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Rafael J. Tamargo, Allen K. Sills Jr., Carla S. Reinhard, Michael L. Pinn, Donlin M. Long and Henry Brem

✓ Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically.

Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 µg of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections.

The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.

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Lisa R. Rogers, Jack P. Rock, Allen K. Sills, Michael A. Vogelbaum, John H. Suh, Thomas L. Ellis, Volker W. Stieber, Anthony L. Asher, Robert W. Fraser, Judith S. Billingsley, Paul Lewis, Dawid Schellingerhout, Brain Metastasis Study Group and Edward G. Shaw

Object

The aim of this study was to evaluate the effectiveness of brachytherapy using the GliaSite Radiation Therapy System in patients with a newly diagnosed resected single brain metastasis. The primary end point of the study was local tumor control. The secondary end points included patient survival, distant brain recurrence, quality of life, and treatment toxicity.

Methods

The authors conducted a prospective multiinstitutional phase II study of GliaSite brachytherapy prescribed at a 60-Gy dose administered to a 1-cm depth after resection of a single brain metastasis. No whole-brain radiation therapy was given. Patients were assessed at 1 and 3 months after brachytherapy and every 3 months thereafter for up to 2 years.

Seventy-one patients were enrolled at 13 centers. A GliaSite balloon catheter was implanted in 62 patients. Fifty-four patients received brachytherapy. The median patient age was 60 years. The most common tumor (54%) was non–small cell lung cancer. Fifty-seven percent of patients had brain metastasis only, whereas 43% had extracranial metastasis. The median final administered dose was 60 Gy. The magnetic resonance imaging–determined local control rate, based on several different methods, was 82 to 87%. Both the median patient survival time and the median duration of functional independence were 40 weeks. Among the 35 patients who died, the cause of death was neurological in 11%. Thirteen patients underwent reoperation for suspected tumor recurrence or radiation necrosis, and histological diagnoses included radiation necrosis without tumor (nine patients), radiation necrosis mixed with tumor (two patients), and tumor only (two patients). Extracranial metastasis, tumor size, and radiation necrosis were significant factors affecting patient survival.

Conclusions

In patients with a resected single brain metastasis, GliaSite brachytherapy leads to a local control rate, median patient survival time, and duration of functional independence similar to those achieved with resection plus whole-brain radiation therapy.

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Scott L. Zuckerman, Gary S. Solomon, Jonathan A. Forbes, Richard F. Haase, Allen K. Sills and Mark R. Lovell

Object

Several studies have suggested a gender difference in response to sports-related concussion (SRC). The Concussion in Sport group did not include gender as a modifying factor in SRC, concluding that the evidence at that point was equivocal. In the present study the authors endeavored to assess acute neurocognitive and symptom responses to an SRC in equivalent cohorts of male and female soccer players. The authors hypothesized that female athletes would experience greater levels of acute symptoms and neurocognitive impairment than males.

Methods

Baseline symptom and neurocognitive scores were determined in 40 male and 40 female soccer players by using the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) scale prior to any SRC. After sustaining an SRC, each athlete completed postconcussion ImPACT tests and was carefully matched on a wide array of biopsychosocial variables. Baseline symptom and neurocognitive test scores were compared, and their acute symptoms and neurocognitive responses to concussive injury were assessed.

Results

Specific a priori hypotheses about differences between males and females at baseline and at postconcussion measurements of verbal and visual memory ImPACT scores were evaluated according to simple main effects of the gender variable and according to baseline-to-postconcussion main effect and interaction of 2 × 2 split-plot ANOVA. Neither the interaction nor the main effects nor the simple main effects for either ImPACT variable were found to be statistically significant. Exploratory ANOVAs applied to the remaining ImPACT variables of visualmotor speed, reaction time, impulse control, and symptom total scores revealed only a single statistically significant baseline-to-postconcussion main effect for the symptom total.

Conclusions

The results failed to replicate prior findings of gender-specific baseline neurocognitive differences in verbal and visual memory. The findings also indicated no differential gender-based acute response to concussion (symptoms or neurocognitive scores) among high school soccer players. The implications of these findings for the inclusion of gender as a modifying factor in this tightly matched cohort are addressed. Potential explanations for the null findings are discussed.

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Scott L. Zuckerman, Andrew Kuhn, Michael C. Dewan, Peter J. Morone, Jonathan A. Forbes, Gary S. Solomon and Allen K. Sills

Object

Sports-related concussions (SRCs) represent a significant and growing public health concern. The vast majority of SRCs produce mild symptoms that resolve within 1–2 weeks and are not associated with imaging-documented changes. On occasion, however, structural brain injury occurs, and neurosurgical management and intervention is appropriate.

