Consistent Intraocular Pressure Reduction by Solid Drug Nanoparticles in Fixed Combinations for Glaucoma Therapy.

Efficient topical drug delivery remains a significant challenge in glaucoma management. Although nanoparticle formulations offer considerable promise, their complex preparation processes, co-delivery issues, and batch consistency have hindered their potential. A scalable fabrication strategy is developed here for preparing solid drug nanoparticles (SDNs) with enhanced drug delivery efficiency. Utilizing hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX), uniform fixed combination BM/BX SDNs are fabricated through a continuous process, improving batch-to-batch consistency for combined glaucoma treatment. With trehalose being used as a lyoprotectant, BM/BX SDNs can be stored as dry powder and easily reconstituted in phosphate buffered saline. Importantly, reconstituted BM/BX SDNs form clear, homogenous solutions, and exhibit negligible cytotoxicity and irritation, making them well-suited for topical administration as eyedrops. Ex vivo and in vivo studies demonstrated that topically applied BM/BX SDNs permeate through the cornea significantly (about two fold to three fold) compared to their hydrophilic counterparts, i.e., brimonidine tartrate, and betaxolol hydrogen chloride. Notably, BM/BX SDNs displayed consistent intraocular pressure lowering effects in vivo in both normotensive rats and glaucoma mice. Collectively, this study demonstrates the potential of the scalable fabrication strategy and the resultant BM/BX SDNs for improving glaucoma management through eyedrops.

Intraarterial Transplantation of Mitochondria After Ischemic Stroke Reduces Cerebral Infarction.

Background-: Transplantation of autologous mitochondria into ischemic tissue may mitigate injury caused by ischemia and reperfusion. Methods-: Using murine stroke models of middle cerebral artery occlusion, we sought to evaluate feasibility of delivery of viable mitochondria to ischemic brain parenchyma. We evaluated the effects of concurrent focused ultrasound activation of microbubbles, which serves to open the blood-brain barrier, on efficacy of delivery of mitochondria. Results-: Following intra-arterial delivery, mitochondria distribute through the stroked hemisphere and integrate into neural and glial cells in the brain parenchyma. Consistent with functional integration in the ischemic tissue, the transplanted mitochondria elevate concentration of adenosine triphosphate in the stroked hemisphere, reduce infarct volume and increase cell viability. Additional of focused ultrasound leads to improved blood brain barrier opening without hemorrhagic complications. Conclusions-: Our results have implications for the development of interventional strategies after ischemic stroke and suggest a novel potential modality of therapy after mechanical thrombectomy.

Preclinical models of middle cerebral artery occlusion: new imaging approaches to a classic technique.

Stroke remains a major burden on patients, families, and healthcare professionals, despite major advances in prevention, acute treatment, and rehabilitation. Preclinical basic research can help to better define mechanisms contributing to stroke pathology, and identify therapeutic interventions that can decrease ischemic injury and improve outcomes. Animal models play an essential role in this process, and mouse models are particularly well-suited due to their genetic accessibility and relatively low cost. Here, we review the focal cerebral ischemia models with an emphasis on the middle cerebral artery occlusion technique, a "gold standard" in surgical ischemic stroke models. Also, we highlight several histologic, genetic, and in vivo imaging approaches, including mouse stroke MRI techniques, that have the potential to enhance the rigor of preclinical stroke evaluation. Together, these efforts will pave the way for clinical interventions that can mitigate the negative impact of this devastating disease.

Reperfusion injury in acute ischemic stroke: Tackling the irony of revascularization.

Reperfusion injury is an unfortunate consequence of restoring blood flow to tissue after a period of ischemia. This phenomenon can occur in any organ, although it has been best studied in cardiac cells. Based on cardiovascular studies, neuroprotective strategies have been developed. The molecular biology of reperfusion injury remains to be fully elucidated involving several mechanisms, however these mechanisms all converge on a similar final common pathway: blood brain barrier disruption. This results in an inflammatory cascade that ultimately leads to a loss of cerebral autoregulation and clinical worsening. In this article, the authors present an overview of these mechanisms and the current strategies being employed to minimize injury after restoration of blood flow to compromised cerebral territories.

