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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.

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.

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.

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.

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.

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.

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.

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.

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 The astrocytic contribution to the blood-brain barrier (BBB) in metastatic and primary malignant brain tumors is not well understood. To better understand the vascular properties associated with metastatic and primary malignant brain tumors, the authors systematically analyzed the astrocytic component of the BBB in brain neoplasms. Methods Twelve patients who underwent resection of metastatic or primary brain neoplasms (4 metastatic lesions, 2 low-grade astrocytomas, 2 anaplastic astrocytomas, and 4 glioblastoma multiforme) were included. Clinical, MRI, operative, histopathological and immunohistochemical (glial fibrillary acidic protein [GFAP], CD31, and aquaporin 4 [AQ4]) findings were analyzed. Results Intratumoral regions of MRI enhancement corresponded with breakdown of the normal astrocyte–endothelial cell relationship in the BBB in metastatic deposits and malignant gliomas. Metastases demonstrated lack of perivascular GFAP and AQ4 on CD31-positive intratumoral vessels. At the metastasis-brain interface, normalization of GFAP and AQ4 staining associated with intraparenchymal vessels was observed. Intratumoral vasculature in enhancing regions of high-grade gliomas revealed gaps in GFAP and AQ4 staining consistent with disintegration of the normal astrocyte–endothelial cell association in the BBB. Intratumoral vasculature in low-grade and nonenhancing regions of high-grade gliomas maintained the normal astrocyte–endothelial cell relationship seen in an intact BBB, with GFAP- and AQ4-positive glial processes that were uniformly associated with the CD31-positive vasculature. Conclusions Regions of MRI enhancement in metastatic and primary malignancies correspond to areas of breakdown of the physiological astrocyte–endothelial cell relationship of the BBB, including loss of normal perivascular astrocytic architecture on GFAP and AQ4 immunohistochemistry. Nonenhancing areas are associated with preservation of the normal astrocyte–endothelial cell relationship of the intact BBB.

Object To determine if physiologically based MRI sequences can be used to detect endolymphatic sac tumor (ELST)–associated hydrops, the authors performed contrast-enhanced delayed FLAIR imaging in consecutive ELST patients with clinical findings consistent with hydrops. Methods Consecutive patients with von Hippel-Lindau (VHL) disease and clinical findings of endolymphatic hydrops and ELSTs underwent contrast-enhanced delayed FLAIR MRI. Clinical, audiological, operative, and imaging findings were analyzed. Results Three patients (2 male, 1 female) with 4 ELSTs (1 patient had bilateral ELSTs) were identified who had clinical findings consistent with endolymphatic hydrops. Computed tomography and MRI evidence of an ELST was found in all patients. Their mean age at initial evaluation was 39.7 years (range 28–51 years). All patients demonstrated progressive sensorineural hearing loss that was associated with episodic vertigo and tinnitus. Contrast-enhanced delayed FLAIR MRI clearly demonstrated dilation of the membranous labyrinth consistent with hydrops in the affected ears but not the unaffected ears. Two patients underwent resection of the associated ELST that resulted in stabilization of progressive hearing loss, as well as amelioration of tinnitus and vertigo. Conclusions Contrast-enhanced delayed FLAIR MRI can be used to detect ELST-associated hydrops. Noninvasive MRI detection of hydrops can permit earlier detection of ELSTs in patients with VHL disease and provides direct insight into a mechanism that underlies ELST-associated audiovestibular morbidity.

Object Tumor-initiating cells are uniquely resilient to current treatment modalities and play an important role in tumor resistance and recurrence. The lack of specific tumor-initiating cell markers to identify and target these cells presents a major obstacle to effective directed therapy. Methods To identify tumor-initiating cell markers in primary brain tumors, the authors compared the proteomes of glioma tumor-initiating cells to their differentiated progeny using a novel, nongel/shotgun-based, multidimensional liquid-chromatography protein separation technique. An in vivo xenograft model was used to demonstrate the tumorigenic and stem cell properties of these cells. Western blot and immunofluorescence analyses were used to confirm findings of upregulated ciliary neurotrophic factor receptor subunit–α (CNTFRα) in undifferentiated tumor-initiating cells and gliomas of increasing tumor grade. Sequencing of the CNTFRα coding regions was performed for mutation analysis. Finally, antibody-dependent cell-mediated cytotoxicity was used to establish the role of CNTFRα as a potential immunotherapeutic target. Results Ciliary neurotrophic factor receptor subunit–α expression was increased in tumor-initiating cells and was decreased in the cells' differentiated progeny, and expression levels increased with glioma grade. Mutations of CNTFRα are not common in gliomas. Functional studies using CNTF treatment in glioma tumor-initiating cells showed induction of differentiation through the CNTFRα pathway. Treatment with anti-CNTFRα antibody resulted in increased antibody-dependent cell-mediated cytotoxicity in CNTFRα expressing DAOY cells but not in cell lines that lack CNTFRα. Conclusions These data indicate that CNTFRα plays a role in the formation or maintenance of tumor-initiating cells in gliomas, is a marker that correlates with histological grade, may underlie treatment resistance in some cases, and is a potential therapeutic target.

