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At present there is a significant unmet need for clinically available treatments for Parkinson’s disease (PD) patients to stably restore balance to dopamine network function, leaving patients with inadequate management of symptoms as the disease progresses. Gene therapy is an attractive approach to impart a durable effect on neuronal function through introduction of genetic material to reestablish dopamine levels and/or functionally recover dopaminergic signaling by improving neuronal health. Ongoing clinical gene therapy trials in PD are focused on enzymatic enhancement of dopamine production and/or the restoration of the nigrostriatal pathway to improve dopaminergic network function. In this review, we discuss data from current gene therapy trials for PD and recent advances in study design and surgical approaches.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function., Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.

OBJECTIVE While high-velocity missile injury (gunshot) is associated with kinetic and thermal injuries, non-missile penetrating head injury (NMPHI) results in primary damage along the tract of the piercing object that can be associated with significant secondary complications. Despite the unique physical properties of NMPHI, factors associated with complications, expected outcomes, and optimal management have not been defined. In this study, the authors attempted to define those factors. METHODS Consecutive adult patients with NMPHI who presented to Tygerberg Academic Hospital (Cape Town, South Africa) in the period from August 1, 2011, through July 31, 2018, were enrolled in a prospective study using a defined treatment algorithm. Clinical, imaging, and laboratory data were analyzed. RESULTS One hundred ninety-two patients (185 males [96%], 7 females [4%]) with 192 NMPHIs were included in this analysis. The mean age at injury was 26.2 ± 1.1 years (range 18–58 years). Thirty-four patients (18%) presented with the weapon in situ. Seventy-one patients (37%) presented with a Glasgow Coma Scale (GCS) score of 15. Weapons included a knife (156 patients [81%]), screwdriver (18 [9%]), nail gun (1 [0.5%]), garden fork (1 [0.5%]), barbeque fork (1 [0.5%]), and unknown (15 [8%]). The most common wound locations were temporal (74 [39%]), frontal (65 [34%]), and parietal (30 [16%]). The most common secondary complications were vascular injury (37 patients [19%]) and infection (27 patients [14%]). Vascular injury was significantly associated with imaging evidence of deep subarachnoid hemorrhage and an injury tract crossing vascular territory (p ≤ 0.05). Infection was associated with delayed referral (> 24 hours), lack of prophylactic antibiotic administration, and weapon in situ (p ≤ 0.05). A poorer outcome was associated with a stab depth > 50 mm, a weapon removed by the assailant, vascular injury, and eloquent brain involvement (p ≤ 0.05). Nineteen patients (10%) died from their injuries. The Glasgow Outcome Scale (GOS) score was linearly related to the admission GCS score (p < 0.001). One hundred forty patients (73%) had a GOS score of 4 or better at discharge. CONCLUSIONS The most common NMPHI secondary complications are vascular injury and infection, which are associated with specific NMPHI imaging and clinical features. Identifying these features and using a systematic management paradigm can effectively treat the primary injury, as well as diagnose and manage NMPHI-related complications, leading to a good outcome in the majority of patients.

BACKGROUND: Retrobulbar hemangioblastomas involving the optic apparatus in patients with von Hippel-Lindau disease (VHL) are rare, with only 25 reported cases in the literature. OBJECTIVE: To analyze the natural history of retrobulbar hemangioblastomas in a large cohort of VHL patients in order to define presentation, progression, and management. METHODS: Clinical history and imaging of 250 patients with VHL in an ongoing natural history trial and 1774 patients in a neurosurgical protocol were reviewed. The clinical course, magnetic resonance images, treatment, and outcomes were reviewed for all included patients. RESULTS: A total of 18 patients with retrobulbar hemangioblastoma on surveillance magnetic resonance imaging met the inclusion criteria for this study. Of the 17 for whom clinical information was available, 10 patients presented with symptoms related to the hemangioblastoma, and 7 were asymptomatic. The mean tumor volume was larger for symptomatic (810.6 ± 545.5 mm(3)) compared to asymptomatic patients (307.6 ± 245.5 mm(3); P

OBJECTIVEThe objective of this study was to assess the feasibility, accuracy, effectiveness, and safety of an MRI-compatible frameless stereotactic ball-joint guide array (BJGA) as a platform for cannula placement and convection-enhanced delivery (CED).METHODSThe authors analyzed the clinical and imaging data from consecutive patients with aromatic l-amino acid decarboxylase (AADC) deficiency who underwent infusion of adeno-associated virus (AAV) containing the AADC gene (AAV2-AADC).RESULTSEleven patients (7 females, 4 males) underwent bilateral MRI-guided BJGA cannula placement and CED of AAV2-AADC (22 brainstem infusions). The mean age at infusion was 10.5 ± 5.2 years (range 4–19 years). MRI allowed for accurate real-time planning, confirmed precise cannula placement after single-pass placement, and permitted on-the-fly adjustment. Overall, the mean bilateral depth to the target was 137.0 ± 5.2 mm (range 124.0–145.5 mm). The mean bilateral depth error was 0.9 ± 0.7 mm (range 0–2.2 mm), and the bilateral radial error was 0.9 ± 0.6 mm (range 0.1–2.3 mm). The bilateral absolute tip error was 1.4 ± 0.8 mm (range 0.4–3.0 mm). Target depth and absolute tip error were not correlated (Pearson product-moment correlation coefficient, r = 0.01).CONCLUSIONSUse of the BJGA is feasible, accurate, effective, and safe for cannula placement, infusion MRI monitoring, and cannula adjustment during CED. The low-profile universal applicability of the BJGA streamlines and facilitates MRI-guided CED.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Introduction. Vector-based intracerebral gene therapies are being used to treat specific neurodegenerative conditions such as Parkinson’s Disease (PD). This review presents a basis for central nervous system (CNS) gene therapy treatments of neurodegenerative diseases such as PD, as well as the need for novel skill sets and health delivery strategies within the clinical neurosciences (neurology and neurosurgery) to meet future demand for such therapies. State of the art. Preclinical vector-based gene therapy approaches have been translated into clinical trials for PD and other neurodegenerative conditions. Unfortunately, such trials, and parallel efforts using other therapeutics, have yet to provide a breakthrough. Image-guided convection enhanced delivery (CED) optimises the parenchymal distribution of gene therapies applied within the CNS, and may ultimately provide such a breakthrough. Clinical implications. Currently, image-guided CED and gene therapy are not part of training programmes for most neurosurgeons and neurologists. As a result, few medical centres and hospitals have sufficiently experienced teams to participate in gene transfer clinical trials for PD or other neurological conditions. If CNS gene therapies prove to be efficacious for PD and/or other conditions, the demand for such treatments will overwhelm the available number of experienced clinical neuroscience teams and treatment centres. Future directions. Expanded indications and demand for CNS gene therapies will require a worldwide educational effort to supplement the training of clinical neuroscience practitioners. Initially, a limited number of Centres of Excellence will need to establish relevant educational training requirements and best practice for such therapeutic approaches. Advanced technologies, including robotics and artificial intelligence, are especially germane in this regard, and will expand the treatment team’s capabilities while assisting in the safe and timely care of those afflicted.

