Persistent GDNF Expression 45 Months after Putaminal Infusion of AAV2-GDNF in a Patient with Parkinson's Disease.

OBJECTIVE: Gene therapy by convection-enhanced delivery of type 2 adeno-associated virus-glial cell derived neurotrophic factor (AAV2-GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). METHODS: A 63-year-old man with advanced PD received AAV2-GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F-Fluorodopa (18F-FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2-GDNF infusion. RESULTS: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. CONCLUSION: After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Preoperative prescription opioid use as an independent predictor of 90-day mortality and adverse events in craniotomy and craniectomy patients.

OBJECTIVE: A growing body of literature suggests that preoperative opioid exposure is an independent predictor of poor outcomes in surgical patients. No outcomes data exist on preoperative opioid use and craniotomies/craniectomies. The objective of this study was to determine the impact of preoperative opioid use on 90-day adverse events after craniotomy or craniectomy. METHODS: A single-center retrospective cohort study of 2445 patients undergoing a craniotomy/craniectomy between January 1, 2013, and October 1, 2018, was conducted. Baseline demographics, pre- and postoperative opioid use (morphine milligram equivalents [MMEs]), and surgical metrics were recorded. Patients were categorized based on whether they took prescription opioids preoperatively, defined as within 1 month of surgery, or were opioid naive. The outcomes were mortality and adverse events 90 days after craniotomy/craniectomy. RESULTS: Overall, 26.6% of patients composed the preoperative opioid group. The median daily MME intake among this group was 34.6 (IQR 14.1-90) MMEs. Lower employment rates (p < 0.001), uninsured status (p = 0.016), and intravenous drug use (p = 0.006) were associated with preoperative opioid use. Preoperative opioid use was associated with increased venous thromboembolism (p = 0.001), acute kidney injury (p = 0.002), acute respiratory failure (p < 0.001), myocardial infarction (p = 0.002), delirium (p < 0.001), and infection (p < 0.001). Preoperative opioid use was an independent predictor of overall 90-day adverse events (OR 1.643, 95% CI 1.289-2.095; p < 0.001) and 90-day mortality (OR 1.690, 95% CI 1.254-2.277; p < 0.001). CONCLUSIONS: Preoperative opioid use was independently associated with 90-day postoperative adverse events and mortality. Opioid use increases vulnerability in craniotomy/craniectomy patients and necessitates close monitoring to improve outcomes.

Real-Time Magnetic Resonance Imaging During Convective Gene Therapy Perfusion of the Brain.

This article discusses use of intraoperative MRI in convective gene therapy perfusion.

Adjuvant convection-enhanced delivery for the treatment of brain tumors.

BACKGROUND: Malignant gliomas are a therapeutic challenge and remain nearly uniformly fatal. While new targeted chemotherapeutic agentsagainst malignant glioma have been developed in vitro, these putative therapeutics have not been translated into successful clinical treatments. The lack of clinical effectiveness can be the result of ineffective biologic strategies, heterogeneous tumor targets and/or the result of poortherapeutic distribution to malignant glioma cells using conventional nervous system delivery modalities (intravascular, cerebrospinal fluid and/orpolymer implantation), and/or ineffective biologic strategies. METHODS: The authors performed a review of the literature for the terms "convection enhanced delivery", "glioblastoma", and "glioma". Selectclinical trials were summarized based on their various biological mechanisms and technological innovation, focusing on more recently publisheddata when possible. RESULTS: We describe the properties, features and landmark clinical trials associated with convection-enhanced delivery for malignant gliomas.We also discuss future trends that will be vital to CED innovation and improvement. CONCLUSION: Efficacy of CED for malignant glioma to date has been mixed, but improvements in technology and therapeutic agents arepromising.

Survey of United States neurosurgeons on firearm injury prevention.

