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Lawrence S. Chin, Nicholas J. Szerlip and William F. Regine

Meningiomas are benign tumors attached to the dura that typically have a slow growth rate. After gliomas, they are the most common primary tumor of the brain. They are ideal radiobiological targets because single-fraction radiation has a high biologically effective dose. Furthermore, a highly conformal radiation plan can provide effective treatment to the tumor while sparing the surrounding brain. Meningioma control rates range from 90 to 95%, and the risk of morbidity is low. Radiosurgery is an excellent treatment for asymptomatic, small- to moderate-sized meningiomas. It is also ideal for patients with incompletely resected meningiomas, recurrent meningiomas, and risk factors precluding conventional surgery.

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Yamaan S. Saadeh, Brandon W. Smith, Jacob R. Joseph, Sohaib Y. Jaffer, Martin J. Buckingham, Mark E. Oppenlander, Nicholas J. Szerlip and Paul Park

OBJECTIVE

Spinal cord injury (SCI) results in significant morbidity and mortality. Improving neurological recovery by reducing secondary injury is a major principle in the management of SCI. To minimize secondary injury, blood pressure (BP) augmentation has been advocated. The objective of this study was to review the evidence behind BP management after SCI.

METHODS

This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Using the PubMed database, the authors identified studies that investigated BP management after acute SCI. Information on BP goals, duration of BP management, vasopressor selection, and neurological outcomes were analyzed.

RESULTS

Eleven studies that met inclusion criteria were identified. Nine studies were retrospective, and 2 were single-cohort prospective investigations. Of the 9 retrospective studies, 7 reported a goal mean arterial pressure (MAP) of higher than 85 mm Hg. For the 2 prospective studies, the MAP goals were higher than 85 mm Hg and higher than 90 mm Hg. The duration of BP management varied from more than 24 hours to 7 days in 6 of the retrospective studies that reported the duration of treatment. In both prospective studies, the duration of treatment was 7 days. In the 2 prospective studies, neurological outcomes were stable to improved with BP management. The retrospective studies, however, were contradictory with regard to the correlation of BP management and outcomes. Dopamine, norepinephrine, and phenylephrine were the agents that were frequently used to augment BP. However, more complications have been associated with dopamine use than with the other vasopressors.

CONCLUSIONS

There are no high-quality data regarding optimal BP goals and duration in the management of acute SCI. Based on the highest level of evidence available from the 2 prospective studies, MAP goals of 85–90 mm Hg for a duration of 5–7 days should be considered. Norepinephrine for cervical and upper thoracic injuries and phenylephrine or norepinephrine for mid- to lower thoracic injuries should be considered.

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Moaaz Soliman, Neil K. Taunk, Robert E. Simons, Joseph R. Osborne, Michelle M. Kim, Nicholas J. Szerlip and Daniel E. Spratt

Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS.

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Jacques J. Lara-Reyna, Rafael Uribe-Cardenas, Imali Perera, Nicholas Szerlip, Anastasios Giamouriadis, Nicole Savage, Therese Haussner and Mark M. Souweidane

OBJECTIVE

Removal of colloid cysts of the third ventricle using a purely endoscopic method has been established as a safe and advantageous technique. It is hypothesized that endoscopic removal in recurrent cases might pose more technical challenges and result in less success. The objective of this study was to assess the feasibility and outcomes of using a purely endoscopic approach for the management of recurrent colloid cysts compared to primary cysts.

METHODS

A retrospective cohort study was performed on patients who underwent purely endoscopic removal of their colloid cyst. Descriptive statistics were compared for patients undergoing surgery for a recurrent cyst and those for a control cohort undergoing surgery for a primary cyst. Bivariate analysis was conducted using a Fisher’s exact test for categorical variables and Mann-Whitney U-test for continuous variables.

RESULTS

In total, 121 patients had a primary colloid cyst endoscopically removed and 10 patients had a total of 11 recurrent cysts removed. Recurrence or progression after surgery occurred in 3 (2.5%) cases in the primary cyst group and 2 (18.2%) cases in the recurrent cyst group. Symptomatic presentation during the follow-up period occurred in 6 (54.5%) cases in the recurrent cyst group versus 75 (62%) cases in the primary cyst group (p = 0.749). Two patients (20%) in the recurrent group had a second recurrence in a mean period of 30 months (1 patient at 15 and 1 patient at 45 months). One of these patients required a tertiary endoscopic removal 8 years after the second resection. No immediate postoperative complications or new morbidities were observed after repeat endoscopic surgery. The authors’ findings indicated a nonsignificant trend toward a higher recurrence rate (18.2% vs 2.5%, p = 0.055) and a decreased proportion of complete removal (90.9% vs 81.8%, p = 0.296) in the recurrent cyst group compared to the primary cyst group. However, a significantly higher rate of preoperative hydrocephalus was observed in the primary cyst group compared with the recurrent cyst group (63.6% vs 18.2%, p = 0.007).