Background Gamma knife (GK) and linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) both offer excellent local control in the management of multiple brain metastases. The efficacy and toxicity of LINAC and GK SRS have not been directly compared in the modern era. We studied outcomes in patients treated with LINAC SRS and GK at two separate institutions. Methods We identified patients treated with either LINAC or GK who were treated to ≥2 lesions and had available follow up. LINAC patients were treated using single-isocenter multitarget technique. We used Cox regression, Fine and Gray competing risks regression, and nearest neighbor propensity score matching to account for confounders and imbalance between cohorts. Kaplan–Meier curves were used to estimate overall survival and rates of radionecrosis. Results We identified 391 patients who were treated in 537 courses to a total 2699 lesions (LINAC: 1014, GK: 1685). After propensity score matching, GK was associated with similar overall survival (HR = 0.86; 95% CI 0.59–1.24; p = 0.41) and higher rate of radionecrosis (HR = 3.83; 95% CI 1.66–8.84; p = 0.002) compared to LINAC. In a secondary propensity score matched analysis comparing radionecrosis in single-fraction LINAC and GK, GK remained associated with higher incidence of radionecrosis (HR = 4.42; 95% CI 1.28–15.29; p = 0.019). Conclusions In this multi-institutional study, we found similar overall survival with lower incidence of radionecrosis in patients treated with LINAC compared to GK SRS. These findings are hypothesis generating and should be validated in an independent cohort.

Purpose Multiple studies have reported favorable outcomes for stereotactic radiosurgery (SRS) in the treatment of limited brain metastases. An obstacle of SRS in the management of numerous metastases is the longer treatment time using traditional radiosurgery. Single-isocenter multitarget (SIMT) SRS is a novel technique that permits rapid therapy delivery to multiple metastases. There is a lack of clinical evidence regarding its efficacy and safety. We report the outcomes of patients treated with this technique. Methods and Materials We reviewed the records of patients with intact or resected brain metastases treated with SRS in 1 to 5 fractions using SIMT technique at our institution, with at least 1 available follow-up brain magnetic resonance imaging. Survival, disease control, and toxicity were evaluated using Cox regression, logistic regression, and Kaplan-Meier analysis. Results We identified 173 patients with 1014 brain metastases. Median follow up was 12.7 months. Median beam-on time was 4.1 minutes. The median dose to the brain was 219.4 cGy. Median overall survival and freedom from intracranial progression were 13.2 and 6.3 months, respectively. Overall survival did not differ between patients treated with greater than or less than 4 lesions (hazard ratio, 1.03; 95% confidence interval 0.66-1.61; P = .91). Actuarial 1- and 2-year local control were 99.0% and 95.1%, respectively. Rates of grade 2 and grade 3 or higher radionecrosis were 1.4% and 0.9%, respectively. Conclusions SIMT radiosurgery delivered in 1 to 5 fractions offers excellent local control and acceptable toxicity in the treatment of multiple intact and postoperative brain metastases. This technique should be evaluated prospectively.

OBJECTIVE To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P

In MRI-negative cases Cushing’s disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. 18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD. Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two 18F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read 18F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins. The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas. The results of the current study suggest that oCRH-stimulation may lead to increased 18F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging. 18F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).

Background Laser-interstitial thermal therapy (LITT) has been supported by some authors as an ablative treatment of glioblastoma multiforme (GBM). Although the effects of LITT have been modeled in vivo, the histologic effects in a clinical circumstance have not been described. We analyzed tissue from a patient who underwent LITT as primary treatment for GBM. Case presentation A 62-year-old male was diagnosed with a left temporal GBM and underwent LITT at an outside institution. Despite corticosteroid therapy, the patient was referred with increasing headache and acalculia associated with progressive peritumoral edema two weeks after LITT procedure. En bloc resection of the enhancing lesion and adjacent temporal lobe was performed with steroid-independent symptom resolution (follow-up, > 2 years). Histologic analysis revealed three distinct histologic zones concentrically radiating from the center of the treatment site. An acellular central region of necrosis (Zone 1) was surrounded by a rim of granulation tissue with macrophages (CD68) (Zone 2; mean thickness, 1.3 ± 0.3 mm [±S.D.]). Viable tumor cells (identified by Ki-67, p53 and Olig2 immunohistochemistry) were found (Zone 3) immediately adjacent to granulation tissue. The histologic volume of thermal tissue ablation/granulation was consistent with preoperative (pre-resection) magnetic resonance (MR)-imaging. Conclusion These findings are the first in vivo in humans to reveal that LITT causes a defined pattern of tissue necrosis, concentric destruction of tumor and tissue with viable tumor cells just beyond the zones of central necrosis and granulation. Furthermore, MR-imaging appears to be an accurate surrogate of tissue/tumor ablation in the early period (2 weeks) post-LITT treatment. Surgery is an effective strategy for patients with post-LITT swelling which does not respond to steroids.

