Publications by authors named "David O Okonkwo"

260 Publications

Prognostic Value of Hemorrhagic Brainstem Injury on Early Computed Tomography: A TRACK-TBI Study.

Neurocrit Care 2021 Jul 26. Epub 2021 Jul 26.

Department of Neurological Surgery, Harborview Medical Center, University of Washington School of Medicine, 325 9th Ave, Box 359924, Seattle, WA, 98104, USA.

Background: Traumatic brainstem injury has yet to be incorporated into widely used imaging classification systems for traumatic brain injury (TBI), and questions remain regarding prognostic implications for this TBI subgroup. To address this, retrospective data on patients from the multicenter prospective Transforming Research and Clinical Knowledge in TBI study were studied.

Methods: Patients with brainstem and cerebrum injury (BSI+) were matched by age, sex, and admission Glasgow Coma Scale (GCS) score to patients with cerebrum injuries only. All patients had an interpretable head computed tomography (CT) scan from the first 48 hours after injury and a 6-month Glasgow Outcome Scale Extended (GOSE) score. CT scans were reviewed for brainstem lesions and, when present, characterized by location, size, and type (traumatic axonal injury, contusion, or Duret hemorrhage). Clinical, demographic, and outcome data were then compared between the two groups.

Results: Mann-Whitney U-tests showed no significant difference in 6-month GOSE scores in patients with BSI+ (mean 2.7) compared with patients with similar but only cerebrum injuries (mean 3.9), although there is a trend (p = 0.10). However, subclassification by brainstem lesion type, traumatic axonal injury (mean 4.0) versus Duret hemorrhage or contusion (mean 1.4), did identify a proportion of BSI+ with significantly less favorable outcome (p = 0.002). The incorporation of brainstem lesion type (traumatic axonal injury vs. contusion/Duret), along with GCS into a multivariate logistic regression model of favorable outcome (GOSE score 4-8) did show a significant contribution to the prognostication of this brainstem injury subgroup (odds ratio 0.08, 95% confidence interval 0.00-0.67, p = 0.01).

Conclusions: These findings suggest two groups of patients with brainstem injuries may exist with divergent recovery potential after TBI. These data support the notion that newer CT imaging classification systems may augment traditional clinical measures, such as GCS in identifying those patients with TBI and brainstem injuries that stand a higher chance of favorable outcome.
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http://dx.doi.org/10.1007/s12028-021-01263-8DOI Listing
July 2021

Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury.

JAMA Netw Open 2021 Jul 1;4(7):e2116839. Epub 2021 Jul 1.

Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Intracerebral hemorrhage progression is associated with unfavorable outcome after traumatic brain injury (TBI). No effective treatments are currently available. This secondary injury process reflects an extreme form of vasogenic edema and blood-brain barrier breakdown. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) cation channel is a key underlying mechanism. A phase 2 trial of SUR1-TRPM4 inhibition in contusional TBI is ongoing, and a phase 3 trial is being designed. Targeted identification of patients at increased risk for hemorrhage progression may inform prognostication, trial design (including patient selection), and ultimately treatment response.

Objective: To determine whether ABCC8 (SUR1) and TRPM4 genetic variability are associated with intraparenchymal hemorrhage (IPH) progression after severe TBI, based on the putative involvement of the SUR1-TRPM4 channel in this pathophysiology.

Design, Setting, And Participants: In this genetic association study, DNA was extracted from 416 patients with severe TBI prospectively enrolled from a level I trauma academic medical center from May 9, 2002, to August 8, 2014. Forty ABCC8 and TRPM4 single-nucleotide variants (SNVs) were genotyped (multiplex, unbiased). Data were analyzed from January 7, 2020, to May 3, 2021.

Main Outcomes And Measures: Primary analyses addressed IPH progression at 6, 24, and 120 hours in patients without acute craniectomy (n = 321). Multivariable regressions and receiver operating characteristic curves assessed SNV and haplotype associations with progression. Spatial modeling and functional predictions were determined using standard software.

Results: Of the 321 patients included in the analysis (mean [SD] age, 37.0 [16.3] years; 247 [76.9%] male), IPH progression occurred in 102. Four ABCC8 SNVs were associated with markedly increased odds of progression (rs2237982 [odds ratio (OR), 2.60-3.80; 95% CI, 1.14-5.90 to 1.80-8.02; P = .02 to P < .001], rs2283261 [OR, 3.37-4.77; 95% CI, 1.07-10.77 to 1.89-12.07; P = .04 to P = .001], rs3819521 [OR, 2.96-3.92; 95% CI, 1.13-7.75 to 1.42-10.87; P = .03 to P = .009], and rs8192695 [OR, 3.06-4.95; 95% CI, 1.02-9.12 to 1.67-14.68]; P = .03-.004). These are brain-specific expression quantitative trait loci (eQTL) associated with increased ABCC8 messenger RNA levels. Regulatory annotations revealed promoter and enhancer marks and strong and/or active brain-tissue transcription, directionally consistent with increased progression. Three SNVs (rs2283261, rs2237982, and rs3819521) in this cohort have been associated with intracranial hypertension. Four TRPM4 SNVs were associated with decreased IPH progression (rs3760666 [OR, 0.40-0.49; 95% CI, 0.19-0.86 to 0.27-0.89; P = .02 to P = .009], rs1477363 [OR, 0.40-0.43; 95% CI, 0.18-0.88 to 0.23-0.81; P = .02 to P = .006], rs10410857 [OR, 0.36-0.41; 95% CI, 0.20-0.67 to 0.20-0.85; P = .02 to P = .001], and rs909010 [OR, 0.27-0.40; 95% CI, 0.12-0.62 to 0.16-0.58; P = .002 to P < .001]). Significant SNVs in both genes cluster downstream, flanking exons encoding the receptor site and SUR1-TRPM4 binding interface. Adding genetic variation to clinical models improved receiver operating characteristic curve performance from 0.6959 to 0.8030 (P = .003).

Conclusions And Relevance: In this genetic association study, 8 ABCC8 and TRPM4 SNVs were associated with IPH progression. Spatial clustering, brain-specific eQTL, and regulatory annotations suggest biological plausibility. These findings may have important implications for neurocritical care risk stratification, patient selection, and precision medicine, including an upcoming phase 3 trial design for SUR1-TRPM4 inhibition in severe TBI.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.16839DOI Listing
July 2021

Pathological Computed Tomography Features Associated With Adverse Outcomes After Mild Traumatic Brain Injury: A TRACK-TBI Study With External Validation in CENTER-TBI.

JAMA Neurol 2021 Jul 19. Epub 2021 Jul 19.