CONCLUSIONS

Purely endoscopic approaches for the removal of recurrent colloid cysts of the third ventricle are feasible and equally safe compared with endoscopic removal of primary cysts. The study’s findings did not show a statistically significant difference in the rate of recurrence between the 2 groups. The proportion of patients with symptomatic cysts on presentation was lower in patients with recurrent cysts than in patients with primary cysts. Due to the high rate of complete removal with negligible morbidity, the authors continue to advocate for an endoscopic removal at the time of cyst recurrence.

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Jennylee S. Swallow, Jacob R. Joseph, Kylene Willsey, Andrea A. Almeida, Matthew T. Lorincz, Paul Park, Nicholas J. Szerlip and Steven P. Broglio

OBJECTIVE

The authors of recent concussion guidelines have sought to form a consensus on injury management, but it is unclear if they have been effective in conveying this information to the public. Many parents and athletes obtain medical recommendations via the Internet. This review is aimed at evaluating consistency between online resources and published guideline statements in postconcussion return-to-play (RTP) decisions.

METHODS

Five websites were selected through a Google search for RTP after concussion, including a federal government institution (Centers for Disease Control and Prevention) website, a national high school association (National Federation of State High School Associations) website, a popular nationally recognized medical website for patients (WebMD), a popular parent-driven website for parents of children who participate in sports (MomsTeam), and the website of a private concussion clinic (Sports Concussion Institute), along with a university hospital website (University of Michigan Medicine). Eight specific items from the Zurich Sport Concussion Consensus Statement 2012 were used as the gold standard for RTP recommendations. Three independent reviewers graded each website for each of the 8 recommendations (A = states guideline recommendations appropriately; B = mentions guideline recommendation; C = does not mention guideline recommendation; F = makes inappropriate recommendation).

RESULTS

A grade of A was assigned for 45.8% of the recommendations, B for 25.0%, C for 25.0%, and F for 4.2%. All the websites were assigned an A grade for the recommendation of no RTP on the day of injury. Only 1 website (WebMD) mentioned medication usage in conjunction with the Zurich statement, and only 2 websites (Sports Concussion Institute and University of Michigan Medicine) mentioned appropriate management of persistent symptoms. None of these websites commented correctly on all 8 guideline recommendations.

CONCLUSIONS

Online resources are inconsistent in relaying guideline recommendations for RTP and provide a potential source of confusion in the management of concussion for athletes and their parents, which can result in inappropriate RTP decisions.

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Nicholas J. Szerlip, Elizabeth Fox, Frances Manosca, Linda D. Pegram and Russell R. Lonser

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Jacob R. Joseph, Jennylee S. Swallow, Kylene Willsey, Andrew P. Lapointe, Shokoufeh Khalatbari, Frederick K. Korley, Mark E. Oppenlander, Paul Park, Nicholas J. Szerlip and Steven P. Broglio

OBJECTIVE

This prospective observational cohort study of high-school football athletes was performed to determine if high-acceleration head impacts (HHIs) that do not result in clinically diagnosed concussion still lead to increases in serum levels of biomarkers indicating traumatic brain injury (TBI) in asymptomatic athletes and to determine the longitudinal profile of these biomarkers over the course of the football season.

METHODS

Sixteen varsity high-school football athletes underwent baseline neurocognitive testing and blood sampling for the biomarkers tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light protein (NF-L), glial fibrillary acidic protein (GFAP), and spectrin breakdown products (SBDPs). All athletes wore helmet-based accelerometers to measure and record head impact data during all practices and games. At various time points during the season, 6 of these athletes met the criteria for HHI (linear acceleration > 95g and rotational acceleration > 3760 rad/sec); in these athletes a second blood sample was drawn at the end of the athletic event during which the HHI occurred. Five athletes who did not meet the criteria for HHI underwent repeat blood sampling following the final game of the season. In a separate analysis, all athletes who did not receive a diagnosis of concussion during the season (n = 12) underwent repeat neurocognitive testing and blood sampling after the end of the season.