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.

Diffuse midline glioma with histone H3 lysine27-to-methionine mutation (H3 K27M mutation) is a rare, aggressive tumor that is designated as World Health Organization (WHO) grade IV regardless of histologic features. Preoperative diagnosis remains challenging due to limited evidence regarding distinctive clinical and imaging characteristics. We describe the case of a young woman who presented with progressively worsening headaches due to communicating hydrocephalus. MR imaging with contrast of the cervical and thoracic spine revealed diffuse leptomeningeal enhancement with focal areas of intramedullary and subarachnoid T2 hyperintensity and enhancement, suggestive of a potential infectious process. Intraoperatively, no epidural pathology was identified, and with the differential diagnosis remaining broad, a second procedure was conducted involving intradural exploration and biopsy of a lesion. This was then identified as a diffuse midline glioma with H3 K27M mutation. The nonfocal clinical presentation in the setting of communicating hydrocephalus as well as the significant exophytic tumor growth and imaging findings made the initial diagnosis unique and challenging. This case, therefore, emphasizes the rare presentation of this tumor, and the need for further understanding of the clinical and imaging characteristics of this disease as well as the need for effective therapeutics.

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.

PURPOSE/OBJECTIVE(S) The standard of care for elderly glioblastoma patients (GBM) is 40 Gy in 15 fractions with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that dose escalated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. MATERIALS/METHODS Elderly patients (> 60 yo) who received hypofractionated radiation with TMZ were included in this analysis. Overall survival (OS) and progression free survival (PFS) were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared with pairwise tests. Univariate and multivariate analyses were performed. RESULTS 66 newly-diagnosed patients were eligible for this analysis. 39 patients were treated with 40 Gy in 15 fractions, and 27 patients were treated with 52.5 Gy in 15 fractions. The median follow up for this cohort was 8.8 months. Patients were well balanced with no significant differences in age, sex, MGMT, extent of resection, or KPS. The median OS was 7.9 months in the 40 Gy arm and 13.1 months in the 52.5 Gy arm (P = 0.035). For unmethylated patients, the median OS was 6.7 months in the 40 Gy arm and 11.3 months in the 52.5 Gy arm (P = 0.012). Increasing planning treatment volume (P = 0.007) was associated with decreased OS. On multivariate analysis, MGMT methylation (HR 0.45 [0.23-0.87] P = 0.018) and dose escalation (HR 0.45 [0.21-0.96] 0.04) remained independent prognostic factors for OS. In a multivariate model for PFS, only dose-escalation was significant (HR 0.49 [0.25-0.98] P = 0.045). No significant differences in toxicity were observed between treatment groups. CONCLUSION Dose-escalation to 52.5 Gy in 15 fractions was associated with superior OS and PFS compared to standard of care 40 Gy in 15 fractions. This treatment regimen gives the elderly population an alternative to Stupp that is not de-escalating therapy. These hypothesis generating data support dose-escalated hypofractionation in future prospective trials. AUTHOR DISCLOSURE H.K. Perlow: None. M. Yang: None. B. Klamer: None. R. Raval: None. D.M. Blakaj: None. A.L. Arnett: None. S. Beyer: None. J.C. Grecula: None. M. Ammirati: None. J.B. Elder: None. R.R. Lonser: None. D. Hardesty: None. S.S. Ong: None. P. Giglio: None. C. Pillainayagam: None. J. Goranovich: None. A. Chakravarti: None. V. Gondi: Partner; Radiation Oncology Consultants, Ltd. Honoraria; UpToDate, RaySearch. Partnership; Radiation Oncology Consultants, Ltd. Co-Principal Investigator; NRG Oncology. P.D. Brown: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.

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.

The American Board of Neurological Surgery (ABNS) was incorporated in 1940 in recognition of the need for detailed training in and special qualifications for the practice of neurological surgery and for self-regulation of quality and safety in the field. The ABNS believes it is the duty of neurosurgeons to place a patient’s welfare and rights above all other considerations and to provide care with compassion, respect for human dignity, honesty, and integrity. At its inception, the ABNS was the 13th member board of the American Board of Medical Specialties (ABMS), which itself was founded in 1933. Today, the ABNS is one of the 24 member boards of the ABMS.To better serve public health and safety in a rapidly changing healthcare environment, the ABNS continues to evolve in order to elevate standards for the practice of neurological surgery. In connection with its activities, including initial certification, recognition of focused practice, and continuous certification, the ABNS actively seeks and incorporates input from the public and the physicians it serves. The ABNS board certification processes are designed to evaluate both real-life subspecialty neurosurgical practice and overall neurosurgical knowledge, since most neurosurgeons provide call coverage for hospitals and thus must be competent to care for the full spectrum of neurosurgery.The purpose of this report is to describe the history, current state, and anticipated future direction of ABNS certification in the US.