University of Washington, Seattle.

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.

Objective: To identify pathological CT features associated with adverse outcomes after mTBI.

Design, Setting, And Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.

Exposures: Acute nonpenetrating head trauma.

Main Outcomes And Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.

Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.

Conclusions And Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.
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http://dx.doi.org/10.1001/jamaneurol.2021.2120DOI Listing
July 2021

Functional Outcomes Over the First Year After Moderate to Severe Traumatic Brain Injury in the Prospective, Longitudinal TRACK-TBI Study.

JAMA Neurol 2021 Jul 6. Epub 2021 Jul 6.

University of Cincinnati, Cincinnati, Ohio.

Importance: Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI.

Objective: To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI.

Design, Setting, And Participants: This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021.

Exposures: Moderate or severe TBI.

Main Outcomes And Measures: The Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed.

Results: A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months.

Conclusions And Relevance: In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.
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http://dx.doi.org/10.1001/jamaneurol.2021.2043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261688PMC
July 2021

Polytrauma Is Associated with Increased Three- and Six-Month Disability after Traumatic Brain Injury: A TRACK-TBI Pilot Study.

Neurotrauma Rep 2020 23;1(1):32-41. Epub 2020 Jul 23.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Polytrauma and traumatic brain injury (TBI) frequently co-occur and outcomes are routinely measured by the Glasgow Outcome Scale-Extended (GOSE). Polytrauma may confound GOSE measurement of TBI-specific outcomes. Adult patients with TBI from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study had presented to a Level 1 trauma center after injury, received head computed tomography (CT) within 24 h, and completed the GOSE at 3 months and 6 months post-injury. Polytrauma was defined as an Abbreviated Injury Score (AIS) ≥3 in any extracranial region. Univariate regressions were performed using known GOSE clinical cutoffs. Multi-variable regressions were performed for the 3- and 6-month GOSE, controlling for known demographic and injury predictors. Of 361 subjects (age 44.9 ± 18.9 years, 69.8% male), 69 (19.1%) suffered polytrauma. By Glasgow Coma Scale (GCS) assessment, 80.1% had mild, 5.8% moderate, and 14.1% severe TBI. On univariate logistic regression, polytrauma was associated with increased odds of moderate disability or worse (GOSE ≤6; 3 month odds ratio [OR] = 2.57 [95% confidence interval (CI): 1.50-4.41; 6 month OR = 1.70 [95% CI: 1.01-2.88]) and death/severe disability (GOSE ≤4; 3 month OR = 3.80 [95% CI: 2.03-7.11]; 6 month OR = 3.33 [95% CI: 1.71-6.46]). Compared with patients with isolated TBI, more polytrauma patients experienced a decline in GOSE from 3 to 6 months (37.7 vs. 24.7%), and fewer improved (11.6 vs. 22.6%). Polytrauma was associated with greater univariate ordinal odds for poorer GOSE (3 month OR = 2.79 [95% CI: 1.73-4.49]; 6 month OR = 1.73 [95% CI: 1.07-2.79]), which was conserved on multi-variable ordinal regression (3 month OR = 3.05 [95% CI: 1.76-5.26]; 6 month OR = 2.04 [95% CI: 1.18-3.42]). Patients with TBI with polytrauma are at greater risk for 3- and 6-month disability compared with those with isolated TBI. Methodological improvements in assessing TBI-specific disability, versus disability attributable to all systemic injuries, will generate better TBI outcomes assessment tools.
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http://dx.doi.org/10.1089/neur.2020.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240880PMC
July 2020

Acute DNA Methylation Trajectories in Cerebrospinal Fluid and Associations With Outcomes Following Severe Traumatic Brain Injury in Adults.

Neurorehabil Neural Repair 2021 Jun 25:15459683211028245. Epub 2021 Jun 25.

Department of Human Genetics, 51303University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.

. Epigenetic biomarkers have the potential to explain outcome heterogeneity following traumatic brain injury (TBI) but are largely unexplored. . This exploratory pilot study characterized () DNA methylation trajectories following severe TBI. . DNA methylation trajectories in cerebrospinal fluid (CSF) over the first 5 days following severe TBI in 112 adults were examined in association with 3- and 12-month outcomes. . Group-based trajectory analysis revealed low and high DNA methylation groups at two cytosine-phosphate-guanine (CpG) targets that showed suggestive associations ( < .05) with outcomes. Membership in the high DNA methylation groups was associated with better outcomes after controlling for age, sex, and injury severity. Associations of age × trajectory group interactions with outcomes at a third CpG site revealed a pattern of the same or better outcomes with higher ages in the high DNA methylation group and worse outcomes with higher ages in the low DNA methylation group. . Although no observed associations met the empirical significance threshold after correcting for multiple comparisons, suggestive associations of the main effect models were consistent in their direction of effect and were observed across two CpG sites and two outcome time points. Results suggest that higher acute CSF DNA methylation may promote recovery following severe TBI in adults, and this effect may be more robust with higher age. While the results require replication in larger and racially diverse independent samples, DNA methylation may serve as an early postinjury biomarker helping to explain outcome heterogeneity following TBI.
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http://dx.doi.org/10.1177/15459683211028245DOI Listing
June 2021

Incidence of adjacent-segment surgery following stand-alone lateral lumbar interbody fusion.

J Neurosurg Spine 2021 Jun 18:1-5. Epub 2021 Jun 18.

Objective: Adjacent-segment disease (ASD) requiring operative intervention is a relatively common long-term consequence of lumbar fusion surgery. Although the incidence of ASD requiring reoperation is well described for traditional posterior lumbar approaches (2.5%-3.9% per year), it remains poorly characterized for stand-alone lateral lumbar interbody fusion (LLIF). In this study, the authors report their institutional experience with ASD requiring reoperation after LLIF over an extended follow-up period of 4 years.

Methods: Medical records were reviewed for 276 consecutive patients who underwent stand-alone LLIF by a single surgeon for degenerative spinal disorders. Inclusion criteria (single-stage, stand-alone LLIF without posterior supplementation, with no prior lumbar instrumentation, and a minimum of 4 years of follow-up) were met by 182 patients, who were analyzed for operative ASD incidence (per-year rate), demographics, and Oswestry Disability Index (ODI) score. Operative ASD was strictly defined as new-onset pathology following index surgery at directly adjacent levels to the prior construct. Operative, rather than symptomatic or radiographic, ASD was analyzed to provide a consistent and impactful endpoint while avoiding retrospective diagnosis.