OBJECTIVE: Firearm-related injuries and deaths are an endemic problem in the US, posing a burden on the healthcare system with significant social and economic consequences. As front-line care providers for these patients, neurosurgeons are both knowledgeable about these injuries and credible messengers in the public discussion of ways to reduce firearm injuries. The purpose of this study was to explore US-based neurosurgeons' views and behaviors regarding firearms to understand and define a potential role for neurosurgical organizations in advocacy efforts to reduce firearm death and injuries. METHODS: The authors conducted an anonymous survey of US neurosurgeons using the American Association of Neurological Surgeons (AANS) member database from April to June 2023. The 22-question survey included questions related to firearm ownership, personal views on firearms, and support for both general and policy-specific advocacy efforts to reduce firearm deaths and injuries. RESULTS: The survey response rate was 20.7%, with 1568 of the 7587 members invited completing the survey. The survey completion rate was 93.4%, with 1465 of the 1568 surveys completed and included in this analysis. The majority of respondents were male (raw: 81.7%; weighted 81.1%), White (raw: 69.7%; weighted 70.2%), and older than 50 years (raw: 56.2%; weighted: 54%). Most respondents reported treating patients with firearm injuries (raw: 83.3%; weighted: 82%), 85.5% (weighted: 85.1%) had used a firearm, and 42.4% (weighted: 41.5%) reported owning a firearm. Overall, 78.8% (weighted: 78.7%) of respondents felt that organized neurosurgery should participate in advocacy efforts. When examining individual policies, those that restrict the acquisition of firearms garnered the support of at least 65% of respondents, while nonrestrictive policies were supported by more than 75% of respondents. Free-text responses provided insight into both motivations for and objections to organizational advocacy. CONCLUSIONS: The majority of US-based neurosurgeons support involvement in advocacy efforts to reduce firearm deaths and injuries. Themes expressed by members both supporting and objecting to advocacy provide insight into approaches that could ensure broad support. Neurosurgical organizations such as the AANS and Congress of Neurological Surgeons may use the results of this survey to make informed decisions regarding involvement in advocacy efforts on behalf of their membership to lessen the burden of firearm injury in the US.

Surgical Characteristics of Intracranial Biopsy Using a Frameless Stereotactic Robotic Platform: A Single-Center Experience.

BACKGROUND AND OBJECTIVES: Cranial robotics are a burgeoning field of neurosurgery. To date, all cranial robotic systems described have been computerized, arm-based instruments that take up significant space in the operating room. The Medtronic Stealth Autoguide robot has a smaller operating room footprint and offers multiaxial, frame-based surgical targeting. The authors set out to define the surgical characteristics of a novel robotic platform for brain biopsy in a large patient cohort. METHODS: Patients who underwent stereotactic biopsy using the Stealth Autoguide cranial robotic platform from July 2020 to March 2023 were included in this study. Clinical, surgical, and histological data were collected and analyzed. RESULTS: Ninety-six consecutive patients (50 female, 46 male) were included. The mean age at biopsy was 53.7 ± 18.0 years. The mean target depth was 68.2 ± 15.3 mm. The biopsy diagnostic tissue acquisition rate was 100%. The mean time from incision to biopsy tissue acquisition was 15.4 ± 9.9 minutes. Target lesions were located throughout the brain: in the frontal lobe (n = 32, 33.3%), parietal lobe (n = 21, 21.9%), temporal lobe (n = 22, 22.9%), deep brain nuclei/thalamus (n = 13, 13.5%), cerebellum (n = 7, 7.3%), and brainstem (n = 1, 1.0%). Most cases were gliomas (n = 75, 78.2%). Patients were discharged home on postoperative day 0 or 1 in 62.5% of cases. A total of 7 patients developed postoperative complications (7.2%). CONCLUSION: This cranial robotic platform can be used for efficient, safe, and accurate cranial biopsies that allow for reliable diagnosis of intracranial pathology in a minimally invasive setting.

Proteostasis Modulation in Germline Missense von Hippel Lindau Disease.

PURPOSE: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. PATIENTS AND METHODS: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). RESULTS: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. CONCLUSIONS: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.

Intraoperative Predictor of Remission in Cushing Disease.

BACKGROUND: Cushing disease represents a challenge for neurosurgeons, with high recurrence rates reported. Characteristics associated with remission are incompletely understood; thus, an intraoperative predictor for outcome would be valuable for assessing resection of adrenocorticotropic hormone (ACTH) secreting tissue. OBJECTIVE: To evaluate whether intraoperative ACTH measurement could predict outcome after surgery for Cushing disease. METHODS: Retrospective cohort study of 55 consecutive encounters with Cushing disease who had peripheral plasma ACTH levels measured intraoperatively before, during, and after tumor resection. The primary outcome measure was remission, defined by either 2 negative 24-hour urine free cortisol or 2 negative midnight salivary cortisol measurements. A logistic regression machine learning model was generated using recursive feature elimination. RESULTS: Fifty-five operative encounters, comprising 49 unique patients, had a mean follow-up of 2.73 years (±2.11 years) and a median follow-up of 2.07 years. Remission was achieved in 69.1% (n = 38) of all operations and in 78.0% (n = 32) of those without cavernous sinus invasion. The final ACTH level measured intraoperatively correctly predicted outcome (area under the curve = 0.766; P value = .002). The odds ratio of remission in patients with the lowest quartile vs highest quartile final intraoperative ACTH was 23.4 ( P value = .002). Logistic regression machine learning model resulted in incorporating postoperative day 1 morning cortisol, final intraoperative ACTH that predicted outcome with an average area under the curve of 0.80 ( P = .0027). CONCLUSION: Intraoperative ACTH may predict outcome after surgery in Cushing disease; furthermore, investigation is warranted.