Object Although pulsatile and continuous infusion paradigms have been described for convective delivery of drugs, the effectiveness and properties of each flow paradigm are unknown. To determine the effectiveness and properties of pulsatile and continuous convective infusion paradigms, the authors compared these convective flow methods in the gray and white matter of primates. Methods Six primates (Macaca mulatta) underwent convective infusion of Gd-DPTA (5 mM) into the cerebral gray matter (thalamus) or white matter (frontal lobe) using pulsed (intermittent pulses of 15 μl/min) or continuous (1 μl/min) convective flow. Results were assessed by clinical MRI and histological analyses. Results Distribution of Gd-DTPA infusate in gray and white matter by pulsed and continuous flow was clearly identified using MRI, which revealed that both convective flow methods demonstrated an increase in the volume of distribution (Vd) with increasing volume of infusion (Vi) in the surrounding gray and white matter. Although the mean (± SD) gray matter Vd:Vi ratio for the pulsed infusions (4.2 ± 0.5) was significantly lower than the mean Vd:Vi ratio for continuous infusions (5.4 ± 0.5; a 22% difference [p = 0.0006]), the difference between pulsed (3.8 ± 0.4) and continuous (4.3 ± 1.2) infusions in white matter was not significantly different (p = 0.3). Pulsed infusions were associated with more leakback (12.3% ± 6.4% of Vi) than continuous infusions (3.9% ± 7.8%), although this difference was not significant (p = 0.2). All animals tolerated the infusions and there was no histological evidence of tissue injury at the infusion sites. Conclusions Although pulsed and continuous infusion flow paradigms can be safely and effectively used for convective delivery into both gray and white matter, continuous infusion is associated with a higher Vd:Vi ratio than pulsatile infusion in gray matter. High rates of infusion (15 μl/min) can be used to deliver infusate without any significant leakback and without any clinical or histological evidence of injury.

Object Prior cases suggest that pregnancy increases the development and progression of CNS hemangioblastomas and/or peritumoral cysts. To determine the effect of pregnancy on CNS hemangioblastomas and peritumoral cysts, the authors prospectively evaluated serial clinical and imaging findings in patients with von Hippel-Lindau (VHL) disease who became pregnant and compared findings during pregnancy to findings in the same patients when they were not pregnant as well as to findings from a cohort of VHL patients who did not become pregnant. Methods Female VHL disease patients enrolled in a prospective natural history study who were of reproductive age (16–35 years at study entrance) were included. Analysis of serial clinical and imaging findings was performed. Results Thirty-six consecutive female VHL disease patients harboring 177 hemangioblastomas were included (mean follow-up [± SD] 7.5 ± 2.3 years). Nine patients (25%) became pregnant (pregnancy cohort). The mean rates of development of new hemangioblastomas and peritumoral cysts in these women during pregnancy (0.4 ± 0.4 tumors/year; 0.1 ± 0.2 cysts/year) did not differ significantly (p > 0.05) from the mean rates in the same group during nonpregnant periods (0.3 ± 0.4 tumors/year; 0.1 ± −0.1 cysts/year) or from the rate in the 27 patients who did not become pregnant (the no-pregnancy cohort: 0.3 ± 0.5 tumors/year; 0.1 ± 0.2 cysts/year). Hemangioblastoma growth rates were similar (p > 0.05) during pregnancy (mean 29.8% ± 42.7% increase in volume per year) compared with during nonpregnant periods (41.4% ± 51.4%) in the pregnancy cohort and the no-pregnancy cohort (34.3% ± 55.3%). Peritumoral cyst growth rates during pregnancy (571.0% ± 887.4%) were similar (p > 0.05) to those of the no-pregnancy cohort (483.9% ± 493.9%), but the rates were significantly higher for women in the pregnancy cohort during nonpregnant periods (2373.6% ± 3392.9%; p < 0.05 for comparison with no-pregnancy cohort). There was no significant difference (p > 0.05) in the need for resection or the mean age at resection between the pregnancy (28% of hemangioblastomas in cohort; mean patient age at resection 30.2 ± 2.6 years) and no-pregnancy cohorts (19%; 32.3 ± 5.6 years). Conclusions Pregnancy is not associated with increased hemangioblastoma or peritumoral cyst development or progression in patients with VHL disease.

Object Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage. Methods Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution. Results Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was –2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity. Conclusions The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.

Object Neurofibromatosis Type 2 (NF2) is a heritable tumor predisposition syndrome that leads to the development of multiple intracranial tumors, including meningiomas and schwannomas. Because the natural history of these tumors has not been determined, their optimal management has not been established. To define the natural history of NF2-associated intracranial tumors and to optimize management strategies, the authors evaluated long-term clinical and radiographic data in patients with NF2. Methods Consecutive NF2 patients with a minimum of 4 years of serial clinical and MRI follow-up were analyzed. Results Seventeen patients, 9 males and 8 females, were included in this analysis (mean follow-up 9.5 ± 4.8 years, range 4.0–20.7 years). The mean age at initial evaluation was 33.2 ± 15.5 years (range 12.3–57.6 years). Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas [VSs], 11 nonvestibular cranial nerve [CN] schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3 ± 2.1 years, range 0.4–11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p = 0.01) and female sex (p = 0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p = 0.01). Conclusions Neurofibromatosis Type 2–associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years).

