The effect of COVID-19 on trainee operative experience at a multihospital academic neurosurgical practice: A first look at case numbers.

BACKGROUND: COVID-19 has had a significant impact on the economy, health care, and society as a whole. To prevent the spread of infection, local governments across the United States issued mandatory lockdowns and stay-at-home orders. In the surgical world, elective cases ceased to help "flatten the curve" and prevent the infection from spreading to hospital staff and patients. We explored the effect of the cancellation of these procedures on trainee operative experience at our high-volume, multihospital neurosurgical practice. METHODS: Our department cancelled all elective cases starting March 16, 2020, and resumed elective surgical and endovascular procedures on May 11, 2020. We retrospectively reviewed case volumes for 54 days prelockdown and 54 days postlockdown to evaluate the extent of the decrease in surgical volume at our institution. Procedure data were collected and then divided into cranial, spine, functional, peripheral nerve, pediatrics, and endovascular categories. RESULTS: Mean total cases per day in the prelockdown group were 12.26 ± 7.7, whereas in the postlockdown group, this dropped to 7.78 ± 5.5 (P = 0.01). In the spine category, mean cases per day in the prelockdown group were 3.13 ± 2.63; in the postlockdown group, this dropped to 0.96 ± 1.36 (P < 0.001). In the functional category, mean cases per day in the prelockdown group were 1.31 ± 1.51, whereas in the postlockdown group, this dropped to 0.11 ± 0.42 (P < 0.001). For cranial (P = 0.245), peripheral nerve (P = 0.16), pediatrics (P = 0.34), and endovascular (P = 0.48) cases, the volumes dropped but were not statistically significant decreases. CONCLUSION: The impact of this outbreak on operative training does appear to be significant based solely on statistics. Although the drop in case volumes during this time can be accounted for by the pandemic, it is important to understand that this is a multifactorial effect. Further studies are needed for these results to be generalizable and to fully understand the effect this pandemic has had on trainee operative experience.

A Stereotactic Device for Intraparenchymal Spinal Cord Injections: Latest Developments for Practical Clinical Use.

This manuscript introduces the latest generation of a patient-mounted platform designed for segmental injections of therapeutics direct into the spinal cord parenchyma. It emphasizes its importance and it presents the rationale for developing this delivery methodology. It compares the newest with the previous generations, detailing how the modifications can streamline transportation, assembly, sterilization, and utilization of the platform by different surgeons. Finally, the illustrations depict the main alterations, as well as a cadaveric assessment of the device prototype in the cervical and thoracolumbar regions.

Radiofrequency Ablation Through Previously Effective Deep Brain Stimulation Leads for Parkinson Disease: A Retrospective Series.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is the surgical method of choice to treat the canonical symptoms of Parkinson disease, occasionally surgical sites become infected or the hardware erodes, necessitating explantation. Usual practice is to remove and reimplant replacement leads after tissue healing, leaving patients without the clinical benefits of DBS for several months, and at risk for DBS withdrawal in some, and some patients are no longer good surgical candidates for reimplantation. Radiofrequency ablation through the DBS lead is an option for these patients. METHODS: We performed a retrospective chart review of all patients who underwent radiofrequency ablation of the STN or GPi through indwelling DBS leads performed before hardware removal at our institution. We generated patient-specific anatomic models to determine lesion locations and volumes. RESULTS: Six patients underwent radiofrequency ablation of the STN (n = 4) and GPi (n = 2) through indwelling DBS leads. All 6 of these patients initially showed comparable motor symptom relief to that experienced with DBS before lesioning, with 4 patients sustaining meaningful long-term (≥2 years) improvement. Better outcomes were achieved in those patients with a higher percentage of the planned target lesioned. CONCLUSIONS: Radiofrequency ablation through indwelling DBS leads before explantation could be considered a viable alternative to subsequent reimplantation or stereotactic lesion in patients with Parkinson disease in whom hardware explantation is necessary, if the patient achieved substantive symptom relief with DBS. This approach avoids symptom exacerbation while awaiting revision surgery.