Results: The study cohort of 182 patients had an operative ASD rate of 3.3% (n = 6 procedures) over 4 years of follow-up, for an incidence on Kaplan-Meier survival analysis of 0.88% (95% CI 0.67%-1.09%) per year. In comparing patients with operative ASD with those without, there were no significant differences in mean age (53.7 vs 56.2 years), male sex (33.3% vs 44.9%), smoking status (16.7% vs 25.0%), or number of levels fused (mean 1.33 vs 1.46). The operative ASD cohort had a greater mean BMI (37.3 vs 30.2, p < 0.01). Operative ASD patients had lower baseline ODI scores (33.8 vs 48.3, p = 0.02); however, no difference was observed in ODI at 6 weeks (34.0 vs 39.0) or 3 months (16.0 vs 32.8) postoperatively.

Conclusions: The incidence of ASD in LLIF for degenerative lumbar etiologies in this cohort was 0.88% (95% CI 0.67%-1.09%) per year. Meanwhile, the reported reoperation rates for ASD in posterior spinal approaches was 2.5% to 3.9% per year, which implies that LLIF may be preferable for well-selected patients.
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http://dx.doi.org/10.3171/2020.12.SPINE201218DOI Listing
June 2021

Targeted Intervention Improves Symptoms and Impairments in Patients With Mild Traumatic Brain Injury With Chronic Symptom: A Prospective, Multiple Interventional Research Trial.

J Spec Oper Med 2021 ;21(2):61-66

Background: Mild traumatic brain injury (mTBI) and its potential long-term consequences is a primary concern for the US military. The purpose of the study is to evaluate if participants improved in anxiety/mood symptoms, sleep quality, and vestibular/ocular symptoms following a 6-month active intervention, and to explore the effect of targeted treatment for those with specific symptoms/impairments (e.g., psychological, sleep, ocular, vestibular).

Materials And Methods: A multidisciplinary clinical team adjudicated participants (n=72, 35.8±8.6 years old, 19% female) to have one of the following primary clinical trajectories: psychological (PSYCH; n=34), sleep (SLEEP; n=25) and vestibular/ocular (VESTIB/OCULAR; n=18). Participants returned for follow-up assessment 6 months later. Assessments included the Post-Concussion Symptom Scale [PCSS], Generalized Anxiety Disorder-7 [GAD-7], Pittsburgh Sleep Quality Index [PSQI], and Dizziness Handicap Inventory [DHI]. Change in concussion symptoms and primary outcome for the given trajectory (i.e., PSYCH=GAD-7, SLEEP=PSQI, VESTIB/OCULAR=DHI) was assessed.

Results: Following the 6-month intervention, participants reduced PCSS Score (-14.5±2.4; p<.001; η2=0.34), GAD-7 (-3.1±0.5; p<.001; η2=0.34), PSQI (-2.7±0.5; p<.001; η2=0.34) and DHI (-9.2±2.0; p<.001; η2=0.23). PSYCH (n=34) reduced PCSS score (-17.9±3.6; p<.001; η2=0.45) and GAD-7 (-3.1±0.7; p<.001; η2=0.38). SLEEP (n=25) reduced PCSS score (-8.8±4.4; p=.06; η2=0.15) and PSQI (-3.6±0.9; p<.001; η2=0.45) scores. VESTIB/OCULAR (n=18) reduced PCSS score (-16.7±4.8; p=.03; η2=0.45), and DHI (-15.7±5.5; p=.012; η2=0.35).

Conclusions: Large effects were observed for concussion, anxiety, sleep, and dizziness symptom reduction over 6-month treatment. Each primary outcome demonstrated a larger treatment effect for the given trajectory than the overall sample, indicating that targeted treatment can reduce symptom burden in patients with mTBI with chronic symptoms.
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June 2021

Predictors of six-month inability to return to work in previously employed subjects after mild traumatic brain injury: A TRACK-TBI pilot study.

J Concussion 2021 Jan-Dec;5. Epub 2021 Apr 6.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

Introduction: Return to work (RTW) is an important milestone of mild traumatic brain injury (mTBI) recovery. The objective of this study was to evaluate whether baseline clinical variables, three-month RTW, and three-month postconcussional symptoms (PCS) were associated with six-month RTW after mTBI.

Methods: Adult subjects from the prospective multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with mTBI (Glasgow Coma Scale 13-15) who were employed at baseline, with completed three-and six-month RTW status, and three-month Acute Concussion Evaluation (ACE), were extracted. Univariate and multivariable analyses were performed for six-month RTW, with focus on baseline employment, three-month RTW, and three-month ACE domains (physical, cognitive, sleep, and/or emotional postconcussional symptoms (PCS)). Odds ratios (OR) and 95% confidence intervals [CI] were reported. Significance was assessed at p < 0.05.

Results: In 152 patients aged 40.7 ± 15.0years, 72% were employed full-time at baseline. Three- and six-month RTW were 77.6% and 78.9%, respectively. At three months, 59.2%, 47.4%, 46.1% and 31.6% scored positive for ACE physical, cognitive, sleep, and emotional PCS domains, respectively. Three-month RTW predicted six-month RTW (OR = 19.80, 95% CI [7.61-51.52]). On univariate analysis, scoring positive in any three-month ACE domain predicted inability for six-month RTW (OR = 0.10-0.11). On multivariable analysis, emotional symptoms predicted inability to six-month RTW (OR = 0.19 [0.04-0.85]). Subjects who scored positive in all four ACE domains were more likely to be unable to RTW at six months (4 domains: 58.3%, vs. 0-to-3 domains: 9.5%; multivariable OR = 0.09 [0.02-0.33]).

Conclusions: Three-month post-injury is an important time point at which RTW status and PCS should be assessed, as both are prognostic markers for six-month RTW. Clinicians should be particularly vigilant of patients who present with emotional symptoms, and patients with symptoms across multiple PCS categories, as these patients are at further risk of inability to RTW and may benefit from targeted evaluation and support.
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http://dx.doi.org/10.1177/20597002211007271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153496PMC
April 2021

Load-Sharing Classification Score as Supplemental Grading System in the Decision-Making Process for Patients With Thoracolumbar Injury Classification and Severity 4.

Neurosurgery 2021 May 26. Epub 2021 May 26.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Patients with Thoracolumbar Injury Classification and Severity (TLICS) score of 4 fall into a gray zone between surgical and conservative management. The integrity of posterior ligamentous complex (PLC) evaluated by magnetic resonance imaging (MRI) contributes to surgical decision-making. Load-sharing classification (LSC) may provide a modifier to further guide decision-making in these patients.

Objective: To evaluate associations between LSC score and MRI acquisition, compromise of PLC on MRI, and surgical intervention in TLICS 4 patients.

