy delivery. Most of the work has been performed in ablative studies and has shown efficacy in treating chronic neuropathic pain. Further research is needed to expand its usage in neurosurgery.

Treatment Strategies for Generator Pocket Pain.

OBJECTIVE: Generator site pain is a relatively common phenomenon in patients undergoing spinal cord stimulation (SCS) that complicates management and effective pain relief. This pain may be managed conservatively, with repositioning of the battery and, in some cases, with explant. Here we explore our experience with management of generator site pain ("pocket pain") in a large single-center study. METHODS: All SCS permanent implants and implantable pulse generator (IPG) placements over 9 years were reviewed. Of 785 cases, we identified 43 patients with pocket pain (5.5%). Demographics and treatments of the pocket pain cohort were analyzed. RESULTS: The mean age (± SEM) of the pocket pain cohort was 46.86 ± 1.06, and there were 10/33 males/females. Females were overrepresented in pocket pain cohort (76.7%) when compared with the total SCS cohort (59.0%) (X2 = 5.93, P = 0.015). Diagnosis included failed back surgery syndrome (51.2%), complex regional pain syndrome (23.3%), and chronic neuropathic pain (25.5%). No patients improved with conservative therapy. All patients either went on to revision (n = 23) or explant (n = 20). Time from initial surgery to development of pocket pain was 7.5 months (range: 0.3-88) and from pocket pain to revision surgery was 4.5 months (range: 0.4-26). In addition, significantly more pocket pain patients (65.1%) had workers' compensation (WC) insurance compared with patients without pocket pain (24.9%) (X2 = 33.3, P < 0.001). CONCLUSION: In our institutional experience, pocket pain was inadequately managed with conservative treatments. Being female and having SCS filed under WC increased risk of pocket pain. Future work will explore the nuances in device placement based on body shape and manual activity responsibilities.

Spinal Cord Stimulation as Treatment for Cancer and Chemotherapy-Induced Pain.

Neuropathic pain is a rampant disease exacting a significant toll on patients, providers, and health care systems around the globe. Neuromodulation has been successfully employed to treat many indications including failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), phantom limb pain (PLP), radiculopathies, and intractable pelvic pain, among many others. Recent studies have also demonstrated efficacy for cancer-related pain and chemotherapy induced neuropathy with these techniques. Spinal cord stimulation (SCS) is the most commonly employed technique and involves implantation of percutaneous or paddle leads targeting the dorsal columns of the spinal cord with the goal of disrupting the pain signals traveling to the brain. Tonic, high frequency, and burst waveforms have all been shown to reduce pain and disability in chronic pain patients. Closed-loop SCS systems that automatically adjust stimulation parameters based on feedback (such as evoked compound action potentials) are becoming increasingly used to help ease the burden placed on patients to adjust their programming to their pain and position. Additionally, dorsal root ganglion stimulation (DRGS) is a newer technique that allows for dermatomal coverage especially in patients with pain in up to two dermatomes. Regardless of the technique chosen, neuromodulation has been shown to be cost-effective and efficacious and should be given full consideration in patients with chronic pain conditions.

Aligned Fingolimod-Releasing Electrospun Fibers Increase Dorsal Root Ganglia Neurite Extension and Decrease Schwann Cell Expression of Promyelinating Factors.

Researchers are investigating the use of biomaterials with aligned guidance cues, like those provided by aligned electrospun fibers, to facilitate axonal growth across critical-length peripheral nerve defects. To enhance the regenerative outcomes further, these aligned fibers can be designed to provide local, sustained release of therapeutics. The drug fingolimod improved peripheral nerve regeneration in preclinical rodent models by stimulating a pro-regenerative Schwann cell phenotype and axonal growth. However, the systemic delivery of fingolimod for nerve repair can lead to adverse effects, so it is necessary to develop a means of providing sustained delivery of fingolimod local to the injury. Here we created aligned fingolimod-releasing electrospun fibers that provide directional guidance cues in combination with the local, sustained release of fingolimod to enhance neurite outgrowth and stimulate a pro-regenerative Schwann cell phenotype. Electrospun fiber scaffolds were created by blending fingolimod into poly(lactic-co-glycolic acid) (PLGA) at a w/w% (drug/polymer) of 0.0004, 0.02, or 0.04%. We examined the effectiveness of these scaffolds to stimulate neurite extension in vitro by measuring neurite outgrowth from whole and dissociated dorsal root ganglia (DRG). Subsequently, we characterized Schwann cell migration and gene expression in vitro. The results show that drug-loaded PLGA fibers released fingolimod for 28 days, which is the longest reported release of fingolimod from electrospun fibers. Furthermore, the 0.02% fingolimod-loaded fibers enhanced neurite outgrowth from whole and dissociated DRG neurons, increased Schwann cell migration, and reduced the Schwann cell expression of promyelinating factors. The in vitro findings show the potential of the aligned fingolimod-releasing electrospun fibers to enhance peripheral nerve regeneration and serve as a basis for future in vivo studies.

Phospholipid phosphatase related 1 (PLPPR1) increases cell adhesion through modulation of Rac1 activity.

Phospholipid Phosphatase-Related Protein Type 1 (PLPPR1) is a six-transmembrane protein that belongs to the family of plasticity-related gene proteins, which is a novel brain-specific subclass of the lipid phosphate phosphatase superfamily. PLPPR1-5 have prominent roles in synapse formation and axonal pathfinding. We found that PLPPR1 overexpression in the mouse neuroblastoma cell line (Neuro2a) results in increase in cell adhesion and reduced cell migration. During migration, these cells leave behind long fibrous looking extensions of the plasma membrane causing a peculiar phenotype. Cells expressing PLPPR1 showed decreased actin turnover and decreased disassembly of focal adhesions. PLPPR1 also reduced active Rac1, and expressing dominant negative Rac1 produced a similar phenotype to overexpression of PLPPR1. The PLPPR1-induced phenotype of long fibers was reversed by introducing constitutively active Rac1. In summary, we show that PLPPR1 decreases active Rac1 levels that leads to cascade of events which increases cell adhesion.

Exploring the effects of electrospun fiber surface nanotopography on neurite outgrowth and branching in neuron cultures.

Three aligned, electrospun fiber scaffolds with unique surface features were created from poly-L-lactic acid (PLLA). Fibers without surface nanotopography (smooth fibers), fibers with surface divots (shallow pits), and fibers with surface pits (deeper pits) were fabricated, and fiber alignment, diameter, and density were characterized using scanning electron microscopy (SEM). Whole dorsal root ganglia (DRG) were isolated from rats and placed onto uncoated fibers or fibers coated with laminin. On uncoated fibers, neurite outgrowth was restricted by fibers displaying divoted or pitted nanotopography when compared to neurite outgrowth on smooth fibers. However, neurites extending from whole DRG cultured on laminin-coated fibers were not restricted by divoted or pitted surface nanotopography. Thus, neurites extending on laminin-coated fibers were able to extend long neurites even in the presence of surface divots or pits. To further explore this result, individual neurons isolated from dissociated DRG were seeded onto laminin-coated smooth, pitted, or divoted fibers. Interestingly, neurons on pitted or divoted fibers exhibited a 1.5-fold increase in total neurite length, and a 2.3 or 2.7-fold increase in neurite branching compared to neurons on smooth fibers, respectively. Based on these findings, we conclude that fiber roughness in the form of pits or divots can promote extension and branching of long neurites along aligned electrospun fibers in the presence of an extracellular matrix protein coating. Thus, aligned, electrospun fibers can be crafted to not only direct the extension of axons but to induce unique branching morphologies.