Long-term retinal protection by MEK inhibition in Pax6 haploinsufficiency mice.

Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6Sey-Neu/+ exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6Sey-Neu/+ mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6Sey-Neu/+ eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6Sey-Neu/+ retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects.

A subset of arachnoid granulations in humans drain to the venous circulation via intradural lymphatic vascular channels.

OBJECTIVE: The discovery of dural lymphatics has spurred interest in the mechanisms of drainage of interstitial fluid from the CNS, the anatomical components involved in clearance of macromolecules from the brain, mechanisms of entry and exit of immune components, and how these pathways may be involved in neurodegenerative diseases and cancer metastasis. In this study the authors describe connections between a subset of arachnoid granulations (AGs) and the venous circulation via intradural vascular channels (IVCs), which stain positively with established lymphatic markers. The authors postulate that the AGs may serve as a component of the human brain's lymphatic system. METHODS: AGs and IVCs were examined by high-resolution dissection under stereoscope bilaterally in 8 fresh and formalin-fixed human cadaveric heads. The superior sagittal sinus (SSS) and adjacent dura mater were immunostained with antibodies against Lyve-1 (lymphatic marker), podoplanin (lymphatic marker), CD45 (panhematopoietic marker), and DAPI (nuclear marker). RESULTS: AGs can be classified as intradural or interdural, depending on their location and site of drainage. Interdural AGs are distinct from the dura, adhere to arachnoid membranes, and occasionally open directly in the inferolateral wall or floor of the SSS, although some cross the infradural folds of the dura's inner layer to meet with intradural AGs and IVCs. Intradural AGs are located within the leaflets of the dura. The total number of openings from the AGs, lateral lacunae, and cortical veins into the SSS was 45 ± 5.62 per head. On average each cadaveric head contained 6 ± 1.30 intradural AGs. Some intradural AGs do not directly open into the SSS and use IVCs to connect to the venous circulation. Using immunostaining methods, the authors demonstrate that these tubular channels stain positively with vascular and lymphatic markers (Lyve-1, podoplanin). CONCLUSIONS: AGs consist of two subtypes with differing modes of drainage into the SSS. A subset of AGs located intradurally use tubular channels, which stain positively with vascular and lymphatic markers to connect to the venous lacunae and ultimately to the SSS. The present study suggests that AGs may function as a component of brain lymphatics. This finding has important clinical implications for cancer metastasis to and from the CNS and may shed light on mechanisms of altered clearance of macromolecules in the setting of neurodegenerative diseases.

Biomarkers Predictive of Long-Term Outcome After Ischemic Stroke: A Meta-Analysis.

BACKGROUND AND OBJECTIVE: The goal of this study was to systematically review the usefulness of serum biomarkers in the setting of ischemic stroke (IS) to predict long-term outcome. METHODS: A systematic literature review was performed using the PubMed and MEDLINE databases for studies published between 1986 and 2018. All studies assessing long-term functional outcome (defined as ≥30 days) after IS with respect to serum biomarkers were included. Data were extracted and pooled using a meta-analysis of odds ratios. RESULTS: Of the 2928 articles in the original literature search, 183 studies were selected. A total of 127 serum biomarkers were included. Biomarkers were grouped into several categories: inflammatory (n = 32), peptide/enzymatic (n = 30), oxidative/metabolic (n = 28), hormone/steroid based (n = 23), and hematologic/vascular (n = 14). The most commonly studied biomarkers in each category were found to be CRP, S100ß, albumin, copeptin, and D-dimer. With the exception of S100ß, all were found to be statistically associated with >30-day outcome after ischemic stroke. CONCLUSIONS: Serum-based biomarkers have the potential to predict functional outcome in patients with IS. This meta-analysis has identified C-reactive protein, albumin, copeptin, and D-dimer to be significantly associated with long-term outcome after IS. These biomarkers have the potential to serve as a platform for prognosticating stroke outcomes after 30 days. These serum biomarkers, some of which are routinely ordered, can be combined with imaging biomarkers and used in artificial intelligence algorithms to provide refined predictive outcomes after injury. These tools will assist physicians in providing guidance to families regarding long-term independence of patients.