Background Spine surgery is indicated for select patients with mechanical instability, pain, and/or malignant epidural spinal cord compression, with or without neurological compromise. Stereotactic body radiotherapy (SBRT) is an option for durable local control (LC) for metastatic spine disease. Objective To determine factors associated with LC and progression-free survival (PFS) for patients receiving postoperative stereotactic spine radiosurgery. Methods We analyzed consecutive patients from 2013 to 2019 treated with surgical intervention followed by SBRT. Surgical interventions included laminectomy and vertebrectomy. SBRT included patients treated with 1 to 5 fractions of radiosurgery. We analyzed LC, PFS, overall survival (OS), and toxicity. Univariate and multivariate analyses were performed. Results A total of 63 patients were treated with a median follow-up of 12.5 mo. Approximately 75% of patients underwent vertebrectomy and 25% underwent laminectomy. One-year cumulative incidence of local failure was 19%. LC was significantly improved for patients receiving radiosurgery ≤40 d from surgery compared to that for patients receiving radiosurgery ≥40 d from surgery, 94% vs 75%, respectively, at 1 yr (P = .03). Patients who received preoperative embolization had improved LC with 1-yr LC of 88% vs 76% for those who did not receive preoperative embolization (P = .037). Significant predictors for LC on multivariate analysis were time from surgery to radiosurgery, higher radiotherapy dose, and preoperative embolization. The 1-yr PFS and OS was 56% and 60%, respectively. Conclusion Postoperative radiosurgery has excellent and durable LC for spine metastasis. An important consideration when planning postoperative radiosurgery is minimizing delay from surgery to radiosurgery. Preoperative embolization and higher radiotherapy dose were associated with improved LC warranting further study.

OBJECTIVE To increase the number of independent National Institutes of Health (NIH)–funded neurosurgeons and to enhance neurosurgery research, the National Institute of Neurological Disorders and Stroke (NINDS) developed two national comprehensive programs (R25 [established 2009] for residents/fellows and K12 [2013] for early-career neurosurgical faculty) in consultation with neurosurgical leaders and academic departments to support in-training and early-career neurosurgeons. The authors assessed the effectiveness of these NINDS-initiated programs to increase the number of independent NIH-funded neurosurgeon-scientists and grow NIH neurosurgery research funding. METHODS NIH funding data for faculty and clinical department funding were derived from the NIH, academic departments, and Blue Ridge Institute of Medical Research databases from 2006 to 2019. RESULTS Between 2009 and 2019, the NINDS R25 funded 87 neurosurgical residents. Fifty-three (61%) have completed the award and training, and 39 (74%) are in academic practice. Compared to neurosurgeons who did not receive R25 funding, R25 awardees were twice as successful (64% vs 31%) in obtaining K-series awards and received the K-series award in a significantly shorter period of time after training (25.2 ± 10.1 months vs 53.9 ± 23.0 months; p < 0.004). Between 2013 and 2019, the NINDS K12 has supported 19 neurosurgeons. Thirteen (68%) have finished their K12 support and all (100%) have applied for federal funding. Eleven (85%) have obtained major individual NIH grant support. Since the establishment of these two programs, the number of unique neurosurgeons supported by either individual (R01 or DP-series) or collaborative (U- or P-series) NIH grants increased from 36 to 82 (a 2.3-fold increase). Overall, NIH funding to clinical neurological surgery departments between 2006 and 2019 increased from $66.9 million to $157.3 million (a 2.2-fold increase). CONCLUSIONS Targeted research education and career development programs initiated by the NINDS led to a rapid and dramatic increase in the number of NIH-funded neurosurgeon-scientists and total NIH neurosurgery department funding.

Molecular biological insights have led to a fundamental understanding of the underlying genomic mechanisms of nervous system disease. These findings have resulted in the identification of therapeutic genes that can be packaged in viral capsids for the treatment of a variety of neurological conditions, including neurodegenerative, metabolic, and enzyme deficiency disorders. Recent data have demonstrated that gene-carrying viral vectors (most often adeno-associated viruses) can be effectively distributed by convection-enhanced delivery (CED) in a safe, reliable, targeted, and homogeneous manner across the blood-brain barrier. Critically, these vectors can be monitored using real-time MRI of a co-infused surrogate tracer to accurately predict vector distribution and transgene expression at the perfused site. The unique properties of CED of adeno-associated virus vectors allow for cell-specific transgene manipulation of the infused anatomical site and/or widespread interconnected sites via antero- and/or retrograde transport. The authors review the convective properties of viral vectors, associated technology, and clinical applications.

Background The origin of syrinx fluid is controversial. Objective To elucidate the mechanisms of syringomyelia associated with cerebrospinal fluid pathway obstruction and with intramedullary tumors, contrast transport from the spinal subarachnoid space (SAS) to syrinx was evaluated in syringomyelia patients. Methods We prospectively studied patients with syringomyelia: 22 with Chiari I malformation and 16 with SAS obstruction-related syringomyelia before and 1 wk after surgery, and 9 with tumor-related syringomyelia before surgery only. Computed tomography-myelography quantified dye transport into the syrinx before and 0.5, 2, 4, 6, 8, 10, and 22 h after contrast injection by measuring contrast density in Hounsfield units (HU). Results Before surgery, more contrast passed into the syrinx in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia than in tumor-related syringomyelia, as measured by (1) maximum syrinx HU, (2) area under the syrinx concentration-time curve (HU AUC), (3) ratio of syrinx HU to subarachnoid cerebrospinal fluid (CSF; SAS) HU, and (4) AUC syrinx/AUC SAS. More contrast (AUC) accumulated in the syrinx and subarachnoid space before than after surgery. Conclusion Transparenchymal bulk flow of CSF from the subarachnoid space to syrinx occurs in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia. Before surgery, more subarachnoid contrast entered syringes associated with CSF pathway obstruction than with tumor, consistent with syrinx fluid originating from the subarachnoid space in Chiari I malformation and spinal obstruction-related syringomyelia and not from the subarachnoid space in tumor-related syringomyelia. Decompressive surgery opened subarachnoid CSF pathways and reduced contrast entry into syringes associated with CSF pathway obstruction.