Although he never performed a pituitary operation for the disease, Harvey Cushing was the first to describe and treat patients with Cushing disease (CD). Other surgeons at the time were reluctant to operate on the pituitary due to the normal sella on skull radiographs in CD and the unclear etiology of the disorder. To better define and understand factors influencing the history of pituitary surgery for CD, the authors analyzed historical texts related to CD biology, diagnosis, and treatment. Cushing's monograph on basophilic pituitary adenomas and cortisol excess appeared in 1932. One year later in 1933, Alfred Pattison performed the first successful pituitary operation for CD by implanting radon seeds in the sella. Resection of a pituitary adenoma for CD was attempted 1 month later in 1933 by Howard Naffziger, resulting in only transient improvement that corresponded to the lack of tumor in the resected tissue. Soon thereafter, Susman in 1935 and Costello in 1936 described pituitary basophilic adenomas at autopsy in patients without premorbid endocrinopathy. They concluded that the adrenal gland was the cause of CD, which resulted in a 3-decade abandonment of pituitary surgery for CD. Jules Hardy in 1963 used the operating microscope to perform the first selective removal of an adrenocorticotropic hormone (ACTH)–secreting microadenoma, which established a pituitary cause and defined the modern treatment of CD. Subsequent reports by Hardy, Laws, and Wilson resulted in widespread acceptance of pituitary surgery for CD. Initial reluctance to operate on the pituitary for CD was multifaceted and included general uncertainty surrounding the etiology of Cushing syndrome as well as a lack of early surgical success, both due to the small size of ACTH-secreting adenomas. Selective removal of ACTH-secreting adenomas identified the source of CD and ended the delay in acceptance of pituitary surgery for CD.

Object Dural invasion by adrenocorticotropic hormone (ACTH)-secreting adenomas is a significant risk factor for incomplete resection and recurrence in Cushing disease (CD). Since ACTH-producing adenomas are often the smallest of the various types of pituitary tumors at the time of resection, examining their invasion provides the best opportunity to identify the precise sites of early dural invasion by pituitary adenomas. To characterize the incidence and anatomical distribution of dural invasion by ACTH-secreting adenomas, the authors prospectively and systematically analyzed features of dural invasion in patients with CD. Methods The authors prospectively studied consecutive patients with CD undergoing the systematic removal of ACTH-secreting adenoma and histological analysis of the anterior sella dura as well as other sites of dural invasion that were evident at surgery. Clinical, imaging, histological, and operative findings were analyzed. Results Eighty-seven patients with CD (58 females and 29 males) were included in the study. Overall, dural invasion by an ACTH-positive adenoma was histologically confirmed in 30 patients (34%). Eighteen patients (60% of dural invasion cases, 21% of all patients) had evidence of cavernous sinus wall invasion (4 of these patients also had other contiguous sites of invasion), and 12 patients (40% of dural invasion cases) had invasion of the sella dura excluding the cavernous sinus wall. Eleven patients (13% all patients) had invasion of the routinely procured anterior sella dura specimen. Preoperative MR imaging revealed an adenoma in 64 patients (74%) but accurately predicted dural invasion in only 4 patients (22%) with cavernous sinus invasion and none of the patients with non–cavernous sinus invasion. Adenomas associated with dural invasion (mean ± SD, 10.9 ± 7.8 mm, range 2–37 mm) were significantly larger than those not associated with dural invasion (5.7 ± 2.1 mm, range 2.5–12 mm; p = 0.0006, Mann-Whitney test). Conclusions Dural invasion by ACTH-producing adenomas preferentially occurs laterally into the wall of the cavernous sinus. Preoperative MR imaging infrequently detects dural invasion, including cavernous sinus invasion. Invasion is directly associated with tumor size. To provide a biochemical cure and avoid recurrence after resection, identification and removal of invaded sella dura, including the medial cavernous sinus wall, are necessary.

Object Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO2) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO2 can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established. Methods Subarachnoid hemorrhage–induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO2 infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF. Results Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO2 infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF. Conclusions These findings indicate that the intravenous infusion of NaNO2 can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Object Astrocytomas and oligodendrogliomas are primary CNS tumors that remain a challenge to differentiate histologically because of their morphological variability and because there is a lack of reliable differential diagnostic markers. To identify proteins that are differentially expressed between astrocytomas and oligodendrogliomas, the authors analyzed the proteomic expression patterns and identified uniquely expressed proteins in these neoplasms. Methods Proteomes of astrocytomas and oligodendrogliomas were analyzed using 2D gel electrophoresis and subsequent computerized gel analysis to detect differentially expressed proteins. The proteins were identified using high-performance liquid chromatography accompanied by tandem mass spectrometry. To determine the role of the differentially expressed proteins in astrocytes, undifferentiated glial cell cultures were treated with dibutyryl–cyclic adenosine monophosphate (cAMP). Results Two-dimensional gel electrophoresis revealed that glutamine synthetase was differentially expressed in astrocytomas and oligodendrogliomas. Western blot and immunohistochemical analyses confirmed the increased expression of glutamine synthetase in astrocytomas compared with oligodendrogliomas. Whereas glutamine synthetase expression was demonstrated across all grades of astrocytomas (Grade II–IV [15 tumors]) and oligoastrocytomas (4 tumors), it was expressed in only 1 oligodendroglioma (6% [16 tumors]). Treatment of undifferentiated glial cell cultures with dibutyryl-cAMP resulted in astrocyte differentiation that was associated with increased levels of glial fibrillary acidic protein and glutamine synthetase. Conclusions These data indicate that glutamine synthetase expression can be used to distinguish astrocytic from oligodendroglial tumors and may play a role in the pathogenesis of astrocytomas.