Methods: A cohort of 111 neurologically intact patients with isolated thoracolumbar burst fracture with TLICS 4 was evaluated. LSC score was determined based on degree of comminution (1-3), apposition (1-3), and kyphosis (1-3), total composite score of 3 to 9.

Results: Overall, 44 patients underwent MRI, 15 had PLC injury, and 32 (28.8%) underwent surgery. LSC score was higher in patients who had an MRI (median 6 vs 3, P < .001) and patients who had surgery (median 7 vs 4, P < .001). In univariate logistic regression, LSC score was associated with MRI acquisition (odds ratio [OR] 1.7; 1.32-2.12; P < .001), presence of PLC injury on MRI (OR 1.5; 1.2-2.0; P = .002) and, in multivariate logistic regression, undergoing surgical intervention (OR 3.7; 2.3-5.9; P < .001), independent of MRI or PLC injury.

Conclusion: LSC score in neurologically intact patients with isolated thoracolumbar burst fracture with TLICS 4 was independently associated with operative intervention. The application of LSC may further guide decision-making in this patient group.
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http://dx.doi.org/10.1093/neuros/nyab179DOI Listing
May 2021

Safety of lateral access to the concave side for adult spinal deformity.

J Neurosurg Spine 2021 May 14:1-5. Epub 2021 May 14.

1Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and.

Objective: Minimally invasive surgery (MIS) techniques, particularly lateral lumbar interbody fusion (LLIF), have become increasingly popular for adult spinal deformity (ASD) correction. Much discussion has been had regarding theoretical and clinical advantages to addressing coronal curvature from the convex versus concave side of the curve. In this study, the authors aimed to broadly evaluate the clinical outcomes of addressing ASD with circumferential MIS (cMIS) techniques while accessing the lumbar coronal curvature from the concave side.

Methods: A multi-institution, retrospective chart and radiographic review was performed for all ASD patients with at least a 10° curvature, as defined by the Scoliosis Research Society, who underwent cMIS correction. The data collected included convex versus concave access to the coronal curve, durable or sensory femoral nerve injury lasting longer than 6 weeks, vascular injury, visceral injury, and any additional major complication, with at least a 2-year follow-up. Neither health-related quality-of-life metrics nor spinopelvic parameters were included within the scope of this study.

Results: A total of 152 patients with ASD treated with cMIS correction via lateral access were identified and analyzed. Of these, 126 (82.9%) were approached from the concave side and 26 (17.1%) were approached from the convex side. In the concave group, 1 (0.8%) motor and 4 (3.2%) sensory deficit cases remained at 6 weeks after the operation. No vascular, visceral, or catastrophic intraoperative injuries were encountered in the concave group. Of the 26 patients in the convex group, 2 (7.7%) experienced motor deficits lasting longer than 6 weeks and 5 (19.2%) had lower-extremity sensory deficits.

Conclusions: It has been reported that lateral access to the convex side is associated with similar clinical and radiographic outcomes with fewer complications when compared with access to the concave side. Advantages to approaching the lumbar spine from the concave side include using one incision to access multiple levels, breaking the operative table to assist with curvature correction, easier access to the L4-5 disc space, the ability to release the contracted side, and, often, avoidance of the need to access or traverse the thoracic cavity. This study illustrates the largest reported cohort of concave access for cMIS scoliosis correction; few postoperative sensory and motor deficits were found.
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http://dx.doi.org/10.3171/2020.10.SPINE191270DOI Listing
May 2021

Staged Repositioning in Endoscopic Endonasal Odontoidectomy Maximizes Decompression While Allowing Preservation of the C1 Anterior Arch: A Technical Note.

World Neurosurg 2021 Jul 30;151:118-123. Epub 2021 Apr 30.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Preservation of the anterior arch of C1 in endoscopic endonasal odontoidectomy has been proposed as an alternative to complete C1 arch resections, potentially affording less destabilization of the craniocervical junction. Nonetheless, this approach may limit the decompression achieved. In this case, intraoperative repositioning allowed maximal decompression while preserving the anterior arch of C1.

Methods: A 79-year-old woman presented with suboccipital pain caused by an expansile and compressive mass centered on the dens. Notably, the mass occluded both vertebral arteries resulting in small cerebellar strokes. An endoscopic endonasal approach for diagnosis and decompression was performed followed by posterior fixation.

Results: Given the significant compression, the patient was initially positioned in slight cervical extension. After rhinopharyngeal flap harvest, the top half of the anterior arch of C1 was resected, maintaining its structural integrity. The odontoidectomy was completed flush to the superior border of the reduced C1 arch. After an intraoperative computed tomography (CT) scan, performed in a neutral position, the patient was then repositioned with cervical flexion. This maneuver presented the residual odontoid above the C1 arch, but, given the partial removal of the dens, it did not result in any change in neuromonitoring. Further odontoid resection was then completed and follow-up CT scan revealed maximal dens removal, extending below the C1 anterior arch in neutral position.

Conclusions: In cases of odontoid/atlantoaxial pathology causing significant neural compression, staged intraoperative repositioning can safely maximize the odontoidectomy, while affording preservation of the structural integrity of the anterior arch of C1.
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http://dx.doi.org/10.1016/j.wneu.2021.04.105DOI Listing
July 2021

Comparison of GFAP and UCH-L1 Measurements from Two Prototype Assays: The Abbott i-STAT and ARCHITECT Assays.

Neurotrauma Rep 2021 7;2(1):193-199. Epub 2021 Apr 7.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) may aid in the evaluation of traumatic brain injury (TBI). The objective of this analysis was to compare GFAP and UCH-L1 values measured using a handheld device compared with a core laboratory platform. We analyzed plasma samples from patients with TBI and healthy controls enrolled in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) cohort study. GFAP and UCH-L1 were measured twice in each subject using prototype assays, first with the Abbott i-STAT™ handheld device, and second with the Abbott ARCHITECT platform. We then quantified the agreement in biomarker values obtained using these two methods. GFAP and UCH-L1 were measured twice in 570 and 572 samples, respectively. GFAP values measured by the ARCHITECT platform (median 143.3 [interquartile range (IQR): 19.8-925.8] pg/mL) were higher than values measured by the i-STAT (median 116.0 [IQR: 9.2-856.5] pg/mL). GFAP values from the two platforms were strongly correlated ( = 0.985). Similarly, UCH-L1 values measured by the ARCHITECT platform (median 163.9 [IQR: 82.5-412.4] pg/mL) were higher than values measured by the i-STAT (median 122.5 [IQR: 63.0-297.3] pg/mL). UCH-L1 values from the two platforms were strongly correlated ( = 0.933). Passing-Bablok regression equations were developed to estimate the relationship between the two platforms, specifically to predict i-STAT values from the ARCHITECT platform. GFAP and UCH-L1 values measured using the prototype assays on the Abbott i-STAT and ARCHITECT platforms are strongly correlated and values from either platform may be converted to the other.
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http://dx.doi.org/10.1089/neur.2020.0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086519PMC
April 2021

Surgery Related Factors Do Not Affect Short-Term Adjacent Segment Kinematics After Anterior Cervical Arthrodesis.