Convection-enhanced delivery (CED) permits for the direct homogeneous delivery of small and large molecular weight putative therapeutics to the nervous system in a manner that bypasses the blood-nervous system barrier. The development of co-infused surrogate imaging tracers (for computed tomography and magnetic resonance imaging) allows for the real-time, non-invasive monitoring of infusate distribution during convective delivery. Real-time image monitoring of convective distribution of therapeutic agents, insures that targeted structures/nervous system regions are adequately perfused, enhances safety, informs efficacy (or lack thereof) of putative agents and provides critical information regarding the properties of CED in normal and various pathologic tissue states.

Background Cauda equina hemangioblastomas in von Hippel-Lindau (VHL) disease can cause significant neurological signs and symptoms. Despite their associated morbidity, the management of these tumors remains incompletely defined. Objective To determine optimal management, we analyzed the functional outcomes after resection of these tumors. Methods VHL patients who underwent surgical resection of cauda equina hemangioblastomas at the National Institutes of Health and the University of Virginia were included. Clinical and radiological follow-up was performed at 6- to 12-month intervals after surgery. Results Fifteen patients underwent 18 operations for 21 cauda equina hemangioblastomas (median follow-up 5.9 years). Patients often presented with multiple symptoms, including pain (67%), numbness (50%), urinary complaints (33%), and weakness (11%). Median preoperative tumor volume was 1.2 cm 3 . Four tumors at 3 operations were not resected due to a motor nerve root origin. Gross total resection was achieved in 14 surgeries (93% of operations when resection was attempted). New mild (non-function limiting) neurological symptoms were noted after 11 operations (61%), which most often (64%) resolved within 2 weeks of surgery. At 6-month follow-up, 15 patients (83%) were stable, 2 (11%) were improved, and 1 (6%) was worse. Histological analysis revealed that all tumors originated from within the involved nerve fascicle. Conclusions VHL-associated cauda equina hemangioblastomas have an intrafascicular origin and require interruption of the rootlet of origin for complete resection. Motor nerve root involvement may preclude complete resection but strategies including bony decompression and/or interruption of vascular supply may provide a therapeutic option. Nevertheless, most VHL patients with symptom-producing lesions improve with resection.

Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD.

BACKGROUND Carney complex (CNC) is a familial neoplasia syndrome that is associated with pituitary-associated hypersecretion of growth hormone (GH) (acromegaly). The underlying cause of pituitary GH hypersecretion and its management have been incompletely defined. OBJECTIVE To provide biological insight into CNC-associated pituitary pathology and improve management, we analyzed findings in CNC patients who underwent transsphenoidal surgery. METHODS Consecutive CNC patients at the National Institutes of Health with acromegaly and imaging evidence of a pituitary adenoma(s) who underwent transsphenoidal resection of tumor(s) were included. Prospectively acquired magnetic resonance imaging and biochemical, surgical, and histological data were analyzed. RESULTS Seven acromegalic CNC patients (2 male, 5 female) were included. The mean age at surgery was 29.7 years (range, 18-44 years). The mean follow-up was 4.7 years (range, 0.2-129 months). Magnetic resonance imaging revealed a single pituitary adenoma in 4 patients and multiple pituitary adenomas in 3 patients. Whereas patients with single discrete pituitary adenomas underwent selective adenomectomy, patients with multiple adenomas underwent selective adenomectomy of multiple tumors, as well as partial or total hypophysectomy. All adenomas were either GH and prolactin positive or exclusively prolactin positive. Pituitary tissue surrounding the adenomas in patients with multiple adenomas revealed hyperplastic GH- and prolactin-positive tissue. CONCLUSION CNC-associated acromegaly results from variable pituitary pathology, including a single GH-secreting adenoma or multiple GH-secreting adenomas and/or GH hypersecretion of the pituitary gland surrounding multiple adenomas. Although selective adenomectomy is the preferred treatment for cases of GH-secreting adenomas, multiple adenomas with associated pituitary gland GH hypersecretion may require partial or complete hypophysectomy to achieve biochemical remission.

OBJECTIVETo develop and assess a convective delivery technique that enhances the effectiveness of drug delivery to nonspherical brain nuclei, the authors developed an occipital “infuse-as-you-go” approach to the putamen and compared it to the currently used transfrontal approach.METHODSEleven nonhuman primates received a bilateral putamen injection of adeno-associated virus with 2 mM gadolinium-DTPA by real-time MR-guided convective perfusion via either a transfrontal (n = 5) or occipital infuse-as-you-go (n = 6) approach.RESULTSMRI provided contemporaneous assessment and monitoring of putaminal infusions for transfrontal (2 to 3 infusion deposits) and occipital infuse-as-you-go (stepwise infusions) putaminal approaches. The infuse-as-you-go technique was more efficient than the transfrontal approach (mean 35 ± 1.1 vs 88 ± 8.3 minutes [SEM; p < 0.001]). More effective perfusion of the postcommissural and total putamen was achieved with the infuse-as-you-go versus transfronatal approaches (100-µl infusion volumes; mean posterior commissural coverage 76.2% ± 5.0% vs 32.8% ± 2.9% [p < 0.001]; and mean total coverage 53.5% ± 3.0% vs 38.9% ± 2.3% [p < 0.01]).CONCLUSIONSThe infuse-as-you-go approach, paralleling the longitudinal axis of the target structure, provides a more effective and efficient method for convective infusate coverage of elongated, irregularly shaped subcortical brain nuclei.