RESULTS

Total tau levels increased 492.6% ± 109.8% from baseline to postsession values in athletes who received an HHI, compared with 164% ± 35% in athletes who did not receive an HHI (p = 0.03). Similarly, UCH-L1 levels increased 738.2% ± 163.3% in athletes following an HHI, compared with 237.7% ± 71.9% in athletes in whom there was no HHI (p = 0.03). At the end of the season, researchers found that tau levels had increased 0.6 ± 0.2 pg/ml (p = 0.003) and UCH-L1 levels had increased 144.3 ± 56 pg/ml (p = 0.002). No significant elevations in serum NF-L, GFAP, or SBDPs were seen between baseline and end-of–athletic event or end-of-season sampling (for all, p > 0.05).

CONCLUSIONS

In this pilot study on asymptomatic football athletes, an HHI was associated with increased markers of neuronal (UCH-L1) and axonal (tau) injury when compared with values in control athletes. These same markers were also increased in nonconcussed athletes following the football season.

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Jacob R. Joseph, Jennylee S. Swallow, Kylene Willsey, Andrea A. Almeida, Matthew T. Lorincz, Robert K. Fraumann, Mark E. Oppenlander, Nicholas J. Szerlip and Steven P. Broglio

OBJECTIVE

Previous studies have shown that clinically asymptomatic high-acceleration head impacts (HHIs) may be associated with neuronal and axonal injury, as measured by advanced imaging and biomarkers. Unfortunately, these methods of measurement are time-consuming, invasive, and costly. A quick noninvasive measurement tool is needed to aid studies of head injury and its biological impact. Quantitative pupillometry is a potential objective, rapid, noninvasive measurement tool that may be used to assess the neurological effects of HHIs. In this study, the authors investigated the effect of HHIs on pupillary metrics, as measured using a pupillometer, in the absence of a diagnosed concussion.

METHODS

A prospective observational cohort study involving 18 high school football athletes was performed. These athletes were monitored for both the frequency and magnitude of head impacts that they sustained throughout a playing season by using the Head Impact Telemetry System. An HHI was defined as an impact exceeding 95g linear acceleration and 3760 rad/sec2 rotational acceleration. Pupillary assessments were performed at baseline, midseason, after occurrence of an HHI, and at the end of the season by using the NeurOptics NPi-200 pupillometer. The Sport Concussion Assessment Tool, 5th Edition (SCAT5), was also used at each time point. Comparisons of data obtained at the various time points were calculated using a repeated-measures analysis of variance and a t-test.

RESULTS

Seven athletes sustained HHIs without a related diagnosed concussion. Following these HHIs, the athletes demonstrated decreases in pupil dilation velocity (mean difference 0.139 mm/sec; p = 0.048), percent change in pupil diameter (mean difference 3.643%; p = 0.002), and maximum constriction velocity (mean difference 0.744 mm/sec; p = 0.010), compared to measurements obtained at the athletes’ own midseason evaluations. No significant changes occurred between the SCAT5 subtest scores calculated at midseason and those after a high impact, although the effect sizes (Cohen’s d) on individual components ranged from 0.41 to 0.65.

CONCLUSIONS

Measurable changes in pupil response were demonstrated following an HHI. These results suggest that clinically asymptomatic HHIs may affect brain reflex pathways, reflecting a biological injury previously seen when more invasive methods were applied.

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Gregory J. A. Murad, Stuart Walbridge, Paul F. Morrison, Nicholas Szerlip, John A. Butman, Edward H. Oldfield and Russell R. Lonser

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.

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Nicholas J. Szerlip, Stuart Walbridge, Linda Yang, Paul F. Morrison, Jeffrey W. Degen, S. Taylor Jarrell, Joshua Kouri, P. Benjamin Kerr, Robert Kotin, Edward H. Oldfield and Russell R. Lonser

Object

Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or feru-moxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging.

Methods

Sixteen rats underwent intrastriatal convective coinfusion with 4 μl of 35S-AAV capsids (0.5–1.0 × 1014 viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of 35S-AAV capsids and 1 mg/ml ferumoxtran-10 (striatum, one animal) or infusion of 1 mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed.

Results

Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypo-intense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran-10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R2 = 0.98). The mean Vd/Vi ratio was 4.1 ± 0.2 (mean ± standard error of the mean) in gray and 2.3 ± 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 μl/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity.

Conclusions

The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds.