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1.
Neurocrit Care ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35028889

RESUMO

BACKGROUND: Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI. METHODS: We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries. RESULTS: Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818. CONCLUSIONS: We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35001020

RESUMO

BACKGROUND: In 2016, the National Academies of Science, Engineering and Medicine (NASEM) called for the development of a National Trauma Research Action Plan (NTRAP). The Department of Defense funded the Coalition for National Trauma Research (CNTR) to generate a comprehensive research agenda spanning the continuum of trauma and burn care. Given the public health burden of injuries to the central nervous system, Neurotrauma was one of 11 panels formed to address this recommendation with a gap analysis and generation of high-priority research questions. METHODS: We recruited interdisciplinary experts to identify gaps in the neurotrauma literature, generate research questions, and prioritize those questions using a consensus-driven Delphi survey approach. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the importance of the questions on a 9-point Likert scale. Consensus was defined as ≥60% of panelists agreeing on the priority category. We then coded research questions using an NTRAP taxonomy of 118 research concepts, which were consistent across all 11 panels. RESULTS: Twenty-eight neurotrauma experts generated 675 research questions. Of these, 364 (53.9%) reached consensus, and 56 were determined to be high priority (15.4%), 303 were deemed to be medium priority (83.2%), and 5 were low priority (1.4%). The research topics were stratified into three groups - severe traumatic brain injury (TBI), mild TBI (mTBI), and spinal cord injury (SCI). The number of high-priority questions for each subtopic was 46 for severe TBI (19.7%), 3 for mTBI (4.3%) and 7 for SCI (11.7%). CONCLUSIONS: This Delphi gap analysis of neurotrauma research identified 56 high-priority research questions. There are clear areas of focus for severe TBI, mild TBI and SCI that will help guide investigators in future neurotrauma research. Funding agencies should consider these gaps when they prioritize future research. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Delphi panel gap analyses.

3.
JAMA Netw Open ; 4(12): e2140191, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34964854

RESUMO

Importance: Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known. Objective: To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort. Design, Setting, and Participants: This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021. Exposure: Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ). Main Outcomes and Measures: Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI). Results: Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P < .001) as well as with anomalous acute head imaging findings (risk ratio, 6.42 [95% CI, 2.71-15.22]). After controlling for age, initial Glasgow Coma Scale score, and imaging findings, compared with patients with TBI and without PTE, patients with TBI and with positive PTE screening results had significantly lower Glasgow Outcome Scale Extended scores (mean [SD], 6.1 [1.7] vs 4.7 [1.5]; P < .001), higher BSI scores (mean [SD], 50.2 [10.7] vs 58.6 [10.8]; P = .02), and higher RCM scores (mean [SD], 3.1 [2.6] vs 5.3 [1.9]; P = .002) at 12 months. Conclusions and Relevance: In this cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes. These findings highlight the need for effective antiepileptogenic therapies after TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Epilepsia Pós-Traumática/epidemiologia , Adulto , Estudos de Coortes , Epilepsia Pós-Traumática/etiologia , Feminino , Escala de Coma de Glasgow , Humanos , Incidência , Masculino , Estudos Prospectivos , Fatores de Risco , Autorrelato , Inquéritos e Questionários , Centros de Traumatologia , Estados Unidos/epidemiologia
4.
J Neurosurg Spine ; : 1-14, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34740175

RESUMO

OBJECTIVE: Previous studies have demonstrated the short-term radiographic and clinical benefits of circumferential minimally invasive surgery (cMIS) and hybrid (i.e., minimally invasive anterior or lateral interbody fusion with an open posterior approach) techniques to correct adult spinal deformity (ASD). However, it is not known if these benefits are maintained over longer periods of time. This study evaluated the 2- and 3-year outcomes of cMIS and hybrid correction of ASD. METHODS: A multicenter database was retrospectively reviewed for patients undergoing cMIS or hybrid surgery for ASD. Patients were ≥ 18 years of age and had one of the following: maximum coronal Cobb angle (CC) ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic incidence-lumbar lordosis mismatch (PI-LL) ≥ 10°, or pelvic tilt (PT) > 20°. Radiographic parameters were evaluated at the latest follow-up. Clinical outcomes were compared at 2- and 3-year time points and adjusted for age, preoperative CC, levels operated, levels with interbody fusion, presence of L5-S1 anterior lumbar interbody fusion, and upper and lower instrumented vertebral level. RESULTS: Overall, 197 (108 cMIS, 89 hybrid) patients were included with 187 (99 cMIS, 88 hybrid) and 111 (60 cMIS, 51 hybrid) patients evaluated at 2 and 3 years, respectively. The mean (± SD) follow-up duration for cMIS (39.0 ± 13.3 months, range 22-74 months) and hybrid correction (39.9 ± 16.8 months, range 22-94 months) were similar for both cohorts. Hybrid procedures corrected the CC greater than the cMIS technique (adjusted p = 0.022). There were no significant differences in postoperative SVA, PI-LL, PT, and sacral slope (SS). At 2 years, cMIS had lower Oswestry Disability Index (ODI) scores (adjusted p < 0.001), greater ODI change as a percentage of baseline (adjusted p = 0.006), less visual analog scale (VAS) back pain (adjusted p = 0.006), and greater VAS back pain change as a percentage of baseline (adjusted p = 0.001) compared to hybrid techniques. These differences were no longer significant at 3 years. At 3 years, but not 2 years, VAS leg pain was lower for cMIS compared to hybrid techniques (adjusted p = 0.032). Those undergoing cMIS had fewer overall complications compared to hybrid techniques (adjusted p = 0.006), but a higher odds of pseudarthrosis (adjusted p = 0.039). CONCLUSIONS: In this review of a multicenter database for patients undergoing cMIS and hybrid surgery for ASD, hybrid procedures were associated with a greater CC improvement compared to cMIS techniques. cMIS was associated with superior ODI and back pain at 2 years, but this difference was no longer evident at 3 years. However, cMIS was associated with superior leg pain at 3 years. There were fewer complications following cMIS, with the exception of pseudarthrosis.