Methods

A literature review was performed to address the epidemiology of SRC with a targeted focus on structural brain injury in the last half decade. MEDLINE and PubMed databases were searched to identify all studies pertaining to structural head injury in sports-related head injuries.

Results

The literature review yielded a variety of case reports, several small series, and no prospective cohort studies.

Conclusions

The authors conclude that reliable incidence and prevalence data related to structural brain injuries in SRC cannot be offered at present. A prospective registry collecting incidence, management, and follow-up data after structural brain injuries in the setting of SRC would be of great benefit to the neurosurgical community.

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Ivan Sosa and Alan Bosnar

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Scott L. Zuckerman, Young M. Lee, Mitchell J. Odom, Gary S. Solomon and Allen K. Sills

Object

Up to 16% of children in the US between the ages of 3 and 17 years have either attention deficit–spectrum disorder or a learning disability (LD). Sports-related concussions among youth athletes represent a significant public health concern, and neurocognitive testing is a method to evaluate the severity of cognitive impairment and recovery after a sports-related concussion. The goal of this study was to assess baseline neurocognitive differences between athletes with attention deficit hyperactivity disorder (ADHD) and/or LD versus those with neither disorder and to establish normative data for these special populations.

Methods

Between August 2007 and March 2012, 6636 young athletes underwent baseline neurocognitive testing performed using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery. Of these participants, 90 had self-reported LD only, 262 had self-reported ADHD only, and 55 reported both. Those with ADHD and/or LD were matched with 407 participants with no history of ADHD or LD by age, sex, and number of prior concussions. The mean scores and SDs were calculated for each group to obtain normative values. A pairwise comparison between each diagnostic group was done to assess whether LD and/or ADHD diagnostic status predicted participants' baseline neurocognitive scores.

Results

Participants with ADHD had significantly lower verbal memory, visual memory, and visual motor processing speed scores, along with significantly higher reaction time, impulse control, and symptom scores compared with those without LD or ADHD. Participants with LD had similar results, with significantly lower verbal memory, visual memory, and visual motor processing speed scores, higher reaction time and symptom score, but did not differ in their impulse control score compared with those without LD or ADHD. Participants with both LD and ADHD had a significantly lower visual motor speed score and a significantly higher reaction time and symptom score than those without LD or ADHD, but did not differ with regard to the other composite scores.

Conclusions

Athletes with ADHD and/or LD have lower baseline ImPACT neurocognitive scores compared with athletes without ADHD and LD. Preliminary normative neurocognitive data for these special populations are provided.

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Young M. Lee, Mitchell J. Odom, Scott L. Zuckerman, Gary S. Solomon and Allen K. Sills

Object

Sport-related concussions (SRCs) in high school and college athletes represent a significant public health concern. Research suggests that younger athletes fare worse symptomatically than older athletes after an SRC. Using reliable change index (RCI) methodology, the authors conducted a study to determine if there are age-related differences in number, severity, and resolution of postconcussion symptoms.

Methods

Between 2009 and 2011, baseline measures of neurocognitive functions and symptoms in high school and college athletes were entered into a regional database. Seven hundred forty of these athletes later sustained an SRC. Ninety-two athletes in the 13- to 16-year-old group and 92 athletes in the 18- to 22-year-old group were matched for number of prior concussions, sex, biopsychosocial variables, and days to first postconcussion testing and symptom assessment. A nonparametric Mann-Whitney U-test was used to compare the severity of each of 22 symptoms comprising the Total Symptom Scale (TSS) at baseline and first postconcussion test. To obtain a family-wise p value of 0.05 for each test, the significance level for each symptom comparison was set at an alpha of 0.05/22 = 0.0023. The number of days to return to baseline TSS score was compared using the RCI methodology, set at the 80% confidence interval, equal to a change in raw score of 9.18 points on the TSS.

Results

There was no statistically significant difference in symptom presence, symptom severity, and total symptoms between the age groups at baseline or at postconcussion testing. There was no statistically significant difference in return to baseline symptom scores between the age groups.

Conclusions

Using RCI methodology, there was no statistically significant difference between younger and older athletes in return to baseline symptoms postconcussion.

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Ann-Christine Duhaime

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Scott L. Zuckerman, Rachel P. Apple, Mitchell J. Odom, Young M. Lee, Gary S. Solomon and Allen K. Sills

Object

Sport-related concussions (SRCs) among youth athletes represent a significant public health concern. Prior research suggests that females fare worse symptomatically after an SRC. The authors aimed to assess sex differences in number, severity, and resolution of postconcussive symptoms using reliable change index (RCI) methodology applied to days to return to symptom baseline.