Structural basis for GPR40 allosteric agonism and incretin stimulation.

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.

The Role of Intraoperative Cerebral Angiography in Transorbital Intracranial Penetrating Trauma: A Case Report and Literature Review.

BACKGROUND: Transorbital intracranial penetrating trauma with a retained intracranial foreign body is a rare event lacking a widely accepted diagnostic and therapeutic algorithm. Intraoperative catheter angiography (IOA) has been advocated by some authorities to rule out cerebrovascular injury before and/or after removal of the object, but no standard of care currently exists. CASE DESCRIPTION: A 19-year-old man was involved in a construction site accident whereby a framing nail penetrated the left globe, traversed the lateral bony orbit, and terminated in the midtemporal lobe. No hematoma or injury to the middle cerebral arteries (MCAs) was apparent on noncontrast head computed tomography (CT) or CT angiography, respectively. The foreign body was removed in the operating room under direct visualization after a frontotemporal craniotomy without incident. No significant venous or arterial bleeding was encountered. All visualized MCA branches appeared intact. Indocyanine green videoangiography performed immediately after object removal showed adequate filling of the MCA branches. Given these uneventful clinical and radiographic findings, IOA was not performed. Postoperative head CT and CT angiography showed no obvious neurovascular injury. On postoperative day 2, the patient was noted to have an expressive aphasia. Cerebral angiography showed absent antegrade filling of the angular artery with some retrograde perfusion. Magnetic resonance imaging confirmed an ischemic infarction in the midtemporal lobe. The patient's expressive aphasia improved to near baseline during his hospitalization and he made an excellent clinical recovery. CONCLUSIONS: In transorbital intracranial penetrating trauma with a retained intracranial object, we advocate microsurgical removal of the object under direct visualization followed immediately by IOA. IOA should be strongly considered even in the setting of minimal intraoperative bleeding and normal findings on videoangiography (a course of action that was not followed in the present case). Given that CT angiography and intraoperative videoangiography may miss a potentially treatable traumatic arterial injury, IOA can help determine whether cerebral revascularization may be necessary.

How safe is Bubble Soccer?

Traumatic neurologic injury in contact sports is a rare but serious consequence for its players. These injuries are most commonly associated with high-impact collisions, for example in football, but are found in a wide variety of sports. In an attempt to minimize these injuries, sports are trying to increase safety by adding protection for participants. Most recently is the seemingly 'safe' sport of Bubble Soccer, which attempts to protect its players with inflatable plastic bubbles. We report a case of a 16-year-old male sustaining a cervical spine burst fracture with incomplete spinal cord injury while playing Bubble Soccer. To our knowledge, this is the first serious neurological injury reported in the sport.

Combined use of intraoperative indocyanine green and dynamic angiography in rotational vertebral artery occlusion.

Rotational vertebral artery occlusion, also known as bow hunter's syndrome, is a well-documented surgically amenable cause of vertebrobasilar insufficiency. Traditionally, patients have been imaged using dynamic rotational angiography. The authors sought to determine whether intraoperative indocyanine green (ICG) angiography could reliably assess the adequacy of surgical decompression of the vertebral artery (VA). The authors report two patients who presented with multiple transient episodes of syncope provoked by turning their head to the right. Rotational dynamic angiography revealed a dominant VA that became occluded with head rotation to the right side. The patients underwent successful surgical decompression of the VA via an anterior cervical approach. Intraoperative ICG angiography demonstrated patency of the VA with head rotation. This was further confirmed by intraoperative dynamic catheter angiography. To our knowledge, we present the first two cases of the use of ICG combined with intraoperative dynamic rotational angiography to document the adequacy of surgical decompression of the VA in a patient with rotational vertebral artery occlusion. Intraoperative ICG angiography is a useful adjunct and may potentially supplant the need for intraoperative catheter angiography.