Object Accurate real-time imaging of coinfused surrogate tracers can be used to determine the convective distribution of therapeutic agents. To assess the effect that a concentration of a Gd-based surrogate tracer has on the accuracy of determining the convective distribution, the authors infused different concentrations of Gd-diethylenetriamine pentaacetic acid (DTPA) in primates during MR imaging. Methods Five nonhuman primates underwent convective infusion (1 or 5 mM, 21–65 μl) of Gd-DTPA alone, Gd-DTPA and 14C-sucrose, or Gd-DTPA and 14C-dextran into the bilateral striata. Animals underwent real-time MR imaging during infusion (5 animals) and autoradiographic analysis (2 animals). Results Gadolinium-DTPA could be seen filling the striata at either concentration (1 or 5 mM) on real-time MR imaging. While the volume of distribution (Vd) increased linearly with the volume of infusion (Vi) for both concentrations of tracer (1 mM: R2 = 0.83; 5 mM: R2 = 0.96), the Vd/Vi ratio was significantly (p < 0.0001) less for the 1-mM (2.3 ± 1.0) as compared with the 5-mM (7.4 ± 1.9) concentration. Autoradiographic and MR volumetric analysis revealed that the 5-mM concentration most accurately estimated the Vd for both small (sucrose [359 D], 12% difference between imaging and autoradiographic distribution) and large (dextran [70 kD], 0.2% difference) molecules compared with the 1-mM concentration (sucrose, 65% difference; dextran, 68% difference). Conclusions The concentration of infused Gd-DTPA plays a critical role in accurately assessing the distribution of molecules delivered by CED. A 5-mM concentration of Gd-DTPA most accurately estimated the Vd over a wide range of molecular sizes.

Object Central nervous system hemangioblastomas are the most common manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor suppressor syndrome that results in loss of VHL protein function and continuous upregulation of hypoxia-inducible factors. These tumors are composed of neoplastic stromal cells and abundant vasculature. Stromal cells express markers consistent with multipotent embryonically arrested hemangioblasts, which are precursors for hematopoietic and vascular lineages. Notch receptors are transmembrane signaling molecules that regulate multiple developmental processes including hematopoiesis and vasculogenesis. To investigate the importance of notch signaling in the development of VHL disease–associated CNS hemangioblastomas, the authors examined the presence of the four notch receptors and downstream notch effectors in this setting. Methods The authors used surgical specimens obtained from confirmed VHL-associated hemangioblastomas. Immunohistochemical analysis for the four notch receptors and the downstream effectors was performed on formalin-fixed paraffin-embedded sections. Western blot analysis for HES1 was performed on frozen specimens. Results All four notch receptors are present in hemangioblastomas. NOTCH1 and NOTCH4 receptors were widely and prominently expressed in both the stromal and vascular cells, NOTCH2 receptor expression was limited to primarily stromal cells, and NOTCH3 receptor expression was limited to vascular cells. All 4 receptors displayed a nuclear presence. Immunohistochemical analysis also demonstrated that downstream notch effectors, HES1 and HES5, were uniformly expressed in tumor stromal and vascular cells, but HES3, HEY1, and HEY2 were not. Strong HES1 expression was confirmed by Western blot analysis. Conclusions The presence of all four notch receptors and downstream effector molecules suggests that the notch signaling pathway plays a critical role in the maintenance of the undifferentiated pluripotent phenotype of these tumors and in the associated vascular response. Moreover, the prominent expression of notch receptors in VHL-associated CNS hemangioblastomas reveals a new and possibly potent therapeutic target.

Object Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates. Methods Three nonhuman primates underwent thalamic convective infusions (5 infusions) with 14C-sucrose (MW 342 D) or 14C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging). Imaging, histological, and autoradiographic findings were analyzed. Results Real-time T2- and diffusion-weighted imaging clearly demonstrated the region of infusion, and serial images revealed progressive filling of the bilateral thalami during infusion. Imaging analysis for T2- and diffusion-weighted sequences revealed that the tissue volume of distribution (Vd) increased linearly with volume of infusion (Vi; R2 = 0.94, R2 = 0.91). Magnetic resonance imaging analysis demonstrated that the mean ± SD Vd/Vi ratios for T2-weighted (3.6 ± 0.5) and diffusion-weighted (3.3 ± 0.4) imaging were similar (p = 0.5). While 14C-sucrose and 14C-dextran were homogeneously distributed over the infused region, autoradiographic analysis revealed that T2-weighted and diffusion-weighted imaging significantly underestimated the Vd of both 14C-sucrose (mean differences 51.3% and 52.3%, respectively; p = 0.02) and 14C-dextran (mean differences 49.3% and 59.6%; respectively, p = 0.001). Conclusions Real-time T2- and diffusion-weighted MR imaging significantly underestimate tissue Vd during convection-enhanced delivery over a wide range of molecular sizes. Application of these imaging modalities may lead to inaccurate estimation of convective drug distribution.