Methods

Between 2009 and 2011, 740 youth athletes completed valid neurocognitive and symptom testing before and after an SRC using Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). A total of 122 female and 122 male athletes were matched on number of prior concussions, age, and number of days to first postconcussion test. At baseline and postconcussion, the authors compared each of the individual 22 symptoms on ImPACT to calculate individual symptom severity and aggregate symptom severity, or the Total Symptom Score (TSS). When comparing individual symptoms, the significance level for the comparison of each symptom was set at 0.05/22 = 0.0023. When comparing aggregate symptom severity, or TSS, a single value was compared, requiring an alpha set to 0.05. The number of days to return to baseline TSS was compared using RCI methods set at the 80% confidence interval, equal to a raw score point value of 9.18 on the TSS.

Results

At baseline, females reported a greater severity for the symptom, “sleeping less than usual,” compared with males (0.88 ± 1.49 vs 0.31 ± 0.86, p < 0.001). However, no other individual symptom severity differences were noted before or after SRC. At baseline, females exhibited a statistically significant greater aggregate symptom severity than males (7.24 ± 10.22 vs 4.10 ± 6.52, p = 0.005). Greater aggregate symptom severity for females was also found postconcussion (21.38 ± 19.02 vs 16.80 ± 17.07, p = 0.049). Females took longer to return to baseline TSS (9.1 ± 7.1 days vs 7.0 ± 5.1 days, p = 0.013).

Conclusions

The results of this retrospective study indicate that females endorse a greater severity of symptoms at baseline and postconcussion than males without significantly different symptom profiles. Furthermore, after suffering an SRC, females take longer to return to their baseline symptom level.

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Clinton D. Morgan, Scott L. Zuckerman, Young M. Lee, Lauren King, Susan Beaird, Allen K. Sills and Gary S. Solomon

OBJECT

Sport-related concussion (SRC) is a major public health problem. Approximately 90% of SRCs in high school athletes are transient; symptoms recover to baseline within 1 week. However, a small percentage of patients remain symptomatic several months after injury, with a condition known as postconcussion syndrome (PCS). The authors aimed to identify risk factors for PCS development in a cohort of exclusively young athletes (9–18 years of age) who sustained SRCs while playing a sport.

METHODS

The authors conducted a retrospective case-control study by using the Vanderbilt Sports Concussion Clinic database. They identified 40 patients with PCS and matched them by age at injury and sex to SRC control patients (1 PCS to 2 control). PCS patients were those experiencing persistent symptoms at 3 months after an SRC. Control patients were those with documented resolution of symptoms within 3 weeks of an SRC. Data were collected in 4 categories: 1) demographic variables; 2) key medical, psychiatric, and family history; 3) acute-phase postinjury symptoms (at 0–24 hours); and 4) subacute-phase postinjury features (at 0–3 weeks). The chi-square Fisher exact test was used to assess categorical variables, and the Mann-Whitney U-test was used to evaluate continuous variables. Forward stepwise regression models (Pin = 0.05, Pout = 0.10) were used to identify variables associated with PCS.

RESULTS

PCS patients were more likely than control patients to have a concussion history (p = 0.010), premorbid mood disorders (p = 0.002), other psychiatric illness (p = 0.039), or significant life stressors (p = 0.036). Other factors that increased the likelihood of PCS development were a family history of mood disorders, other psychiatric illness, and migraine. Development of PCS was not predicted by race, insurance status, body mass index, sport, helmet use, medication use, and type of symptom endorsement. A final logistic regression analysis of candidate variables showed PCS to be predicted by a history of concussion (OR 1.8, 95% CI 1.1–2.8, p = 0.016), preinjury mood disorders (OR 17.9, 95% CI 2.9–113.0, p = 0.002), family history of mood disorders (OR 3.1, 95% CI 1.1–8.5, p = 0.026), and delayed symptom onset (OR 20.7, 95% CI 3.2–132.0, p < 0.001).

CONCLUSIONS

In this age- and sex-matched case-control study of risk factors for PCS among youth with SRC, risk for development of PCS was higher in those with a personal and/or family history of mood disorders, other psychiatric illness, and migraine. These findings highlight the unique nature of SRC in youth. For this population, providers must recognize the value of establishing the baseline health and psychiatric status of children and their primary caregivers with regard to symptom reporting and recovery expectations.

In addition, delayed symptom onset was an unexpected but strong risk factor for PCS in this cohort. Delayed symptoms could potentially result in late removal from play, rest, and care by qualified health care professionals. Taken together, these results may help practitioners identify young athletes with concussion who are at a greater danger for PCS and inform larger prospective studies for validation of risk factors from this cohort.