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Russell R. Lonser, Luke G. F. Smith, Michael Tennekoon, Kavon P. Rezai-Zadeh, Jeffrey G. Ojemann and Stephen J. Korn

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.

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Russell R. Lonser, Asad S. Akhter, Mirosław Zabek, J. Bradley Elder and Krystof S. Bankiewicz

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.

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Bradley M. Harrington, Armin Gretschel, Carl Lombard, Russell R. Lonser and Adriaan J. Vlok

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.

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Vivek Sudhakar, Jerusha Naidoo, Lluis Samaranch, John R. Bringas, Russell R. Lonser, Massimo S. Fiandaca and Krystof S. Bankiewicz

OBJECTIVE

To 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.

METHODS

Eleven 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.

RESULTS

MRI 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]).

CONCLUSIONS

The 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.

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John D. Heiss, Aria Jamshidi, Smit Shah, Staci Martin, Pamela L. Wolters, Davis P. Argersinger, Katherine E. Warren and Russell R. Lonser

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)

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Alaa S. Montaser, Juan M. Revuelta Barbero, Alexandre Todeschini, André Beer-Furlan, Russell R. Lonser, Ricardo L. Carrau and Daniel M. Prevedello

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.

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Russell R. Lonser

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Russell R. Lonser, Lynnette Nieman and Edward H. Oldfield

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.

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Prashant Chittiboina, S. Lalith Talagala, Hellmut Merkle, Joelle E. Sarlls, Blake K. Montgomery, Martin G. Piazza, Gretchen Scott, Abhik Ray-Chaudhury, Russell R. Lonser, Edward H. Oldfield, Alan P. Koretsky and John A. Butman

OBJECTIVE

Pituitary MR imaging fails to detect over 50% of microadenomas in Cushing's disease and nearly 80% of cases of dural microinvasion. Surface coils can generate exceptionally high-resolution images of the immediately adjacent tissues. To improve imaging of the pituitary gland, a receive-only surface coil that can be placed within the sphenoid sinus (the endosphenoidal coil [ESC]) during transsphenoidal surgery (TSS) was developed and assessed.

METHODS

Five cadaver heads were used for preclinical testing of the ESC. The ESC (a double-turn, 12-mm-diameter surface coil made from 1-mm-diameter copper wire) was developed to obtain images in a 1.5-T MR scanner. The ESC was placed (via a standard sublabial TSS approach) on the anterior sella face. Clinical MR scans were obtained using the 8-channel head coil and ESC as the receiver coils. Using the ESC, ultra–high-resolution, 3D, balanced fast field echo (BFFE) and T1-weighted imaging were performed at resolutions of 0.25 × 0.25 × 0.50 mm3 and 0.15 × 0.15 × 0.30 mm3, respectively.

RESULTS

Region-of-interest analysis indicated a 10-fold increase in the signal-to-noise ratio (SNR) of the pituitary when using the ESC compared with the 8-channel head coil. ESC-related improvements (p < 0.01) in the SNR were inversely proportional to the distance from the ESC tip to the anterior pituitary gland surface. High-resolution BFFE MR imaging obtained using ESC revealed a number of anatomical features critical to pituitary surgery that were not visible on 8-channel MR imaging, including the pituitary capsule, the intercavernous sinus, and microcalcifications in the pars intermedia. These ESC imaging findings were confirmed by the pathological correlation with whole-mount pituitary sections.

CONCLUSIONS

ESC can significantly improve SNR in the sellar region intraoperatively using current 1.5-T MR imaging platforms. Improvement in SNR can provide images of the sella and surrounding structures with unprecedented resolution. Clinical use of this ESC may allow for MR imaging detection of previously occult pituitary adenomas and identify microscopic invasion of the dura or cavernous sinus.