Object Despite the increasing use of immunotherapy in the treatment of metastatic melanoma, the effects of this therapy on the management of patients with associated brain metastases are not completely defined. The authors undertook this study to determine the effectiveness of resection and the effects of immunotherapy on brain metastasis management. Methods The authors analyzed data pertaining to consecutive patients with metastatic melanoma treated with immunotherapy within 3 months of discovery of brain metastases that were surgically resected. Results Forty-one patients (median age 44.4 years, range 19.2–63.1 years) underwent resection of 53 brain metastases (median number of metastases 1, range 1–4). The median metastasis volume was 2.5 cm3. Fifteen patients underwent whole-brain radiation therapy (WBRT) and 26 patients did not. Duration of survival from brain metastasis diagnosis was not significantly different between patients who received WBRT (mean 24.9 months) and those who did not (mean 23.3 months) (p > 0.05). Local and distant brain recurrence rates were not statistically different between the WBRT (7.1% and 28.6%, respectively) and non-WBRT (7.7% and 41.0%) groups for the duration of follow-up (p > 0.05). An objective systemic response to immunotherapy was associated with increased duration of survival (p < 0.05). Conclusions Resection of melanoma brain metastases in patients treated with immunotherapy provides excellent local control with low morbidity. An objective response to systemic immunotherapy is associated with a prolonged survival in patients who have undergone resection of melanoma brain metastases. Moreover, adjuvant WBRT in melanoma immunotherapy patients with limited metastatic disease to the brain does not appear to provide a significant survival benefit.

Object Brainstem hemangioblastomas are frequently encountered in patients with von Hippel-Lindau (VHL) disease. These tumors can cause significant morbidity, and their optimal management has not been defined. To better define the outcome and management of these tumors, the authors analyzed the long-term results in patients who underwent resection of brainstem hemangioblastomas. Methods Consecutive patients with VHL disease who underwent resection of brainstem hemangioblastomas with a follow-up of 12 months or more were included in this study. Serial functional assessments, radiographic examinations, and operative records were analyzed. Results Forty-four patients (17 male and 27 female) underwent 51 operations for resection of 71 brainstem hemangioblastomas. The most common presenting symptoms were headache, swallowing difficulties, singultus, gait difficulties, and sensory abnormalities. The mean follow-up was 5.9 ± 5.0 years (range 1.0–20.8 years). Immediately after 34 operations (66.7%), the patients remained at their preoperative functional status; they improved after 8 operations (15.7%) and worsened after 9 operations (17.6%) as measured by the McCormick scale. Eight (88.9%) of the 9 patients who were worse immediately after resection returned to their preoperative status within 6 months. Two patients experienced functional decline during long-term follow-up (beginning at 2.5 and 5 years postoperatively) caused by extensive VHL disease–associated CNS disease. Conclusions Generally, resection of symptomatic brainstem hemangioblastomas is a safe and effective management strategy in patients with VHL disease. Most patients maintain their preoperative functional status, although long-term decline in functional status may occur due to VHL disease–associated progression.

Object Nuclear receptor corepressor (N-CoR) forms a complex that maintains neural stem cells in an undifferentiated state through transcriptional repression. Recently, it has been shown that N-CoR is overexpressed in glioblastoma multiforme (GBM) tumor stem cells and has a putative role in maintaining these cells in an undifferentiated immortal state. To determine the effects of disruption of N-CoR complex function by serine/threonine protein phosphatase 2A (PP2A) inhibition on GBM tumor cell differentiation and proliferation, the authors developed and investigated a competitive small molecule inhibitor (LB1) of PP2A in GBM. Methods The authors investigated the effects of LB1 on GBM proliferation and molecular differentiation pathways using in vitro and in vivo studies. Results The LB1 inhibited PP2A, leading to increased levels of phosphorylated Akt kinase and decreased NCoR expression, as well as dose-dependent antiproliferative activity in cultured U87 and U251 malignant glioma cells (dose range 1–10 μM). Systemic LB1 treatment (1.5 mg/kg/day for 21 days) had significant tumor antiproliferative effects in mice harboring U87 glioma xenografts (73% mean reduction in tumor volume compared with controls; p < 0.001). Moreover, a reduction in PP2A expression and activity after LB1 treatment in vivo correlated with increased Akt phosphorylation, reduced nuclear N-CoR expression and N-CoR cytoplasmic translocation, and increased accumulation of acetylated core histones, which coincided with the appearance of glial fibrillary acidic protein–expressing tumor cells. Conclusions These findings indicate that PP2A inhibition effectively disrupts N-CoR complex function/expression and leads to cytoplasmic translocation of N-CoR with subsequent tumor cell differentiation and/or death. Therapeutic paradigms that target N-CoR function in the cancer stem cell component of malignant gliomas may have treatment utility.