Spine (Phila Pa 1976) 2021 Apr 23. Epub 2021 Apr 23.

Department of Orthopaedic Surgery, University of Pittsburgh Medical Center Department of Neurosurgery, University of Pittsburgh Medical Center.

Study Design: Prospective cohort study.

Objective: To identify surgical factors that affect adjacent segment kinematics after anterior cervical discectomy and fusion (ACDF) as measured by biplane radiography.

Summary Of Background Data: Previous studies investigated the effect of surgical factors on spine kinematics as a potential etiology for adjacent segment disease (ASD). Those studies used static flexion-extension radiographs to evaluate range of motion. However, measurements from static radiographs are known to be unreliable. Furthermore, those studies were unable to evaluate the effect of ACDF on adjacent segment axial rotation.

Methods: Patients had continuous cervical spine flexion/extension and axial rotation movements captured at 30 images per second in a dynamic biplane radiography system preoperatively and 1 year after ACDF. Digitally reconstructed radiographs generated from subject-specific CT scans were matched to biplane radiographs using a previously validated tracking process. Dynamic kinematics, postoperative segmental kyphosis, and disc distraction were calculated from this tracking process. Plate-to-disc distance was measured on postoperative radiographs. Graft type was collected from the medical record. Multivariate linear regression was performed to identify surgical factors associated with 1-year post-surgery changes in adjacent segment kinematics. A secondary analysis was also performed to compare adjacent segment kinematics between each of the surgical factors and previously defined thresholds believed to be associated with adjacent segment degeneration.

Results: Fifty-nine patients completed preoperative and postoperative testing. No association was found between any of the surgical factors and change in adjacent segment flexion/extension or axial rotation range of motion (all p > 0.09). The secondary analysis also did not identify differences between adjacent segment kinematics and surgical factors (all p > 0.07).

Conclusions: Following ACDF for cervical spondylosis, factors related to surgical technique were not associated with short-term changes in adjacent segment kinematics that reflect the hypermobility hypothesized to lead to the development of ASD.Level of Evidence: 2.
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http://dx.doi.org/10.1097/BRS.0000000000004080DOI Listing
April 2021

Three- and 4-Level Lumbar Arthrodesis Using Adjunctive Pulsed Electromagnetic Field Stimulation: A Multicenter Retrospective Evaluation of Fusion Rates and a Review of the Literature.

Int J Spine Surg 2021 Apr 23;15(2):228-233. Epub 2021 Mar 23.

Rothman Institute, Egg Harbor Township, New Jersey.

Background: The incidence of 3- and 4-level lumbar arthrodesis is rising due to an aging population, and fusion rates affect clinical success in this population. Pulsed electromagnetic field (PEMF) stimulation is used as an adjunct to increase fusion rates following multilevel arthrodesis. The purpose of the study was to evaluate the fusion rates for subjects who underwent 3- and 4-level lumbar interbody arthrodesis following PEMF treatment.

Methods: In this retrospective, multicenter study, patient charts that listed 3- or 4-level lumbar arthrodesis with adjunctive use of a PEMF device were evaluated. Inclusion criteria included patients who were diagnosed with lumbar degenerative disease, spinal stenosis, and/or spondylolisthesis (grade 1 or 2). A radiographic evaluation of fusion status was performed at 12 months by the treating physicians. Fusion rates were stratified by graft material, surgical interbody approach, and certain clinical risk factors for pseudoarthrosis.

Results: A total of 55 patients were identified who had a 12-month follow-up. The radiographic fusion rate was 92.7% (51 patients) at 12 months. There were no significant differences in fusion rates for patients treated with allograft or autograft, for patients with different interbody approaches, or for those with or without certain clinical risk factors.

Conclusions: With modern fusion techniques and PEMF, the overall fusion rate was high following 3- and 4-level lumbar arthrodesis.

Level Of Evidence: 4.

Clinical Relevance: PEMF may be a useful adjunct for treatment of patients with surgical risk factors, such as multilevel arthrodesis, and clinical risk factors.
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http://dx.doi.org/10.14444/8031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059393PMC
April 2021

Impact of Coronavirus Disease 2019 Shutdown on Neurotrauma Volume in Pennsylvania.

World Neurosurg 2021 07 20;151:e178-e184. Epub 2021 Apr 20.

Department of Neurological Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.

Objective: The 2020 coronavirus disease 2019 (COVID-19) pandemic resulted in state-specific quarantine protocols and introduced the concept of social distancing into modern parlance. We assess the impact of the COVID-19 pandemic on neurotrauma presentations in the first 3 months after shutdown throughout Pennsylvania.

Methods: The Pennsylvania Trauma Systems Foundation was queried for registry data from the Pennsylvania Trauma Outcomes Study between March 12 and June 5 in each year from 2017 to 2020.

Results: After the COVID-19 shutdown, there was a 27% reduction in neurotrauma volume, from 2680 cases in 2017 to 2018 cases in 2020, and a 28.8% reduction in traumatic brain injury volume. There was no significant difference in neurotrauma phenotype incurred relative to total cases. Injury mechanism was less likely to be motor vehicle collision and more likely caused by falls, gunshot wound, and recreational vehicle accidents (P < 0.05). Location of injury was less likely on roads and public locations and more likely at indoor private locations (P < 0.05). The proportion of patients with neurotrauma with blood alcohol concentration >0.08 g/dL was reduced in 2020 (11.4% vs. 9.0%; P < 0.05). Mortality was higher during 2020 compared with pre-COVID years (7.7% vs. 6.4%; P < 0.05).

Conclusions: During statewide shutdown, neurotrauma volume and alcohol-related trauma decreased and low-impact traumas and gunshot wounds increased, with a shift toward injuries occurring in private, indoor locations. These changes increased mortality. However, there was not a change in the types of injuries sustained.
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http://dx.doi.org/10.1016/j.wneu.2021.04.004DOI Listing
July 2021

Association of Sex and Age With Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI Study.

JAMA Netw Open 2021 Apr 1;4(4):e213046. Epub 2021 Apr 1.