Esophageal perforation after anterior cervical spine surgery: a systematic review of the literature.

OBJECTIVE Esophageal perforation is a rare but well-known complication of anterior cervical spine surgery. The authors performed a systematic review of the literature to evaluate symptomatology, direct causes, repair methods, and associated complications of esophageal injury. METHODS A PubMed search that adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines included relevant clinical studies and case reports (articles written in the English language that included humans as subjects) that reported patients who underwent anterior spinal surgery and sustained some form of esophageal perforation. Available data on clinical presentation, the surgical procedure performed, outcome measures, and other individual variables were abstracted from 1980 through 2015. RESULTS The PubMed search yielded 65 articles with 153 patients (mean age 44.7 years; range 14-85 years) who underwent anterior spinal surgery and sustained esophageal perforation, either during surgery or in a delayed fashion. The most common indications for initial anterior cervical spine surgery in these cases were vertebral fracture/dislocation (n = 77), spondylotic myelopathy (n = 15), and nucleus pulposus herniation (n = 10). The most commonly involved spinal levels were C5-6 (n = 51) and C6-7 (n = 39). The most common presenting symptoms included dysphagia (n =63), fever (n = 24), neck swelling (n = 23), and wound leakage (n = 18). The etiology of esophageal perforation included hardware failure (n = 31), hardware erosion (n = 23), and intraoperative injury (n = 14). The imaging modalities used to identify the esophageal perforations included modified contrast dye swallow studies, CT, endoscopy, plain radiography, and MRI. Esophageal repair was most commonly achieved using a modified muscle flap, as well as with primary closure. Outcomes measured in the literature were often defined by the time to oral intake following esophageal repair. Complications included pneumonia (n = 6), mediastinitis (n = 4), osteomyelitis (n = 3), sepsis (n = 3), acute respiratory distress syndrome (n = 2), and recurrent laryngeal nerve damage (n = 1). The mortality rate of esophageal perforation in the analysis was 3.92% (6 of 153 reported patients). CONCLUSIONS Esophageal perforation after anterior cervical spine surgery is a rare complication. This systematic review demonstrates that these perforations can be stratified into 3 categories based on the timing of symptomatic onset: intraoperative, early postoperative (within 30 days of anterior spinal surgery), and delayed. The most common source of esophageal injury is hardware erosion or migration, each of which may vary in their time to symptomatic manifestation.

A selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes.

LY2881835 is a selective, potent, and efficacious GPR40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY2881835 was tested in primary islets from WT mice but not in islets from GPR40 KO mice. Furthermore, LY2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY2881835 lowered glucose during OGTTs in WT mice but not in GPR40 KO mice. These findings demonstrate that LY2881835 induces GPR40-mediated activity ex vivo and in vivo. LY2881835 was administered orally at 10 mg/kg to diet-induced obese (DIO) mice (an early model of T2D due to insulin resistance) for 14 days. Statistically significant reductions in glucose were seen during OGTTs performed on days 1 and 15. When a study was done for 3 weeks in Zucker fa/fa rats, a rat model of insulin resistance, normalization of blood glucose levels equivalent to those seen in lean rats was observed. A similar study was performed in streptozotocin (STZ)-treated DIO mice to explore glucose control in a late model of T2D. In this model, pancreatic insulin content was reduced ~80% due to STZ-treatment plus the mice were insulin resistant due to their high fat diet. Glucose AUCs were significantly reduced during OGTTs done on days 1, 7, and 14 compared to control mice. In conclusion, these results demonstrate that LY2881835 functions as a GPR40-specific insulin secretagogue mediating immediate and durable glucose control in rodent models of early- and late-stage T2D.

Less is more: novel less-invasive surgical techniques for mesial temporal lobe epilepsy that minimize cognitive impairment.

PURPOSE OF REVIEW: New minimally invasive techniques are becoming available to treat focal-onset epilepsy. The open surgical treatment of mesial temporal lobe epilepsy (MTLE), although associated with high rates of seizure freedom, is confounded by adverse impacts on neurocognitive function. This review covers new techniques being explored for surgical treatment of MTLE that in early studies have been achieving high seizure-free rates with preservation of memory and other functions referable to the mesial and lateral temporal regions. RECENT FINDINGS: Multiple subpial transections of the hippocampus, and stereotactic approaches including radiofrequency ablation and laser interstitial thermal therapy have achieved rates of seizure freedom comparable to open resection but with fewer neurocognitive adverse effects. Electrical neuromodulation approaches, including responsive neurostimulation, direct hippocampal stimulation, and thalamic deep brain stimulation preserve cognitive function and achieve significant seizure suppression, but have not yet achieved high seizure-free rates. SUMMARY: With the recent success in minimally invasive approaches with respect to seizure freedom and preservation of neurocognitive functions, it is predicted that fewer patients will be receiving 'classic' open resections for MTLE such as temporal lobectomy. These new approaches also promise to decrease discomfort, time away from work, and healthcare utilization.

Introduction to neuropathic pain syndromes.

Chronic pain impairs the quality of life for millions of individuals and therefore presents a serious ongoing challenge to clinicians and researchers. Debilitating chronic pain syndromes cost the US economy more than $600 billion per year. This article provides an overview of the epidemiology, clinical presentation, and treatment outcomes for craniofacial, spinal, and peripheral neurologic pain syndromes. Although the authors recognize that the diagnosis and treatment of the chronic forms of neuropathic pain syndromes represent a clinical challenge, there is an urgent need for standardized classification systems, improved epidemiologic data, and reliable treatment outcomes data.

Deep brain stimulation for chronic pain: intracranial targets, clinical outcomes, and trial design considerations.

For over half a century, neurosurgeons have attempted to treat pain from a diversity of causes using acute and chronic intracranial stimulation. Targets of stimulation have included the sensory thalamus, periventricular and periaqueductal gray, the septum, the internal capsule, the motor cortex, posterior hypothalamus, and more recently, the anterior cingulate cortex. The current work focuses on presenting and evaluating the evidence for the efficacy of these targets in a historical context while also highlighting the major challenges to having a double-blind placebo-controlled clinical trial. Considerations for pain research in general and use of intracranial targets specifically are included.

PARP-14 binds specific DNA sequences to promote Th2 cell gene expression.

PARP-14, a member of the poly ADP-ribose polymerase super family, promotes T helper cell 2 (Th2) differentiation by regulating interleukin-4 (IL-4) and STAT6-dependent transcription. Yet, whether PARP-14 globally impacts gene regulation has not been determined. In this report, using an RNA pol II ChIP-seq approach, we identify genes in Th2 cells that are regulated by PARP-14, and either dependent or independent of ADP-ribosyltransferase catalytic activity. Our data demonstrate that PARP-14 enhances the expression of Th2 genes as it represses the expression of Th1-associated genes. Among the relevant targets are Signal Transducer and Activator of Transcription genes required for polarizing Th1 and Th2 cells. To define a mechanism for PARP-14 function, we use an informatics approach to identify putative PARP-14 DNA binding sites. Two putative PARP-14 binding motifs are identified in multiple Th2 cytokine genes, and we demonstrate that PARP-14 interacts with each motif using in vitro binding assays. Taken together our results indicate that PARP-14 is an important factor for T helper cell differentiation and it binds to specific DNA sequences to mediate its function.

Cellular therapeutics delivery to the spinal cord: technical considerations for clinical application.

Current literature demonstrates the efficacy of cell-based therapeutics in small animal models of varied spinal cord diseases. However, logistic challenges remain towards development of an optimized delivery approach to the human spinal cord. Clinical trials utilize a variety of methods to achieve this aim. In this article, the authors review currently employed delivery methods, compare the merits of alternate delivery paradigms, introduce their implementation in completed and ongoing clinical trials, and discuss promising near-term advances in image-guided delivery and in vivo graft tracking.

Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease.

BACKGROUND: IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T(H)2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both T(H)2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. OBJECTIVE: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. METHODS: The role of PARP-14 and its enzyme activity in AAD and T(H)2 differentiation were examined by using a murine model of AAD and in vitro T(H) cell differentiation. RESULTS: PARP-14-deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a T(H)2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. CONCLUSION: PARP-14 and the catalytic activity associated with it promote T(H)2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma.

Surgical technique for spinal cord delivery of therapies: demonstration of procedure in gottingen minipigs.

This is a compact visual description of a combination of surgical technique and device for the delivery of (gene and cell) therapies into the spinal cord. While the technique is demonstrated in the animal, the procedure is FDA-approved and currently being used for stem cell transplantation into the spinal cords of patients with ALS. While the FDA has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for validating the combination of a surgical procedure, a device, and the safety of a final therapy for human use. The size, anatomy, and general vulnerability of the spine and spinal cord of the swine are recognized to better model the human. Moreover, the surgical process of exposing and manipulating the spinal cord as well as closing the wound in the pig is virtually indistinguishable from the human. We believe that the healthy pig model represents a critical first step in the study of procedural safety.

Platform and cannula design improvements for spinal cord therapeutics delivery.

BACKGROUND: Only recently have data been published attempting to validate a technology and technique suitable for targeted delivery of biological payloads to the human spinal cord. OBJECTIVE: To characterize the development and evolution of a spine-stabilized microinjection platform as a vehicle for biologics delivery to the cervical and thoracolumbar spine on the basis of preclinical experience in both non-Good Laboratory Practice (GLP) experimental series and GLP studies. METHODS: Our laboratory completed > 100 cervical and lumbar porcine microinjection procedures between July 2004 and June 2010. This included both non-GLP- and GLP-adherent survival series to validate the safety and accuracy achievable with intraspinal microinjection. During this time, 3 different microinjection platforms, injection stages, and cannula designs were tested. RESULTS: Repetitive technological improvements reduced incision length, decreased procedural complexity, and simplified ventral horn targeting and accuracy. These changes reduced procedural invasiveness and the likelihood of neurological morbidity while improving targeting accuracy. In part as a result of these technological improvements and procedural modifications, we have safely progressed from single unilateral microinjections to multiple bilateral injections without long-term neurological sequelae. CONCLUSION: Technological and procedural refinements have significantly enhanced the capabilities of intraspinal microinjection-based biologics delivery. Reductions in procedural invasiveness and the capability to deliver sequential biological payloads effectively have broadened the flexibility of intraspinal microinjection to a widened array of intrinsic spinal cord pathologies. These advances have laid the groundwork for clinical translation of spinal cord microinjections.

PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation.

A subset of poly ADP-ribose polymerases (PARP) that also contain macro domains regulate transcription. One such macro PARP, PARP-14 alters interleukin 4 (IL-4) and Stat6-dependent transcription. Stat6, activated by IL-4 plays an important role in T helper cell immunity and B cell responses. Here we define the mechanism by which PARP-14 regulates Stat6-activated transcription. Under non-stimulating conditions, PARP-14 recruits HDAC 2 and 3 to IL-4 responsive promoters. In the presence of IL-4, PARP-14 promotes efficient binding of Stat6 to its target genes. Moreover, HDAC 2 and 3 are released from the promoter with an IL-4 signal, this is aided by the ADP-ribosylation of the HDACs by PARP-14. The HDACs and PARP-14 get replaced by coactivators containing HAT activity. Based on these observations we put forth a mechanism in which PARP-14 functions as a transcriptional switch for Stat6-dependent gene induction. Thus, in the absence of a signal PARP-14 acts as a transcriptional repressor by recruiting HDACs. In contrast, in the presence of IL-4 the catalytic activity of PARP-14 facilitates Stat6 binding to the promoter, and release of HDACs so as to activate transcription.