Object Muscimol is a potent γ-aminobutyric acid-A receptor agonist that temporarily and selectively suppresses neurons. Targeted muscimol suppression of neuronal structures could provide insight into the pathophysiological processes and treatment of a variety of neurological disorders. To determine if muscimol delivered to the brain by convection-enhanced delivery could be monitored using a coinfused surrogate MR imaging tracer, the authors perfused the striata of primates with tritiated muscimol and Gd–diethylenetriamine pentaacetic acid (DTPA). Methods Three primates underwent convective coinfusion of 3H-muscimol (0.8 μM) and Gd-DTPA (5 mM) into the bilateral striata. Primates underwent serial MR imaging during infusion, and the animals were killed immediately after infusion. Postmortem quantitative autoradiography and histological analysis was performed. Results Real-time MR imaging revealed that infusate (tritiated muscimol and Gd-DTPA) distribution was clearly discernible from the noninfused parenchyma. Real-time MR imaging of the infusion revealed the precise region of anatomical perfusion in each animal. Imaging analysis during infusion revealed that the distribution volume (Vd) of infusate linearly increased (R = 0.92) with volume of infusion (Vi). Overall, the mean (± SD) Vd/Vi ratio was 8.2 ± 1.3. Autoradiographic analysis revealed that MR imaging of Gd-DTPA closely correlated with the distribution of 3H-muscimol, and precisely estimated its Vd (mean difference in Vd, 7.4%). Quantitative autoradiograms revealed that muscimol was homogeneously distributed over the perfused region in a square-shaped concentration profile. Conclusions Muscimol can be effectively delivered to clinically relevant volumes of the primate brain. Moreover, the distribution of muscimol can be tracked using coinfusion of Gd-DTPA and MR imaging. The ability to perform accurate monitoring and to control the anatomical extent of muscimol distribution during its convection-enhanced delivery will enhance safety, permit correlations of muscimol distribution with clinical effect, and should lead to an improved understanding of the pathophysiological processes underlying a variety of neurological disorders.

Object Pituitary stalk hemangioblastomas are rare, and information on them is limited to a small number of case reports. To gain insight into the incidence, clinical effects, and management of pituitary stalk hemangioblastomas, the authors analyzed a series of patients with von Hippel–Lindau (VHL) disease. Methods Patients with VHL disease who were enrolled in a prospective National Institutes of Health natural history study were included. Clinical, imaging, and laboratory findings were analyzed. Results Two hundred fifty patients were included in the study (120 male and 130 female patients). In 8 patients (3%), 8 pituitary stalk hemangioblastomas were identified on MR imaging. This anatomical location was the most common supratentorial site for these lesions; 29% of all supratentorial hemangioblastomas were found there. The mean (± standard deviation) pituitary stalk hemangioblastoma volume was 0.5 ± 0.9 cm3 (range 0.08–2.8 cm3). Results of endocrine laboratory profiles were normal in all patients. All patients remained asymptomatic and none required treatment during the follow-up period (mean duration 41.4 ± 14.4 months). Conclusions The pituitary stalk is the most common site for the development of supratentorial hemangioblastomas in patients with VHL disease. Pituitary stalk hemangioblastomas often remain asymptomatic and do not require treatment. These findings indicate that pituitary stalk hemangioblastomas in patients with VHL disease may be managed with observation and that surgery for them can be reserved until associated signs or symptoms occur.

Object Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces. Methods Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed. Results Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images. Conclusions Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

Object Despite the frequency of cerebellar hemangioblastomas in von Hippel–Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas. Methods Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8 ± 10.3 years, follow-up duration 96.0 ± 60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed. Results Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8 ± 1.9 cm; volume 2.8 ± 3.4 cm3; p < 0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p < 0.05) than asymptomatic tumors (diameter 1.1 ± 0.9 cm; volume 0.7 ± 0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p < 0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5 ± 15.0 months) revealed no recurrences. Conclusions Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.

✓Recent preclinical studies have demonstrated that convection-enhanced delivery (CED) can be used to perfuse the brain and brainstem with therapeutic agents while simultaneously tracking their distribution using coinfusion of a surrogate magnetic resonance (MR) imaging tracer. The authors describe a technique for the successful clinical application of this drug delivery and monitoring paradigm to the brainstem. Two patients with progressive intrinsic brainstem lesions (one with Type 2 Gaucher disease and one with a diffuse pontine glioma) were treated with CED of putative therapeutic agents mixed with Gd–diethylenetriamene pentaacetic acid (DTPA). Both patients underwent frameless stereotactic placement of MR imaging–compatible outer guide–inner infusion cannulae. Using intraoperative MR imaging, accurate cannula placement was confirmed and real-time imaging during infusion clearly demonstrated progressive filling of the targeted region with the drug and Gd-DTPA infusate. Neither patient had clinical or imaging evidence of short- or long-term infusate-related toxicity. Using this technique, CED can be used to safely perfuse targeted regions of diseased brainstem with therapeutic agents. Coinfused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with a variety of intrinsic brainstem and other central nervous system disorders may benefit from a similar treatment paradigm.

Object The authors conducted an analysis of the distribution of glial cell line–derived neurotrophic factor in the human striatum following convection-enhanced delivery. Methods Computational examinations of the effects of differing catheters, infusion rates, infusate concentrations, and target placement on distribution were completed based on the protocols of three recent clinical trials. Results Similar drug distributions around on-target end-hole catheters were predicted in two of the trials (AmgenUT study and Bristol study), although there was slightly deeper penetration for one of the trials (Bristol) due to a higher infusate concentration. However, when positioning uncertainly located catheter tips close to gray–white matter interfaces, backflow could diminish delivery, shunting infusate across the interfaces. For delivery via a multiport catheter at a constant base infusion rate plus a periodic bolus inflow rate (Kentucky study), base inflow alone generated a somewhat smaller distribution volume relative to those in the other trials, was positioned more anteriorly in the putamen, and was somewhat elongated axially; the bolus component extended this putaminal distribution to a larger relative volume but may have been reduced by backflow loss. Conclusions Results of these computations indicated that for catheters placed exactly on the intended target, ideal drug distributions were similar for two of the trials (AmgenUT and Bristol) and different in terms of location and extent in the third study (Kentucky); yet the pattern of trial outcomes did not reflect these same groupings. This finding suggests that other factors are at play, widely varying statistical power and the possible effects of not excluding data from patients who experienced large drug losses across gray tissue boundaries due to variation in catheter placement.