A 13-Year-Old Male With Left Eye Swelling.

A 13-year-old male presented with a 10-day history of left eye swelling and pain. These symptoms prompted presentation to the emergency department. He had no significant past medical history and no preceding fevers or chills. He was found on examination of the eyes and the orbit to have left supraorbital erythema, edema, and pain with upward and medial gaze. Examination of the globe, fundus, and visual fields were normal. His white blood cell count was 6.2 (x1000/mm3) with an erythrocyte sedimentation rate of 4 (mm/hr). Diagnostic endoscopic biopsy was performed. Here we present this case alongside clinical reasoning and diagnostic evaluation with relevant input from respective experts. This case discussion reviews the final diagnosis, as well as the corresponding evaluation and management. Diagnostic algorithms based on literature review and clinical experience are also included.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease.

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Endolymphatic Sac Tumor Screening and Diagnosis in von Hippel-Lindau Disease: A Consensus Statement.

Objective Endolymphatic sac tumors (ELSTs) are a frequent cause of hearing loss and other audiovestibular dysfunction in patients with von Hippel-Lindau disease (VHL). Unified screening recommendations for VHL patients have not been established. To develop consensus guidelines, the VHL Alliance formed an expert committee to define evidence-based clinical screening recommendations. Patients and Methods Recommendations were formulated by using the Grading of Recommendations, Assessment, Development, and Evaluation framework after a comprehensive literature review. Results Diagnosis of ELSTs in VHL requires a combination of clinical evaluation and imaging and audiometric findings. Audiovestibular signs/symptoms are often an early feature of small ELSTs, including those that are not visible on imaging. Diagnostic audiograms have the greatest sensitivity for the detection of ELST-associated sensorineural hearing loss and can help confirm clinically relevant lesions, including those that may not be radiographically evident. Magnetic resonance imaging (MRI) can be a more specific test for ELSTs in VHL particularly when supplemented with computed tomography imaging for the identification of small tumors. VHL patients between the ages 10 and 60 years carry high preponderance for ELST presentation. Conclusion We recommend that clinical evaluation (yearly) and diagnostic audiograms (every other year) be the primary screening tools for ELSTs in VHL. We suggest that screening be performed between the ages 11 and 65 years or with the onset of audiovestibular signs/symptoms for synchronicity with other testing regimens in VHL. We recommend that baseline imaging (MRI of the internal auditory canals) can be performed between the ages of 15 and 20 years or after positive screening.

Degenerative Spine Disorders and Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory disease that results in demyelination of the central nervous system (CNS). MS affects as many as 350,000 individuals in the United States and commonly presents before the age of 45 years. Patients with MS, as the general population, are likely to encounter degenerative changes of the spine as they age, and this can pose a unique challenge to both patients with MS and physicians, as both conditions can have a great deal of symptomatic overlap despite stark differences in management. Currently there is no definitive approach that allows physicians to distinguish between the 2 conditions; however, specific clinical and radiologic findings have been identified as being useful in evaluating these patients.

Familial Neoplastic Syndromes.

Familial neoplastic syndromes commonly impact the central and peripheral nervous systems. The most common neoplastic syndromes clinically relevant to neurology and neurologic surgery, include neurofibromatosis type 1, neurofibromatosis type 2, and Von Hippel-Lindau disease. We define the epidemiology, genetics, clinical presentation, and manifestations, as well as screening recommendations and management paradigms for these syndromes and other familial neoplastic syndromes that affect the nervous system. To ensure the optimal care of patients with neoplastic syndromes requires a multi-disciplinary approach and a comprehensive knowledge of the genetics, pathophysiology, manifestations, and management.

Neurosurgery Research and Education Foundation funding conversion to National Institutes of Health funding.