Global and Regional Damages in Retinal Ganglion Cell Axon Bundles Monitored Non-Invasively by Visible-Light Optical Coherence Tomography Fibergraphy.

Retinal ganglion cells (RGCs) exhibit compartmentalized organization, receiving synaptic inputs through their dendrites and transmitting visual information from the retina to the brain through the optic nerve. Little is known about the structure of RGC axon bundles extending from individual RGC somas to the optic nerve head (ONH) and how they respond to disease insults. We recently introduced visible-light optical coherence tomography fibergraphy (vis-OCTF), a technique for directly visualizing and analyzing mouse RGC axon bundles in vivo In this study, we validated vis-OCTF's ability to quantify RGC axon bundles with an increased number of RGCs using mice deficient in BCL2-associated X protein (BAX-/-). Next, we performed optic nerve crush (ONC) injury on wild-type (WT) mice and showed that the changes in RGC axon bundle width and thickness were location-dependent. Our work demonstrates the potential of vis-OCTF to longitudinally quantify and track RGC damage at single axon bundle level in optic neuropathies.SIGNIFICANCE STATEMENT Nearly all clinical and preclinical studies measure the retinal nerve fiber (RNFL) thickness as the sole indicator of retinal ganglion cell (RGC) damage without investigating RGC axon bundles directly. We demonstrated visible-light optical coherence tomography fibergraphy (vis-OCTF) to directly quantify global and regional RGC axon bundle organizations in vivo as a new biomarker for RGC health. We validated in vivo vis-OCTF measures using both confocal microscopy of the immunostained flat-mounted retina and numerical simulations. Vis-OCTF for monitoring RGC axon bundle organization has the potential to bring new insight into RGC damage in optic neuropathies.

Nano-in-Nano Dendrimer Gel Particles for Efficient Topical Delivery of Antiglaucoma Drugs into the Eye.

Low bioavailability of topically applied drugs remains a significant challenge for long-term glaucoma therapy. To enhance drug delivery efficiency, we developed dendrimer gel particles that collectively exhibit structural benefits of dendrimer, hydrogel, and particles, using the inverse emulsion method coupled with the highly efficient aza-Michael addition reaction (IEaMA). This hierarchical approach would maximize the utility of the structural features of existing ocular drug delivery systems. We have tested the delivery efficiency and efficacy of two first-line antiglaucoma drugs, brimonidine tartrate (BT) and timolol maleate (TM), which were loaded into dendrimer gel particles of various sizes, i.e., nDHP (nano-in-nano dendrimer hydrogel particles, ~200 nm), µDHP3 (3 µm), and µDHP10 (9 µm). We found that nDHP was superior to µDHP3 and µDHP10 in terms of cytocompatibility, degradability, drug release kinetics, and corneal permeability. The nDHPs increased drug corneal permeability by 17-fold compared to plain drug solution and enabled zero-order prolonged drug release kinetics. The nDHP-based formulation demonstrated pronounced IOP-lowering effects in both single-dose test and 7-day chronic daily dosing test in both Brown Norway rats and glaucoma mice. Taken together, we have developed nano-in-nano dendrimer gel particles for precise dosing and enabling sustained and synergistic efficacy of antiglaucoma drugs, which could be clinically impactful for improving glaucoma treatment.

Pituitary Tumors in the Computational Era, Exploring Novel Approaches to Diagnosis, and Outcome Prediction with Machine Learning.