Object To determine if the potent antiglioma chemotherapeutic agent gemcitabine could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution using a surrogate magnetic resonance (MR) imaging tracer, the authors used convection-enhanced delivery to perfuse the primate brainstem with gemcitabine and Gd–diethylenetriamine pentaacetic acid (DTPA). Methods Six primates underwent convective brainstem perfusion with gemcitabine (0.4 mg/ml; two animals), Gd-DTPA (5 mM; two animals), or a coinfusion of gemcitabine (0.4 mg/ml) and Gd-DTPA (5 mM; two animals), and were killed 28 days afterward. These primates were observed over time clinically (six animals), and with MR imaging (five animals), quantitative autoradiography (one animal), and histological analysis (all animals). In an additional primate, 3H-gemcitabine and Gd-DTPA were coinfused and the animal was killed immediately afterward. In the primates there was no histological evidence of infusate-related tissue toxicity. Magnetic resonance images obtained during infusate delivery demonstrated that the anatomical region infused with Gd-DTPA was clearly distinguishable from surrounding noninfused tissue. Quantitative autoradiography confirmed that Gd-DTPA tracked the distribution of 3H-gemcitabine and closely approximated its volume of distribution (mean volume of distribution difference 13.5%). Conclusions Gemcitabine can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and at volumes that are higher than those considered clinically relevant. Moreover, MR imaging can be used to track the distribution of gemcitabine by adding Gd-DTPA to the infusate. This delivery paradigm should allow for direct therapeutic application of gemcitabine to brainstem gliomas while monitoring its distribution to ensure effective tumor coverage and to maximize safety.

Object Patients with hereditary cancer syndromes may be at increased risk for the development of tumor-to-tumor metastases. To gain insight into the biological nature of these lesions in the central nervous system (CNS), to determine their prevalence in a familial neoplasia syndrome, and to better define their management, the authors retrospectively examined a series of cases in which metastatic lesions developed within hemangioblastomas in patients with von Hippel–Lindau (VHL) disease. Methods The study included all cases of VHL disease in which patients underwent resection of a CNS hemangioblastoma that contained a metastasis or were found at autopsy to have a metastasis to a hemangioblastoma between January 2002 and December 2005 at the National Institute of Neurological Disorders and Stroke (NINDS). Clinical, histopathological, imaging, and surgical and/or autopsy findings were analyzed. Metastasis to a CNS hemangioblastoma was found in six resected tumors (8% of all hemangioblastomas resected from patients with VHL disease at the NINDS during the study period) from six patients (five women, one man; mean age at surgery 42.5 years). The primary site of metastatic disease was the kidney in five patients (renal cell carcinoma) and the pancreas in one (a pancreatic neuroendocrine tumor). Only one patient had systemic metastases at the time of resection of the hemangioblastoma containing the metastasis. Neurologically, all patients had remained at baseline or were improved at last clinical follow-up examination (mean follow-up duration 16.5 months, range 3–40 months). In all cases, postoperative imaging revealed that the hemangioblastoma resection was complete, and there was no evidence of recurrence in any of the patients at the last follow up. Two patients (including one who was also in the surgical group) were found at autopsy to have CNS metastases exclusively to spinal hemangioblastomas. Conclusions Hemangioblastomas are an early and preferred site for metastasis in VHL disease. Emerging histopathological techniques may lead to recognition of an increasing number of cases of tumor-to-hemangioblastoma metastasis. Management of cases involving tumor-to-hemangioblastoma metastases in VHL disease should be based on the histological characteristics of the primary tumor, extent of the primary disease, and completeness of the resection.

Object. Hemangioblastomas of the brainstem constitute 5 to 10% of central nervous system (CNS) tumors in patients with von Hippel—Lindau (VHL) disease. At present, optimal management of brainstem hemangioblastomas associated with VHL disease is incompletely defined. In an attempt to clarify some of the uncertainty about the operative treatment of these lesions and its outcome, the authors reviewed all cases of VHL disease in which resection of brainstem hemangioblastomas was performed at the National Institutes of Health during a 10-year period. Methods. Twelve consecutive patients with VHL disease (six male and six female patients [mean age 31.7 ± 9 years; range 15–46 years]) who underwent 13 operations to remove 17 brainstem hemangioblastomas were included in this study (mean follow-up period, 88.4 ± 37.4 months; range 37–144 months). Serial examinations, hospital charts, magnetic resonance images, and operative records were reviewed. To evaluate clinical course, clinical grades were assigned to each patient before and after surgery. Preoperative neurological function was the best predictor of long-term outcome. In addition, patients who underwent CNS surgeries for hemangioblastomas were more likely to improve or to remain neurologically stable. Tumor or cyst size, the presence of a cyst, or the location of the tumor (intramedullary, extramedullary, or mixed; posterior medullary, obex, or lateral) did not affect outcome. No patient was neurologically worse after brainstem surgery. At long-term follow-up review (mean 88.4 months), only one patient had declined neurologically and this was due to the cumulative neurological effects caused by eight additional hemangioblastomas of the spinal cord and their surgical treatment. Conclusions. Brainstem hemangioblastomas in patients with VHL disease can be removed safely; they generally should be resected when they become symptomatic or when the tumor has reached a size such that further growth will increase the risks associated with surgery, or in the presence of an enlarging cyst. Magnetic resonance imaging is usually sufficient for preoperative evaluation and presurgical embolization is unnecessary. The goal of surgery is complete resection of the lesion before the patient experiences a disabling neurological deficit.