OBJECTIVE: The Neurosurgery Research and Education Foundation (NREF) provides research support for in-training and early career neurosurgeon-scientists. To define the impact of this funding, the authors assessed the success of NREF awardees in obtaining subsequent National Institutes of Health (NIH) funding. METHODS: NREF in-training (Research Fellowship [RF] for residents) and early career awards/awardees (Van Wagenen Fellowship [VW] and Young Clinician Investigator [YCI] award for neurosurgery faculty) were analyzed. NIH funding was defined by individual awardees using the NIH Research Portfolio Online Reporting tool (1985-2014). RESULTS: Between 1985 and 2014, 207 unique awardees were supported by 218 NREF awards ($9.84 million [M] in funding), including 117 RF ($6.02 M), 32 VW ($1.68 M), and 69 YCI ($2.65 M) awards. Subspecialty funding included neuro-oncology (79 awards; 36% of RF, VW, and YCI awards), functional (53 awards; 24%), vascular (37 awards; 17%), spine (22 awards; 10%), pediatrics (18 awards; 8%), trauma/critical care (5 awards; 2%), and peripheral nerve (4 awards; 2%). These awardees went on to receive $353.90 M in NIH funding that resulted in an overall NREF/NIH funding ratio of 36.0:1 (in dollars). YCI awardees most frequently obtained later NIH funding (65%; $287.27 M), followed by VW (56%; $41.10 M) and RF (31%; $106.59 M) awardees. YCI awardees had the highest NREF/NIH funding ratio (108.6:1), followed by VW (24.4:1) and RF (17.7:1) awardees. Subspecialty awardees who went on to obtain NIH funding included vascular (19 awardees; 51% of vascular NREF awards), neuro-oncology (40 awardees; 51%), pediatrics (9 awardees; 50%), functional (25 awardees; 47%), peripheral nerve (1 awardees; 25%), trauma/critical care (2 awardees; 20%), and spine (2 awardees; 9%) awardees. Subspecialty NREF/NIH funding ratios were 56.2:1 for vascular, 53.0:1 for neuro-oncology, 47.6:1 for pediatrics, 34.1:1 for functional, 22.2:1 for trauma/critical care, 9.5:1 for peripheral nerve, and 0.4:1 for spine. Individuals with 2 NREF awards achieved a higher NREF/NIH funding ratio (83.3:1) compared to those with 1 award (29.1:1). CONCLUSIONS: In-training and early career NREF grant awardees are an excellent investment, as a significant portion of these awardees go on to obtain NIH funding. Moreover, there is a potent multiplicative impact of NREF funding converted to NIH funding that is related to award type and subspecialty.

Resident Night Float or 24-hour Call Hospital Coverage: Impact on Training, Patient Outcome, and Length of Stay.

OBJECTIVE: The impact of neurosurgical resident hospital coverage system, performed via a night float (12-hour shifts overnight) or a 24-hour call, on neurological surgery resident training and patient care is unknown. DESIGN: Retrospective review comparing night float and 24-hour call coverage on trainee surgical experience, elective time, annual program surveys, patient outcomes, and length of stay. SETTING: The Ohio State Wexner Medical Center Neurosurgery residency program, Columbus, Ohio. PARTICIPANTS: The neurosurgical residents from 2016 to 2019. RESULTS: Monthly cases performed by junior residents significantly increased after transitioning to a 24-hour call schedule (18 versus 30, p < 0.001). There were no differences for total cases among program graduates during this time (p = 0.7). Trainee elective time significantly increased after switching to 24-hour call coverage (18 versus 24 months after the transition; p = 0.004). Risk-adjusted mortality and length of stay indices were not different (0.5 versus 0.3, p = 0.1; 0.9 versus 0.9; p = 0.3). Program surveys had minimal change after the transition to 24-hour call. CONCLUSIONS: Transitioning from a night float to a 24-hour call coverage system led to improved junior resident case volume and elective time without detrimental effect on patient-related outcomes.

Hemangioblastoma of the Peripheral Nervous System: A Critical Analysis of Its Rarity in Von Hippel-Lindau Disease.

Von Hippel-Lindau (VHL) disease is a multisystem disease cause by germline mutations of the VHL tumor suppressor gene. Hemangioblastomas are the most common manifestation of VHL disease and can occur in the central nervous system in up to 90% of these patients. By contrast, we found only one true case of a peripheral nervous system (PNS) hemangioblastoma in the setting of VHL. We explore the possible reasons behind the lack of PNS hemangioblastomas in VHL disease.