BACKGROUND: Machine learning has emerged as a viable asset in the setting of pituitary surgery. In the past decade, the number of machine learning models developed to aid in the diagnosis of pituitary lesions and predict intraoperative and postoperative complications following transsphenoidal surgery has increased exponentially. As computational processing power continues to increase, big data sets continue to expand, and learning algorithms continue to surpass gold standard predictive tools, machine learning will serve to become an important component in improving patient care and outcomes. METHODS: Relevant studies were identified based on a literature search in PubMed and MEDLINE databases, as well as from other sources including reference lists of published articles. RESULTS: Radiomics and artificial neural networks comprise the majority of machine learning-based applications in pituitary surgery. Radiomics serves to quantify specific imaging features, which can then be used to noninvasively identify tumor characteristics and make definitive diagnoses, circumventing presurgical biopsy altogether. Neural networks can be adapted to predict intraoperative changes in visual evoked potentials or cerebral spinal fluid leak. In addition, these algorithms may be combined with others to predict tumor aggressiveness, gross total resection, recurrence and remission, and even total cost burden. CONCLUSIONS: The field of machine learning is broad, with radiomics and artificial neural networks comprising 2 commonly used supervised learning methods in pituitary surgery. Given the large heterogeneity of pituitary and sellar lesions, the promise of machine learning lies in its ability to identify relationships and patterns that are otherwise hidden from standard statistical methods. While machine learning has great potential as a clinical adjunct during the surgical preplanning process and in predicting complications and outcomes, challenges moving forward include standardization and validation of these paradigms.

Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation.

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

Systematic Review of Functional Mapping and Cortical Reorganization in the Setting of Arteriovenous Malformations, Redefining Anatomical Eloquence.

Objective: The goal of this study was to systematically review functional mapping and reorganization that takes place in the setting of arteriovenous malformations (AVMs) and its potential impact on grading and surgical decision making. Methods: A systematic literature review was performed using the PubMed database for studies published between 1986 and 2019. Studies assessing brain mapping and functional reorganization in AVMs were included. Results: Of the total 84 articles identified in the original literature search, 12 studies were ultimately selected. This includes studies evaluating the impact of cortical reorganization on patient outcomes and factors impacting and triggering cortical reorganization in AVM. Conclusion: These studies demonstrate the utility of preoperative brain mapping and acknowledgment of functional reorganization in the setting of AVMs. While these findings led to alterations in Spetzler-Martin grading and subsequent surgical decision making, it remains unclear the clinical utility of this information when assessing patient outcomes. While promising, more research is required before recommendations can be made regarding functional brain mapping and cortical reorganization with respect to AVM surgery involving eloquent brain tissue.

Transsphenoidal surgery using robotics to approach the sella turcica: Integrative use of artificial intelligence, realistic motion tracking and telesurgery.

While full integration of robotic surgery has been achieved in other surgical domains, its transition into neurosurgery has been more prolonged, especially with respect to pituitary surgery. The confined working space and precise maneuvers required in endoscopic endonasal surgery makes development of an efficacious and safe robotic system difficult. Nevertheless, preclinical studies have attempted to demonstrate the feasibility of the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA) in both transnasal and transoral approaches. In addition, unique robotics such as the concentric tube robot have been created. This system is optimized specifically for anterior skull base surgery with smaller shaft diameter arms and improved maneuverability in tight corridors. The possible role of concentric tube robotics surgery in skull base pathologies has been explored, and the novel use of telesurgery incorporated into robotic neurosurgery is discussed. An endoscopic endonasal transsphenoidal surgical system has also been developed, integrating computational methods to create a presurgical reconstructive model for surgical planning and automating the line of dissection for an enhanced approach to the sphenoid sinus. While surgical robotics for transsphenoidal surgery remain in its nascency, these preliminary findings are promising and suggest a role for robotic pituitary surgery.

From Bench to Bedside, the Current State of Oncolytic Virotherapy in Pediatric Glioma.

Glioma continues to be a challenging disease process, making up the most common tumor type within the pediatric population. While low-grade gliomas are typically amenable to surgical resection, higher grade gliomas often require additional radiotherapy in conjunction with adjuvant chemotherapy. Molecular profiling of these lesions has led to the development of various pharmacologic and immunologic agents, although these modalities are not without great systemic toxicity. In addition, the molecular biology of adult glioma and pediatric glioma has been shown to differ substantially, making the application of current chemotherapies dubious in children and adolescents. For this reason, therapies with high tumor specificity based on pediatric tumor cell biology that spare healthy tissue are needed. Oncolytic virotherapy serves to fill this niche, as evidenced by renewed interest in this domain of cancer therapy. Initially discovered by chance in the early 20th century, virotherapy has emerged as a viable treatment option. With promising results based on preclinical studies, the authors review several oncolytic viruses, with a focus on molecular mechanism and efficacy of these viruses in tumor cell lines and murine models. In addition, current phase I clinical trials evaluating oncolytic virotherapy in the treatment of pediatric glioma are summarized.