Object. Von Hippel—Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients. Methods. Forty-four consecutive patients with VHL disease (26 men and 18 women) who underwent 55 operations with resection of 86 spinal cord hemangioblastomas (mean age at surgery 34 years; range 20–58 years) at the National Institutes of Health were included in this study (mean clinical follow up 44 months). Patient examination, review of hospital charts, operative findings, and magnetic resonance imaging studies were used to analyze surgical management and its outcome. To evaluate the clinical course, clinical grades were assigned to patients before and after surgery. Preoperative neurological status, tumor size, and tumor location were predictive of postoperative outcome. Patients with no or minimal preoperative neurological dysfunction, with lesions smaller than 500 mm3, and with dorsal lesions were more likely to have no or minimal neurological impairment. Syrinx resolution was the result of tumor removal and was not influenced by whether the syrinx cavity was entered. Conclusions. Spinal cord hemangioblastomas can be safely removed in the majority of patients with VHL disease. Generally in these patients, hemangioblastomas of the spinal cord should be removed when they produce symptoms or signs.

Object. The goals of this study were to define the natural history and growth pattern of hemangioblastomas of the central nervous system (CNS) that are associated with von Hippel—Lindau (VHL) disease and to correlate features of hemangioblastomas that are associated with the development of symptoms and the need for treatment. Methods. The authors reviewed serial magnetic resonance images and clinical histories of 160 consecutive patients with VHL disease who harbored CNS hemangioblastomas and serially measured the volumes of tumors and associated cysts. Six hundred fifty-five hemangioblastomas were identified in the cerebellum (250 tumors), brainstem (64 tumors, all of which were located in the posterior medulla oblongata), spinal cord (331 tumors, 96% of which were located in the posterior half of spinal cord), and the supratentorial brain (10 tumors). The symptoms were related to a mass effect. A serial increase in hemangioblastoma size was observed in cerebellar, brainstem, and spinal cord tumors as patients progressed from being asymptomatic to symptomatic and requiring surgery (p < 0.0001). Twenty-one (72%) of 29 symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of 221 nonsymptomatic cerebellar tumors had tumor-associated cysts (p < 0.0001). Nine (75%) of 12 symptomatic brainstem tumors had associated cysts, compared with only four (8%) of 52 nonsymptomatic brainstem lesions (p < 0.0001). By the time the symptoms appeared and surgery was required, the cyst was larger than the causative tumor; cerebellar and brainstem cysts measured 34 and 19 times the size of their associated tumors at surgery, respectively. Ninety-five percent of symptom-producing spinal hemangioblastomas were associated with syringomyelia. The clinical circumstance was dynamic. Among the 88 patients who had undergone serial imaging for 6 months or longer (median 32 months), 164 (44%) of 373 hemangioblastomas and 37 (67%) of 55 tumor-associated cysts enlarged. No tumors or cysts spontaneously diminished in size. Symptomatic cerebellar and brainstem tumors grew at rates six and nine times greater, respectively, than asymptomatic tumors in the same regions. Cysts enlarged seven (cerebellum) and 15 (brainstem) times faster than the hemangioblastomas causing them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) and then stabilize in a period of arrested growth (quiescent phase). Of 69 patients with documented tumor growth, 18 (26%) harbored tumors with at least two growth phases. Of 160 patients with hemangioblastomas, 34 patients (median follow up 51 months) were found to have 115 new hemangioblastomas and 15 patients new tumor-associated cysts. Conclusions. In this study the authors define the natural history of CNS hemangioblastomas associated with VHL disease. Not only were cysts commonly associated with cerebellar, brainstem, and spinal hemangioblastomas, the pace of enlargement was much faster for cysts than for hemangioblastomas. By the time symptoms appeared, the majority of mass effect—producing symptoms derived from the cyst, rather than from the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth, and many untreated tumors may remain the same size for several years. These characteristics must be considered when determining the optimal timing of screening for individual patients and for evaluating the timing and results of treatment.

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

Von Hippel-Lindau (VHL) disease is an autosomal dominant multiorgan tumor syndrome caused by a germline mutation in the VHL gene. Characteristic tumors include CNS hemangioblastomas (HBs), endolymphatic sac tumors, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Sporadic VHL disease with a de novo germline mutation is rare. The authors describe a case of multiple CNS HBs in a patient with a heterozygous de novo germline mutation at c.239G>T [p.S80I] of VHL. This is the first known case of a sporadic de novo germline mutation of VHL at c.239G>T. Clinicians should continue to consider VHL disease in patients presenting with sporadic CNS HBs, including those without a family history, to confirm or exclude additional VHL-associated visceral lesions.