Virginia Commonwealth University, Richmond, Virginia.

Importance: Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients.

Objective: To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI.

Design, Setting, And Participants: The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021.

Exposures: Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls.

Main Outcomes And Measures: Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales).

Results: A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate-corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate-corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02).

Conclusions And Relevance: This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025125PMC
April 2021

Symptom-Dependent Changes in MEG-Derived Neuroelectric Brain Activity in Traumatic Brain Injury Patients with Chronic Symptoms.

Med Sci (Basel) 2021 Mar 25;9(2). Epub 2021 Mar 25.

Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USA.

Neuroelectric measures derived from human magnetoencephalographic (MEG) recordings hold promise as aides to diagnosis and treatment monitoring and targeting for chronic sequelae of traumatic brain injury (TBI). This study tests novel MEG-derived regional brain measures of tonic neuroelectric activation for long-term test-retest reliability and sensitivity to symptoms. Resting state MEG recordings were obtained from a normative cohort, Cambridge Centre for Ageing and Neuroscience (CamCAN), baseline: = 619; 16-month follow-up: = 253) and a chronic symptomatic TBI cohort, Targeted Evaluation, Action and Monitoring of Traumatic Brain Injury (TEAM-TBI), baseline: = 64; 6-month follow-up: = 39). For the CamCAN cohort, MEG-derived neuroelectric measures showed good long-term test-retest reliability for most of the 103 automatically identified stereotypic regions. The TEAM-TBI cohort was screened for depression, somatization, and anxiety with the Brief Symptom Inventory and for insomnia with the Insomnia Severity Index. Linear classifiers constructed from the 103 regional measures from each TEAM-TBI cohort member distinguished those with and without each symptom, with < 0.01 for each-i.e., the tonic regional neuroelectric measures of activation are sensitive to the presence/absence of these symptoms. The novel regional MEG-derived neuroelectric measures obtained and tested in this study demonstrate the necessary and sufficient properties to be clinically useful-i.e., good test-retest reliability, sensitivity to symptoms in each individual, and obtainable using automatic processing without human judgement or intervention.
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http://dx.doi.org/10.3390/medsci9020020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103254PMC
March 2021

The minimally invasive interbody selection algorithm for spinal deformity.

J Neurosurg Spine 2021 Mar 12:1-8. Epub 2021 Mar 12.

13Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.

Objective: Minimally invasive surgery (MIS) for spinal deformity uses interbody techniques for correction, indirect decompression, and arthrodesis. Selection criteria for choosing a particular interbody approach are lacking. The authors created the minimally invasive interbody selection algorithm (MIISA) to provide a framework for rational decision-making in MIS for deformity.

Methods: A retrospective data set of circumferential MIS (cMIS) for adult spinal deformity (ASD) collected over a 5-year period was analyzed by level in the lumbar spine to identify surgeon preferences and evaluate segmental lordosis outcomes. These data were used to inform a Delphi session of minimally invasive deformity surgeons from which the algorithm was created. The algorithm leads to 1 of 4 interbody approaches: anterior lumbar interbody fusion (ALIF), anterior column release (ACR), lateral lumbar interbody fusion (LLIF), and transforaminal lumbar interbody fusion (TLIF). Preoperative and 2-year postoperative radiographic parameters and clinical outcomes were compared.

Results: Eleven surgeons completed 100 cMISs for ASD with 338 interbody devices, with a minimum 2-year follow-up. The type of interbody approach used at each level from L1 to S1 was recorded. The MIISA was then created with substantial agreement. The surgeons generally preferred LLIF for L1-2 (91.7%), L2-3 (85.2%), and L3-4 (80.7%). ACR was most commonly performed at L3-4 (8.4%) and L2-3 (6.2%). At L4-5, LLIF (69.5%), TLIF (15.9%), and ALIF (9.8%) were most commonly utilized. TLIF and ALIF were the most selected approaches at L5-S1 (61.4% and 38.6%, respectively). Segmental lordosis at each level varied based on the approach, with greater increases reported using ALIF, especially at L4-5 (9.2°) and L5-S1 (5.3°). A substantial increase in lordosis was achieved with ACR at L2-3 (10.9°) and L3-4 (10.4°). Lateral interbody arthrodesis without the use of an ACR did not generally result in significant lordosis restoration. There were statistically significant improvements in lumbar lordosis (LL), pelvic incidence-LL mismatch, coronal Cobb angle, and Oswestry Disability Index at the 2-year follow-up.

Conclusions: The use of the MIISA provides consistent guidance for surgeons who plan to perform MIS for deformity. For L1-4, the surgeons preferred lateral approaches to TLIF and reserved ACR for patients who needed the greatest increase in segmental lordosis. For L4-5, the surgeons' order of preference was LLIF, TLIF, and ALIF, but TLIF failed to demonstrate any significant lordosis restoration. At L5-S1, the surgical team typically preferred an ALIF when segmental lordosis was desired and preferred a TLIF if preoperative segmental lordosis was adequate.
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http://dx.doi.org/10.3171/2020.9.SPINE20230DOI Listing
March 2021

Sport-Related Structural Brain Injury and Return to Play: Systematic Review and Expert Insight.

Neurosurgery 2021 05;88(6):E495-E504

Department of Neurosurgery, Johns Hopkins University Medical Center, Baltimore, Maryland, USA.

Background: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI.

Objective: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions.

Methods: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted.

Results: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (β = -0.58, 95% CI -0.111, -0.005, P = .033).

Conclusion: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations.
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http://dx.doi.org/10.1093/neuros/nyab041DOI Listing
May 2021

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Acta Neuropathol Commun 2021 03 1;9(1):32. Epub 2021 Mar 1.

Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.
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http://dx.doi.org/10.1186/s40478-021-01122-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919306PMC
March 2021

Revision Surgery Rates After Minimally Invasive Adult Spinal Deformity Surgery: Correlation with Roussouly Spine Type at 2-Year Follow-Up?

World Neurosurg 2021 04 11;148:e482-e487. Epub 2021 Jan 11.

Department of Neurosurgery University of California, San Francisco, San Francisco, California, USA.

Background: Spinopelvic parameters have hitherto dictated much of adult spinal deformity (ASD) correction. The Roussouly classification is used for the normal adult spine. We evaluated whether a correlation would be found between the Roussouly type and the rate of revision surgery in patients with ASD undergoing circumferential minimally invasive spinal (cMIS) correction.

