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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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Galal Elsayed, Samuel G. McClugage III, Matthew S. Erwood, Matthew C. Davis, Esther B. Dupépé, Paul Szerlip, Beverly C. Walters and Mark N. Hadley

OBJECTIVE

Insurance disparities can have relevant effects on outcomes after elective lumbar spinal surgery. The aim of this study was to evaluate the association between private/public payer status and patient-reported outcomes in adult patients who underwent decompression surgery for lumbar spinal stenosis.

METHODS

A sample of 100 patients who underwent surgery for lumbar spinal stenosis from 2012 to 2014 was evaluated as part of the prospectively collected Quality Outcomes Database at a single institution. Outcome measures were evaluated at 3 months and 12 months, analyzed in regard to payer status (private insurance vs Medicare/Veterans Affairs insurance), and adjusted for potential confounders.

RESULTS

At baseline, patients had similar visual analog scale back and leg pain, Oswestry Disability Index, and EQ-5D scores. At 3 months postintervention, patients with government-funded insurance reported significantly worse quality of life (mean difference 0.11, p < 0.001) and more leg pain (mean difference 1.26, p = 0.05). At 12 months, patients with government-funded insurance reported significantly worse quality of life (mean difference 0.14, p < 0.001). There were no significant differences at 3 months or 12 months between groups for back pain (p = 0.14 and 0.43) or disability (p = 0.19 and 0.15). Across time points, patients in both groups showed improvement at 3 months and 12 months in all 4 functional outcomes compared with baseline (p < 0.001).

CONCLUSIONS

Both private and public insurance patients had significant improvement after elective lumbar spinal surgery. Patients with public insurance had slightly less improvement in quality of life after surgery than those with private insurance but still benefited greatly from surgical intervention, particularly with respect to functional status.

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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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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/sec2); 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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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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Galal Elsayed, Matthew S. Erwood, Matthew C. Davis, Esther C. Dupépé, Samuel G. McClugage III, Paul Szerlip, Beverly C. Walters and Mark N. Hadley

OBJECTIVE

This study defines the association of preoperative physical activity level with functional outcomes at 3 and 12 months following surgical decompression for lumbar spinal stenosis.

METHODS

Data were collected as a prospective observational registry at a single institution from 2012 through 2015, and then analyzed with a retrospective cohort design. Patients who were able to participate in activities outside the home preoperatively were compared to patients who did not participate in such activities, with respect to 3-month and 12-month functional outcomes postintervention, adjusted for relevant confounders.

RESULTS

Ninety-nine patients were included. At baseline, sedentary/inactive patients (n = 55) reported greater back pain, lower quality of life, and higher disability than similarly treated patients who were active preoperatively. Both cohorts experienced significant improvement from baseline in back pain, leg pain, disability, and quality of life at both 3 and 12 months after lumbar decompression surgery. At 3 months postintervention, sedentary/inactive patients reported more leg pain and worse disability than patients who performed activities outside the home preoperatively. However, at 12 months postintervention, there were no statistically significant differences between the two cohorts in back pain, leg pain, quality of life, or disability. Multivariate analysis revealed that sedentary/inactive patients had improved disability and higher quality of life after surgery compared to baseline. Active patients experienced greater overall improvement in disability compared to inactive patients.

CONCLUSIONS

Sedentary/inactive patients have a more protracted recovery after lumbar decompression surgery for spinal stenosis, but at 12 months postintervention can expect to reach similar long-term outcomes as patients who are active/perform activities outside the home preoperatively.

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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.

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Galal Elsayed, Samuel G. McClugage III, Matthew S. Erwood, Matthew C. Davis, Esther B. Dupépé, Paul Szerlip, Beverly C. Walters and Mark N. Hadley

OBJECTIVE

Insurance disparities can have relevant effects on outcomes after elective lumbar spinal surgery. The aim of this study was to evaluate the association between private/public payer status and patient-reported outcomes in adult patients who underwent decompression surgery for lumbar spinal stenosis.

METHODS

A sample of 100 patients who underwent surgery for lumbar spinal stenosis from 2012 to 2014 was evaluated as part of the prospectively collected Quality Outcomes Database at a single institution. Outcome measures were evaluated at 3 months and 12 months, analyzed in regard to payer status (private insurance vs Medicare/Veterans Affairs insurance), and adjusted for potential confounders.

RESULTS

At baseline, patients had similar visual analog scale back and leg pain, Oswestry Disability Index, and EQ-5D scores. At 3 months postintervention, patients with government-funded insurance reported significantly worse quality of life (mean difference 0.11, p < 0.001) and more leg pain (mean difference 1.26, p = 0.05). At 12 months, patients with government-funded insurance reported significantly worse quality of life (mean difference 0.14, p < 0.001). There were no significant differences at 3 months or 12 months between groups for back pain (p = 0.14 and 0.43) or disability (p = 0.19 and 0.15). Across time points, patients in both groups showed improvement at 3 months and 12 months in all 4 functional outcomes compared with baseline (p < 0.001).

CONCLUSIONS

Both private and public insurance patients had significant improvement after elective lumbar spinal surgery. Patients with public insurance had slightly less improvement in quality of life after surgery than those with private insurance but still benefited greatly from surgical intervention, particularly with respect to functional status.

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Galal A. Elsayed, Esther B. Dupépé, Matthew S. Erwood, Matthew C. Davis, Samuel G. McClugage III, Paul Szerlip, Beverly C. Walters and Mark N. Hadley

OBJECTIVE

The goal of this study was to analyze the effect of patient education level on functional outcomes following decompression surgery for symptomatic lumbar spinal stenosis.

METHODS

Patients with surgically decompressed symptomatic lumbar stenosis were collected in a prospective observational registry at a single institution between 2012 and 2014. Patient education level was compared to surgical outcomes to elucidate any relationships. Outcomes were defined using the Oswestry Disability Index score, back and leg pain visual analog scale (VAS) score, and the EuroQol–5 Dimensions questionnaire score.

RESULTS

Of 101 patients with symptomatic lumbar spinal stenosis, 27 had no college education and 74 had a college education (i.e., 2-year, 4-year, or postgraduate degree). Preoperatively, patients with no college education had statistically significantly greater back and leg pain VAS scores when compared to patients with a college education. However, there was no statistically significant difference in quality of life or disability between those with no college education and those with a college education. Postoperatively, patients in both cohorts improved in all 4 patient-reported outcomes at 3 and 12 months after treatment for symptomatic lumbar spinal stenosis.

CONCLUSIONS

Despite their education level, both cohorts showed improvement in their functional outcomes at 3 and 12 months after decompression surgery for symptomatic lumbar spinal stenosis.