Diseases of the central nervous system (CNS) encompass a large spectrum of pathological states that includes genetic and developmental disorders, neurodegenerative diseases, trauma, and cancer. One limitation of treating these diseases is the protective mechanisms developed by the CNS that limit its exposure to systemically delivered therapies. These mechanisms often affect the efficiency and specificity of CNS drug delivery. This chapter presents an overview of barriers to CNS drug delivery and identifies mechanisms to overcome the protective defenses of the CNS, allowing targeted therapy for specific disease entities.

Central nervous system (CNS) hemangioblastomas are the most common primary posterior fossa neoplasm in adults. These pathologically benign, vascular tumors occur sporadically in approximately two-thirds of cases and arise in the context of the familial neoplasia syndrome, von Hippel-Lindau disease (VHL), in the remainder of cases. Whether they occur sporadically or in association with VHL, 99% of hemangioblastomas occur below the tentorium. Ninety-five percent of VHL patients with a hemangioblastoma will have multiple hemangioblastomas. Due to a germline mutation of the VHL tumor suppressor gene, located on the short arm of chromosome 3, VHL is typically transmitted in an autosomal dominant manner. Nonetheless, germline mutations of the VHL gene can arise de novo in approximately 5% of patients. In addition to CNS hemangioblastomas, VHL patients are also predisposed to endolymphatic sac tumors, renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors.

OBJECTIVE In this clinical trial report, the authors analyze safety and infusion distribution of IL13-Pseudomonas exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG). METHODS This was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion. RESULTS Direct infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes. CONCLUSIONS Even though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients’ performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes. Clinical trial registration no.: NCT00088061 (clinicaltrials.gov) ABBREVIATIONS CED = convection-enhanced delivery; DIPG = diffuse intrinsic pontine glioma; IL-13 = interleukin 13; IL13R = IL-13 receptor; IPI = Impact of Pediatric Illness; KPS = Karnofsky Performance Status; LPS = Lansky Performance Status; MRS = MR spectroscopy; NAA = n-acetyl aspartate; QOL = quality of life; Vd = volume of distribution; Vi = volume of infusion.

Background Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. Objective This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. Methods Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1–4 μg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. Results A total of 10 patients have completed treatment with infusion doses of carboplatin of 1μg, 2μg, and 4μg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). Conclusions IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4μg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.

OBJECT Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease. METHODS Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed. RESULTS One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 ± 13.1 years ([mean ± SD], median 37.9, range 12.3–65.1 years). The mean follow-up was 7.0 ± 1.7 years (median 7.3, range 2.1–9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001). CONCLUSIONS Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene.

OBJECT The object of this study was to assess the feasibility, accuracy, and safety of real-time MRI-compatible frameless stereotactic brain biopsy. METHODS Clinical, imaging, and histological data in consecutive patients who underwent stereotactic brain biopsy using a frameless real-time MRI system were analyzed. RESULTS Five consecutive patients (4 males, 1 female) were included in this study. The mean age at biopsy was 45.8 years (range 29–60 years). Real-time MRI permitted concurrent display of the biopsy cannula trajectory and tip during placement at the target. The mean target depth of biopsied lesions was 71.3 mm (range 60.4–80.4 mm). Targeting accuracy analysis revealed a mean radial error of 1.3 ± 1.1 mm (mean ± standard deviation), mean depth error of 0.7 ± 0.3 mm, and a mean absolute tip error of 1.5 ± 1.1 mm. There was no correlation between target depth and absolute tip error (Pearson product-moment correlation coefficient, r = 0.22). All biopsy cannulae were placed at the target with a single penetration and resulted in a diagnostic specimen in all cases. Histopathological evaluation of biopsy samples revealed dysembryoplastic neuroepithelial tumor (1 case), breast carcinoma (1 case), and glioblastoma multiforme (3 cases). CONCLUSIONS The ability to place a biopsy cannula under real-time imaging guidance permits on-the-fly alterations in the cannula trajectory and/or tip placement. Real-time imaging during MRI-guided brain biopsy provides precise safe targeting of brain lesions.

The optimal approach for deep vein thrombosis (DVT) prophylaxis in the neurosurgery patient is a challenge of balancing the reduction in incidence of DVT and pulmonary embolus (PE) without risking an increase in catastrophic hemorrhages. In this article, the authors review the current literature on DVT/PE prophylaxis in neurosurgery. Mechanical and pharmacologic DVT prophylaxis strategies are discussed in terms of their efficacy in reducing DVT/PE rates as well as safety in terms of catastrophic hemorrhages. The authors offer recommendations regarding the best approach given the current state of the literature.

BACKGROUND: Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function. OBJECTIVE: To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs). METHODS: Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and (3)H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison. RESULTS: MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of (3)H-muscimol (Vd; R = 0.94). Mean Vd of infused animals was 37.9 mm(3) ± 11.7 mm(3) and mean Vd: Vi 7.6 ± 2.3. CONCLUSION: Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.

Context Achievement of hypocortisolemia following transsphenoidal surgery (TSS) for Cushing’s disease (CD) is associated with successful adenoma resection. However, up to one-third of these patients recur. Objective We assessed whether delay in reaching post-operative cortisol nadir may delineate patients at risk of recurrence for CD following TSS. Methods A retrospective review of 257 patients who received 291 TSS procedures for CD at NIH, between 2003 and 2016. Early biochemical remission (serum cortisol nadir Results Of the 268 unique admissions, remission was recorded in 241 instances. Recurrence was observed in 9% of these cases with cortisol nadir ≤5 μg/dL and 6% of cases with cortisol nadir ≤2 μg/dL. The timing of hypocortisolemia was critical in detecting late recurrences. Morning POD-1 cortisol Conclusions In our cohort, early, profound hypocortisolemia could be used as a clinical prediction tool for durable remission. Achievement of hypocortisolemia ≤2 µg/dL before 21 post-operative hours appeared to accurately predict durable remission in the intermediate term.

Arvid Lindau, MD, PhD, consolidated the disparate array of benign and malignant visceral and nervous system lesions into the neoplastic syndrome known as von Hippel-Lindau (VHL) disease. Based on this pioneering work, Dr. Lindau was awarded both a Rockefeller fellowship to work in Dr. Harvey Cushing's laboratory in Boston, Massachusetts, and the Lennmalm Prize. While working in Dr. Cushing's laboratory, Dr. Lindau continued his study of CNS hemangioblastomas. His work with Dr. Cushing led to their lifelong friendship and scientific collaboration. In this paper the authors describe Arvid Lindau's pioneering work in nervous system tumor pathology, his relationship to Dr. Cushing, and his role in advancing neurological surgery and research in Europe.

An intraoperative MRI (iMRI)–compatible system has been developed for direct placement of convection-enhanced delivery (CED) cannulae using real-time imaging. To establish the precision and feasibility of this technology, the authors analyzed findings in patients who underwent direct iMRI CED cannula placement. Three consecutive patients underwent iMRI-guided placement of CED infusion cannulae (6 cannulae) for treatment of diffuse intrinsic brainstem glioma (2 patients) or Parkinson's disease (1 patient). Convective infusion cannulae were guided to the target using the ClearPoint iMRI-based navigation platform (MRI Interventions, Inc.). Placement accuracy was analyzed. Real-time iMRI during infusion cannula insertion allowed for monitoring of trajectory accuracy during placement. During cannula insertion, no reinsertions or changes due to errors in targeting were necessary. The mean radial error was 1.0 ± 0.5 mm (± SD). There was no correlation between the total length of the planned trajectory and the radial error (Pearson's coefficient: −0.40; p = 0.5). The mean anteroposterior and lateral errors were 0.9 ± 0.5 and 0.3 ± 0.2 mm, respectively. The mean in-plane distance error was 1.0 ± 0.4 mm. The mean tip error (scalar distance between the planned target and actual tip) was 1.9 ± 0.9 mm. There was no correlation between the length of the planned trajectory and any of the measured errors. No complications were associated with cannula placement. Real-time iMRI-based targeting and monitoring of infusion cannula placement is a safe, effective, and accurate technique that should enable more selective perfusion of brain regions.

OBJECT High-resolution PET (hrPET) performed using a high-resolution research tomograph is reported as having a resolution of 2 mm and could be used to detect corticotroph adenomas through uptake of18F-fluorodeoxyglucose (18F-FDG). To determine the sensitivity of this imaging modality, the authors compared18F-FDG hrPET and MRI detection of pituitary adenomas in Cushing disease (CD). METHODS Consecutive patients with CD who underwent preoperative18F-FDG hrPET and MRI (spin echo [SE] and spoiled gradient recalled [SPGR] sequences) were prospectively analyzed. Standardized uptake values (SUVs) were calculated from hrPET and were compared with MRI findings. Imaging findings were correlated to operative and histological findings. RESULTS Ten patients (7 females and 3 males) were included (mean age 30.8 ± 19.3 years; range 11–59 years). MRI revealed a pituitary adenoma in 4 patients (40% of patients) on SE and 7 patients (70%) on SPGR sequences.18F-FDG hrPET demonstrated increased18F-FDG uptake consistent with an adenoma in 4 patients (40%; adenoma size range 3–14 mm). Maximum SUV was significantly higher for18F-FDG hrPET–positive tumors (difference = 5.1, 95% CI 2.1–8.1; p = 0.004) than for18F-FDG hrPET–negative tumors.18F-FDG hrPET positivity was not associated with tumor volume (p = 0.2) or dural invasion (p = 0.5). Midnight and morning ACTH levels were associated with18F-FDG hrPET positivity (p = 0.01 and 0.04, respectively) and correlated with the maximum SUV (R = 0.9; p = 0.001) and average SUV (R = 0.8; p = 0.01). All18F-FDG hrPET–positive adenomas had a less than a 180% ACTH increase and18F-FDG hrPET–negative adenomas had a greater than 180% ACTH increase after CRH stimulation (p = 0.03). Three adenomas were detected on SPGR MRI sequences that were not detected by18F-FDG hrPET imaging. Two adenomas not detected on SE (but no adenomas not detected on SPGR) were detected on18F-FDG hrPET. CONCLUSIONS While18F-FDG hrPET imaging can detect small functioning corticotroph adenomas and is more sensitive than SE MRI, SPGR MRI is more sensitive than18F-FDG hrPET and SE MRI in the detection of CD-associated pituitary adenomas. Response to CRH stimulation can predict18F-FDG hrPET–positive adenomas in CD.

Intratumoral glioblastoma therapy has been limited by suboptimal spatial distribution of therapeutic agents. MR-guided convection-enhanced delivery (CED) of MDNA-55 (interleukin-4 fused to Pseudomonasexotoxin) is underway in a Phase 2 open-label study in up to 43 patients with recurrent glioblastoma. Gadolinium-based contrast agent (Gd-DTPA) is co-infused with MDN55 to optimize intra-tumoral catheter placement, monitor drug distribution and identify non-functional catheters. MR images acquired prior to, during, and following infusion are used to determine drug distribution, tissue response, and disease status. Depending on the tumor size up to 60 mL of MDNA55 at a concentration of 1.5 μg/mL is administered as a single infusion through each catheter for a maximum dose of 90 μg. We report preliminary results of tumor distribution in 6 subjects that underwent MR-guided delivery of MDNA55 via implantable flexible catheters. Target enhancing tumor volume varied between 1.5 to 24 mL and tumor diameter varied between 1.8 to 4.7cm. Volume of infusion ranged between 14 to 66 mL and was delivered via 1 to 3 catheters at a flow rate of up to 15mL/min per catheter. MR was employed to monitor initial infusion, allowing adjustment of catheter depth as needed. The bulk of the delivery was performed outside the MR scanner in awake patients. MR confirmation of the distribution was performed within 4 hours post-infusion. In all patients, remarkable tumoral and peri-tumoral distribution has been observed. Tumor coverage ranged from 43% to 100%. Ratio of volume of distribution (Vd) to the volume infusion (Vi) ranged from 2.2 to 0.6. Lower Vd/Vi ratios were associated with drug leakage into the CSF space and/or resection cavity. When catheter placement was inaccurate, real-time imaging of Gd-DTPA distribution enabled adjustments to catheter depth which dramatically improved tumor coverage. MR-guidance during CED is therefore critical for optimal drug distribution in brain tumors.

A 69-year-old female with incidental diagnosis of a dorsum sellae meningioma had shown significant tumor growth after initial conservative management. The procedure started with a microscopic sublabial transsphenoidal approach to the sella and the suprasellar space. Due to limitations to a safe dissection and removal of the retrosellar component, the surgery was converted to a purely endoscopic endonasal approach with left hemi-transposition of the pituitary gland, followed by drilling of the dorsum sellae and removal of the left posterior clinoid process. A complete tumor resection was achieved, and a multilayer skull base reconstruction was performed without complications.The video can be found here: https://youtu.be/BEolyK-To_A.

Although pituitary surgery via the transsphenoidal approach has been performed for over a century, it has only gained widespread acceptance over the past 50 years. As various advances in illumination and magnification through microscopic and endoscopic approaches have improved the safety and efficacy of this technique, it has become the workhorse approach for surgery on the pituitary gland. Further advances, including better understanding of pituitary adenoma biology and improved reconstruction techniques, have extended the utility of this approach to treatment of pathology beyond the sella turcica and its contents. We review the history of pituitary surgery with an emphasis on advances with the transsphenoidal approach.

Object The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined. Methods Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data. Results At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9). Conclusions Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability. Clinical trial registration no.: NCT00005902 (ClinicalTrials.gov).

Object Coinfused surrogate imaging tracers can provide direct insight into the properties of convection-enhanced delivery (CED) in the nervous system. To better understand the distributive properties of CED in a clinical circumstance, the authors analyzed the imaging findings in pediatric diffuse intrinsic pontine glioma (DIPG) patients undergoing coinfusion of Gd-DTPA and interleukin-13–Pseudomonas exotoxin (IL13-PE). Methods Consecutive patients undergoing CED (maximal rates of 5 or 10 μl/minute) of Gd-DTPA (1 or 5 mM) and IL13-PE (0.125 μg/ml or 0.25 μg/ml) for DIPG were included. Real-time MRI was performed during infusions, and imaging results were analyzed. Results Four patients (2 males, 2 females; mean age at initial infusion 13.0 ± 5.3 years; range 5–17 years) underwent 5 infusions into DIPGs. Brainstem infusions were clearly identified on T1-weighted MR images at 1-mM (1 infusion) and 5-mM (4 infusions) coinfused Gd-DTPA concentrations. While the volume of distribution (Vd) increased progressively with volume of infusion (Vi) (mean volume 2.5 ± 0.9 ml; range 1.1–3.7 ml), final Vd:Vi ratios were significantly reduced with lower Gd-DTPA concentration (Vd:Vi for 1 mM of 1.6 compared with a mean Vd:Vi ratio for 5 mM of 3.3 ± 1.0) (p = 0.04). Similarly, anatomical distribution patterns were affected by preferential flow along parallel axial fiber tracts, into prior infusion cannula tracts and intraparenchymal air pockets, and leak back around the infusion cannula at the highest rate of infusion. Conclusions Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. Part of clinical trial no. NCT00880061 (ClinicalTrials.gov).

Context Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results of corticotropin-releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing disease (CD). Objective To predict nonremission after TSS for CD. Design Retrospective case-control study of patients treated at a single center from December 2003 until July 2016. Early and medium-term remission were assessed at 10 days and 11 months. Patients and setting Two hundred and ninety-one consecutive TSS cases from 257 patients with biochemical evidence of CD seen at a clinical center. Interventions Normalized early postoperative values (NEPVs) for cortisol and ACTH were calculated as immediate postoperative cortisol or ACTH levels minus preoperative post-CRH-stimulation test levels. Main outcome measures Prediction of early nonremission was evaluated using logistic regression. Prediction of medium-term remission was assessed using Cox regression. Predictive ability was quantified by area under the receiver operating characteristic curve (AUROC). Results NEPVs for cortisol and ACTH predicted early nonremission [adjusted odds ratio (OR): 1.1; 95% confidence interval (CI): 1.0, 1.1; P = 0.016 and adjusted OR: 1.0; 95% CI: 1.0, 1.0; P = 0.048, respectively]. AUROC for NEPV of cortisol was 0.78 (95% CI: 0.61, 0.95); for NEPV of ACTH, it was 0.80 (95% CI: 0.61, 0.98). NEPVs for cortisol and ACTH predicted medium-term nonremission [hazard ratio (HR): 1.1; 95% CI: 1.0, 1.1; P = 0.023 and HR: 1.0; 95% CI: 1.0, 1.0; P = 0.025, respectively]. Conclusions NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.