Methods: A multicenter retrospective review of patients who had undergone cMIS surgery for ASD was performed. The inclusion criteria were age ≥18 years and 1 of the following: coronal Cobb angle >20°, sagittal vertical axis >5 cm, pelvic tilt >20°, pelvic incidence (PI) to lumbar lordosis (LL) mismatch >10°, cMIS surgery, and a minimum of 2 years of follow-up data available. The patients were classified by Roussouly type, and the clinical and radiographic outcomes were evaluated.

Results: A total of 104 patients were included in the present analysis. Of the 104 patients, 41 had Roussouly type 1, 32 had type 2, 23 had type 3, and 8 had type 4. Preoperatively, the patients with type 4 had the highest PI (P = 0.002) and LL (P < 0.001). Postoperatively, the PI-LL mismatch, Cobb angle, and sagittal vertical axis were not different among the 4 groups. However, the patients with type 2 had had the highest rate of complications (type 1, 29.3%; type 2, 61.3%; type 3, 34.8%; type 4, 25.0%; P = 0.031). The reoperation rates were comparable (type 1, 19.5%; type 2, 38.7%; type 3, 13.0%; type 4, 12.5%; P = 0.097). The reoperation rates for adjacent segment degeneration or proximal junctional kyphosis were also comparable (P = 0.204 and P = 0.060, respectively).

Conclusions: We did not find a clear correlation between Roussouly type and the rate of revision surgery for adjacent segment disease or proximal junctional kyphosis in patients who had undergone cMIS surgery for ASD.
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http://dx.doi.org/10.1016/j.wneu.2021.01.011DOI Listing
April 2021

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

Neurology 2021 Jan 4. Epub 2021 Jan 4.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623).

Methods: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 10, 5.0 × 10, 10 × 10 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15).

Results: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients ( = 0.25).

Conclusions: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.

Classification Of Evidence: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.
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http://dx.doi.org/10.1212/WNL.0000000000011450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055341PMC
January 2021

Smaller Regional Brain Volumes Predict Posttraumatic Stress Disorder at 3 Months After Mild Traumatic Brain Injury.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 03 27;6(3):352-359. Epub 2020 Oct 27.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.

Background: Brain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury.

Methods: Using data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13-15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices.

Results: Overall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors.

Conclusions: Results, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.
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http://dx.doi.org/10.1016/j.bpsc.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946719PMC
March 2021

Impact of Frailty on Outcomes Following Spine Surgery: A Prospective Cohort Analysis of 668 Patients.

Neurosurgery 2021 02;88(3):552-557

The Wolff Center at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background: With an aging population, elderly patients with multiple comorbidities are more frequently undergoing spine surgery and may be at increased risk for complications. Objective measurement of frailty may predict the incidence of postoperative adverse events.

Objective: To investigate the associations between preoperative frailty and postoperative spine surgery outcomes including mortality, length of stay, readmission, surgical site infection, and venous thromboembolic disease.

Methods: As part of a system-wide quality improvement initiative, frailty assessment was added to the routine assessment of patients considering spine surgery beginning in July 2016. Frailty was assessed with the Risk Analysis Index (RAI), and patients were categorized as nonfrail (RAI 0-29) or prefrail/frail (RAI ≥ 30). Comparisons between nonfrail and prefrail/frail patients were analyzed using Fisher's exact test for categorical data or by Wilcoxon rank sum tests for continuous data.

Results: From August 2016 through September 2018, 668 patients (age of 59.5 ± 13.3 yr) had a preoperative RAI score recorded and underwent scheduled spine surgery. Prefrail and frail patients suffered comparatively higher rates of mortality at 90 d (1.9% vs 0.2%, P < .05) and 1 yr (5.1% vs 1.2%, P < .01) from the procedure date. They also had longer in-hospital length of stay (LOS) (3.9 d ± 3.6 vs 3.1 d ± 2.8, P < .001) and higher rates of 60 d (14.6% vs 8.2%, P < .05) and 90 d (15.8% vs 9.8%, P < .05) readmissions.

Conclusion: Preoperative frailty, as measured by the RAI, was associated with an increased risk of readmission and 90-d and 1-yr mortality following spine surgery. The RAI can be used to stratify spine patients and inform preoperative surgical decision making.
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http://dx.doi.org/10.1093/neuros/nyaa468DOI Listing
February 2021

High-Sensitivity C-Reactive Protein is a Prognostic Biomarker of Six-Month Disability after Traumatic Brain Injury: Results from the TRACK-TBI Study.

J Neurotrauma 2021 Apr 28;38(7):918-927. Epub 2020 Dec 28.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The ransforming esearch and linical nowledge in raumatic rain njury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs ( < 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.
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http://dx.doi.org/10.1089/neu.2020.7177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987360PMC
April 2021

Association of Prehospital Plasma With Survival in Patients With Traumatic Brain Injury: A Secondary Analysis of the PAMPer Cluster Randomized Clinical Trial.

JAMA Netw Open 2020 10 1;3(10):e2016869. Epub 2020 Oct 1.

Department of Surgery and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Prehospital plasma administration improves survival in injured patients at risk for hemorrhagic shock and transported by air ambulance. Traumatic brain injury (TBI) is a leading cause of death following trauma, but few early interventions improve outcomes.

Objective: To assess the association between prehospital plasma and survival in patients with TBI.

Design, Setting, And Participants: The Prehospital Air Medical Plasma (PAMPer) trial was a pragmatic, multicenter, phase 3, cluster randomized clinical trial involving injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center. The trial was conducted at 6 US sites with 9 level-I trauma centers (comprising 27 helicopter emergency services bases). The original trial analyzed 501 patients, including 230 patients who were randomized to receive plasma and 271 randomized to standard care resuscitation. This secondary analysis of a predefined subgroup included patients with TBI. Data analysis was performed from October 2019 to February 2020.

Interventions: Patients were randomized to receive standard care fluid resuscitation or 2 units of thawed plasma.

Main Outcomes And Measures: The primary outcome was mortality at 30 days. Patients with TBI were prespecified as a subgroup for secondary analysis and for measurement of markers of brain injury. The 30-day survival benefit of prehospital plasma in subgroups with and without TBI as diagnosed by computed tomography was characterized using Kaplan-Meier survival analysis and Cox proportional hazard regression.