Arteriovenous malformation presenting with epilepsy: a multimodal approach to diagnosis and treatment.

Arteriovenous malformation (AVM) presenting with epilepsy significantly impacts patient quality of life, and it should be considered very much a seizure disorder. Although hemorrhage prevention is the primary treatment aim of AVM surgery, seizure control should also be at the forefront of therapeutic management. Several hemodynamic and morphological characteristics of AVM have been identified to be associated with seizure presentation. This includes increased AVM flow, presence of long pial draining vein, venous outflow obstruction, and frontotemporal location, among other aspects. With the advent of high-throughput image processing and quantification methods, new radiographic attributes of AVM-related epilepsy have been identified. With respect to therapy, several treatment approaches are available, including conservative management or interventional modalities; this includes microsurgery, radiosurgery, and embolization or a combination thereof. Many studies, especially in the domain of microsurgery and radiosurgery, evaluate both techniques with respect to seizure outcomes. The advantage of microsurgery lies in superior AVM obliteration rates and swift seizure response. In addition, by incorporating electrophysiological monitoring during AVM resection, adjacent or even remote epileptogenic foci can be identified, leading to extended lesionectomy and improved seizure control. Radiosurgery, despite resulting in reduced AVM obliteration and prolonged time to seizure freedom, avoids the risks of surgery altogether and may provide seizure control through various antiepileptic mechanisms. Embolization continues to be used as an adjuvant for both microsurgery and radiosurgery. In this study, the authors review the latest imaging techniques in characterizing AVM-related epilepsy, in addition to reviewing each treatment modality.

Endovascular Approach to Cerebral Revascularization: Historical Vignette.

From their origins as cardiovascular research tools, endovascular techniques have evolved to provide a minimally invasive means of diagnosis and therapy for individuals suffering from occlusive artery disease. The techniques were pioneered by William Harvey, whose work set the stage for all subsequent endovascular experiments. These included the bold self-catheterization procedure performed by Werner Forssmann in 1929, which would lead to his dismissal by his superiors, only to regain respect within the medical community in 1956 on receiving the Nobel Prize. Charles Dotter was the first to understand the true potential of endovascular approaches after a chance recanalization that would catapult arterial catheterization first into the cardiovascular surgical arena, then into neurosurgery for intracranial stenoses. Having been meticulously evaluated and compared with open vascular procedures, endovascular neurosurgery has continued to be refined and optimized. Understanding the history and development of these techniques and their applications in neurosurgery is necessary to appreciate the current clinical utility of these procedures, serving to provide the vascular neurosurgeon a greater array of treatment options for patients. Here we explore the major scientific and technological advancements that facilitated the development of the endovascular approach to cerebral revascularization, as well as current indications and ongoing clinical trials.

Endoscopic endonasal surgery outcomes for pediatric craniopharyngioma: a systematic review.

OBJECTIVE: The goal of this study was to systematically review the outcomes of endoscopic endonasal surgery (EES) for pediatric craniopharyngiomas so as to assess its safety and efficacy. METHODS: A systematic literature review was performed using the PubMed and MEDLINE databases for studies published between 1986 and 2019. All studies assessing outcomes following EES for pediatric craniopharyngiomas were included. RESULTS: Of the total 48 articles identified in the original literature search, 13 studies were ultimately selected. This includes comparative studies with other surgical approaches, retrospective cohort studies, and case series. CONCLUSIONS: EES for pediatric craniopharyngiomas is a safe and efficacious alternative to other surgical approaches. Achieving gross-total resection with minimal complications is feasible with EES and is comparable, if not superior in some cases, to traditional means of resection. Ideally, a randomized controlled trial might be implemented in the future to further elucidate the effectiveness of EES for resection of craniopharyngiomas.