Use of the Sports Concussion Assessment Tool 3 in Emergency Department Patients With Psychiatric Disease.

OBJECTIVE: The Sports Concussion Assessment Tool 3 (SCAT3) Symptom Evaluation (SE) is used in the emergency department (ED). This study aimed to examine the effects of psychiatric history on the SCAT3 SE symptom severity score (SSS). SETTING: Three US EDs. PARTICIPANTS: A total of 272 ED patients with suspected concussion. DESIGN: Prospective, nonrandomized, nonblinded study. The SCAT3 SE SSS, demographic data, medical information, and self-reported psychiatric history were obtained from patients by clinical research staff when they presented to the ED seeking standard clinical care. Concussion diagnoses were determined following a comprehensive assessment by an ED physician trained in managing concussions and adjudicated by supervising physicians. MAIN MEASURES: The primary outcome measure was SSS. The association between SSS, self-reported psychiatric disease, and concussion diagnosis was analyzed using multivariable linear regression. RESULTS: 68.4% of subjects were diagnosed with a concussion. After controlling for age, sex, race, history of previous concussion, and interval from injury to ED presentation, self-reported psychiatric history (adjusted regression coefficient (ßa): 16.9; confidence interval [CI]: 10.1, 23.6), and concussion diagnosis (ßa: 21.7; CI: 14.2, 29.2) were both independently associated with a significant increase in SSS. Subjects with a history of concussion had a significantly higher SSS (ßa: 9.1; CI: 1.8, 16.5). Interval from injury to ED presentation was also associated with a significant increase in SSS (ßa: 1.6 per 6-hour increase; CI: 0.4, 2.8). CONCLUSION: Our findings demonstrate that a history of preexisting psychiatric disease, as self-reported by patients with a suspected concussion treated in the ED, is independently associated with significantly higher scores on the SCAT3 SE. This suggests that a history of psychiatric illness may need to be accounted for when the SCAT3 SE is used in the ED for the assessment of concussion.

Analysis of a simulation algorithm for direct brain drug delivery.

Convection enhanced delivery (CED) achieves targeted delivery of drugs with a pressure-driven infusion through a cannula placed stereotactically in the brain. This technique bypasses the blood brain barrier and gives precise distributions of drugs, minimizing off-target effects of compounds such as viral vectors for gene therapy or toxic chemotherapy agents. The exact distribution is affected by the cannula positioning, flow rate and underlying tissue structure. This study presents an analysis of a simulation algorithm for predicting the distribution using baseline MRI images acquired prior to inserting the cannula. The MRI images included diffusion tensor imaging (DTI) to estimate the tissue properties. The algorithm was adapted for the devices and protocols identified for upcoming trials and validated with direct MRI visualization of gadoinium in 20 infusions in non-human primates. We found strong agreement between the size and location of the simulated and gadolinium volumes, demonstrating the clinical utility of this surgical planning algorithm.

Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study.

The PRECISE study used convection enhanced delivery (CED) to infuse IL13-PE38QQR in patients with recurrent glioblastoma multiforme (GBM) and compared survival to Gliadel Wafers (GW). The objectives of this retrospective evaluation were to assess: (1) catheter positioning in relation to imaging features and (2) to examine the potential impact of catheter positioning, overall catheter placement and imaging features on long term clinical outcome in the PRECISE study. Catheter positioning and overall catheter placement were scored and used as a surrogate of adequate placement. Imaging studies obtained on day 43 and day 71 after resection were each retrospectively reviewed. Catheter positioning scores, catheter overall placement scores, local tumor control and imaging change scores were reviewed and correlated using Generalized Linear Mixed Models. Cox PH regression analysis was used to examine whether these imaging based variables predicted overall survival (OS) and progression free survival (PFS) after adjusting for age and KPS. Of 180 patients in the CED group, 20 patients did not undergo gross total resection. Of the remaining 160 patients only 53% of patients had fully conforming catheters in respect to overall placement and 51% had adequate catheter positioning scores. Better catheter positioning scores were not correlated with local tumor control (P = 0.61) or imaging change score (P = 0.86). OS and PFS were not correlated with catheter positioning score (OS: P = 0.53; PFS: P = 0.72 respectively), overall placement score (OS: P = 0.55; PFS: P = 0.35) or imaging changes on day 43 MRI (P = 0.88). Catheter positioning scores and overall catheter placement scores were not associated with clinical outcome in this large prospective trial.

Rapid inverse planning for pressure-driven drug infusions in the brain.

Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials.

Design of an in-dwelling cannula for convection-enhanced delivery.

Failures of recent convection-enhanced delivery (CED) trials have underscored the need for improved CED cannulae. This study presents a novel in-dwelling cannula targeted for use in upcoming neuro-oncological or neurodegeneration trials. The cannula is reflux-resistant and easily integrated into clinical workflows. The cannula was evaluated in non-human primate CED studies performed with magnetic resonance imaging (MRI) to validate the effectiveness and safety of the infusion.

Poor drug distribution as a possible explanation for the results of the PRECISE trial.

OBJECT: Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS: Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS: Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS: The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.