Results: In total, 166 patients had TBI (median [interquartile range] age, 43.00 [25.00-59.75] years; 125 men [75.3%]). When compared with the 92 patients who received standard care, the 74 patients with TBI who received prehospital plasma had improved 30-day survival even after adjustment for multiple confounders and assessment of the degree of brain injury with clinical variables and biomarkers (hazard ratio [HR], 0.55; 95% CI, 0.33-0.94; P = .03). Receipt of prehospital plasma was associated with improved survival among patients with TBI with a prehospital Glasgow Coma Scale score of less than 8 (HR, 0.56; 95% CI, 0.35-0.91) and those with polytrauma (HR, 0.50; 95% CI, 0.28-0.89). Patients with TBI transported from the scene of injury had improved survival following prehospital plasma administration (HR, 0.45; 95% CI, 0.26-0.80; P = .005), whereas patients who were transferred from an outside hospital showed no difference in survival for the plasma intervention (HR, 1.00; 95% CI, 0.33-3.00; P = .99).

Conclusions And Relevance: These findings are exploratory, but they suggest that receipt of prehospital plasma is associated with improved survival in patients with computed tomography-positive TBI. The prehospital setting may be a critical period to intervene in the care of patients with TBI. Future studies are needed to confirm the clinical benefits of early plasma resuscitation following TBI and concomitant polytrauma.

Trial Registration: ClinicalTrials.gov Identifier: NCT01818427.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.16869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563075PMC
October 2020

Multifaceted Benefit of Whole Blood Versus Lactated Ringer's Resuscitation After Traumatic Brain Injury and Hemorrhagic Shock in Mice.

Neurocrit Care 2021 06 4;34(3):781-794. Epub 2020 Sep 4.

Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Despite increasing use in hemorrhagic shock (HS), whole blood (WB) resuscitation for polytrauma with traumatic brain injury (TBI) is largely unexplored. Current TBI guidelines recommend crystalloid for prehospital resuscitation. Although WB outperforms lactated Ringer's (LR) in increasing mean arterial pressure (MAP) in TBI + HS models, effects on brain tissue oxygenation (PbtO), and optimal MAP remain undefined.

Methods: C57BL/6 mice (n = 72) underwent controlled cortical impact followed by HS (MAP = 25-27 mmHg). Ipsilateral hippocampal PbtO (n = 40) was measured by microelectrode. Mice were assigned to four groups (n = 18/group) for "prehospital" resuscitation (90 min) with LR or autologous WB, and target MAPs of 60 or 70 mmHg (LR, WB, LR, WB). Additional LR (10 ml/kg) was bolused every 5 min for MAP below target.

Results: LR requirements in WB (7.2 ± 5.0 mL/kg) and WB (28.3 ± 9.6 mL/kg) were markedly lower than in LR (132.8 ± 5.8 mL/kg) or LR (152.2 ± 4.8 mL/kg; all p < 0.001). WB MAP (72.5 ± 2.9 mmHg) was higher than LR (59.8 ± 4.0 mmHg, p < 0.001). WB MAP (68.7 ± 4.6 mmHg) was higher than LR (53.5 ± 3.2 mmHg, p < 0.001). PbtO was higher in WB (43.8 ± 11.6 mmHg) vs either LR (25.9 ± 13.0 mmHg, p = 0.04) or LR (24.1 ± 8.1 mmHg, p = 0.001). PbtO in WB (40.7 ± 8.8 mmHg) was higher than in LR (p = 0.007). Despite higher MAP in WB vs WB (p = .002), PbtO was similar.

Conclusion: WB resuscitation after TBI + HS results in robust improvements in brain oxygenation while minimizing fluid volume when compared to standard LR resuscitation. WB resuscitation may allow for a lower prehospital MAP without compromising brain oxygenation when compared to LR resuscitation. Further studies evaluating the effects of these physiologic benefits on outcome after TBI with HS are warranted, to eventually inform clinical trials.
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http://dx.doi.org/10.1007/s12028-020-01084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054986PMC
June 2021

Point-of-Care Platform Blood Biomarker Testing of Glial Fibrillary Acidic Protein versus S100 Calcium-Binding Protein B for Prediction of Traumatic Brain Injuries: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.

J Neurotrauma 2020 12 14;37(23):2460-2467. Epub 2020 Sep 14.

Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California, USA.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13-15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3-15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3-15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472-3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26-397) or orthopedic trauma controls ( = 122; median = 13 pg/mL, IQR: 7-20),  < 0.001. Serum S100B levels were likewise higher in CT+ TBI subjects (median = 0.17 μg/L, IQR: 0.09-0.38) than in CT- TBI subjects (median = 0.10 μg/L, IQR: 0.06-0.18),  < 0.001. Receiver operating characteristic curves were generated for prediction of intracranial injury on admission CT scan; area under the curve (AUC) for GFAP was significantly higher than for S100B in the same cohort (GFAP AUC - 0.85, 95% confidence interval [CI] 0.83-0.87; S100B AUC - 0.67, 95% CI 0.64-0.70;  < 0.001). GFAP, measured on a point-of-care platform prototype assay, has high discriminative ability to predict intracranial abnormalities on CT scan in patients with TBI across the full injury spectrum of GCS 3-15 through 24 h post-injury. GFAP substantially outperforms S100B.
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http://dx.doi.org/10.1089/neu.2020.7140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698990PMC
December 2020

Plasma extracellular vesicles as a source of biomarkers in traumatic brain injury.

J Neurosurg 2020 Jul 24:1-8. Epub 2020 Jul 24.

Departments of1Neurological Surgery and.

Objective: The objective of this study was to isolate extracellular vesicles (EVs) from plasma in a cohort of patients with traumatic brain injury (TBI) and analyze their contents for novel biomarkers that could prove useful for rapid diagnosis and classification of brain injury during initial evaluation.

Methods: Plasma EVs were isolated by serial ultracentrifugation from patients with TBI (n = 15) and healthy controls (n = 5). Samples were obtained from the TRACK-TBI biorepository (2010-present). Size and concentration were determined by nanoparticle tracking. Glial fibrillary acidic protein (GFAP) concentration was determined in EV protein. EV RNA was isolated and deep sequencing of short noncoding RNA was performed.

Results: Plasma EVs are physically similar but contained approximately 10 times more GFAP in TBI patients with altered consciousness than patients and controls with normal consciousness. Eleven highly differentially expressed microRNAs (miRNAs) were identified between these groups. Genes targeted by these miRNAs are highly associated with biologically relevant cellular pathways, including organismal injury, cellular development, and organismal development. Multiple additional coding and noncoding RNA species with potential biomarker utility were identified.

Conclusions: Isolating plasma EVs in patients with TBI is feasible. Increased GFAP concentration-a validated plasma TBI marker-in EVs from TBI patients with altered consciousness, along with differential expression of multiple miRNAs targeting TBI-relevant pathways, suggests that EVs may be a useful source of TBI biomarkers. Additional evaluation in larger patient cohorts is indicated.
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http://dx.doi.org/10.3171/2020.4.JNS20305DOI Listing
July 2020
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