5.
Expert Rev Mol Diagn ; 21(12): 1303-1321, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34783274

RESUMO

INTRODUCTION: Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and health-care systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia. AREAS COVERED: This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada. EXPERT OPINION: TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.

6.
Clin Neurol Neurosurg ; 212: 107069, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34844161

RESUMO

OBJECTIVE: Neurosurgical evacuation in elderly trauma patients is controversial. We analyzed impact of craniotomy for acute subdural hematoma on survival in octogenarians and nonagenarians. Methods The study population included all patients aged ≥ 80 years who presented with acute traumatic SDHs 09/01/15 - 01/01/20, with radiography indicating operative eligibility (i.e. MLS >5 mm and/or overall thickness >10 mm). Of 1054 TBIs aged ≥ 80 years, 104 (9.87%) were surgically indicated. Of these, 35 received craniotomy and 69 received supportive measures due to family/patient wishes or surgeon's professional decision. We analyzed these data using a Poisson regression adjusted for influence of covariates. RESULTS: Of 35 craniotomies, 21 (60.00%) were deceased at 2 years of follow-up, compared to 48 (69.57%) deceased of 69 non-surgical patients. No significant demographic differences existed between these groups, other than age (craniotomy patients were younger; median age 84 vs 86; p < 0.001). In outcomes, the craniotomy cohort survived longer and in higher proportions (p = 0.028; Gehan-Breslow-Wilcoxon). When adjusting for covariates, this effect became more pronounced: craniotomy patients died at 41.1% the rate of non-surgical ones. Of all the covariates, only initial GCS significantly impacted the protective effect of craniotomy. In a logarithmic relationship, each point on initial GCS was associated with less benefit from surgery. We also found that patients with GCS< 3 were overall less likely to benefit from surgery. Our conclusions are limited by the impact of patient/surgeon choice on whether or not to operate. It is possible healthier subjects elected for craniotomies. We have attempted to correct for this by including comorbidities as covariates in our regression analyses. CONCLUSIONS: Our results indicate a surgical benefit for this elderly cohort, consistent with prior findings of benefit in the setting of severe traumatic aSDH. Patients with worse neurologic impairment, i.e. low GCS, had the greatest survival benefit from surgical intervention.

7.
Neurol Int ; 13(4): 527-534, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34698266

RESUMO

The development of hydrocephalus after severe traumatic brain injury (TBI) is an under-recognized healthcare phenomenon and can increase morbidity. The current study aims to characterize post-traumatic hydrocephalus (PTH) in a large cohort. Patients were prospectively enrolled age 16-80 years old with Glasgow Coma Scale (GCS) score ≤8. Demographics, GCS, Injury Severity Score (ISS), surgery, and cerebrospinal fluid (CSF) were analyzed. Outcomes were shunt failure and Glasgow Outcome Scale (GOS) at 6 and 12-months. Statistical significance was assessed at p < 0.05. In 402 patients, mean age was 38.0 ± 16.7 years and 315 (78.4%) were male. Forty (10.0%) patients developed PTH, with predominant injuries being subdural hemorrhage (36.4%) and diffuse axonal injury (36.4%). Decompressive hemicraniectomy (DHC) was associated with hydrocephalus (OR 3.62, 95% CI (1.62-8.07), p < 0.01). Eighteen (4.5%) patients had shunt failure and proximal obstruction was most common. Differences in baseline CSF cell count were associated with increased shunt failure. PTH was not associated with worse outcomes at 6 (p = 0.55) or 12 (p = 0.47) months. Hydrocephalus is a frequent sequela in 10.0% of patients, particularly after DHC. Shunt placement and revision procedures are common after severe TBI, within the first 4 months of injury and necessitates early recognition by the clinician.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34629458

RESUMO

BACKGROUND: Rapid platelet function testing is frequently used to determine platelet function in patients with traumatic intracranial hemorrhage (tICH). Accuracy and clinical significance of decreased platelet response detected by these tests is not well understood. We sought to determine whether VerifyNow and Whole Blood Aggregometry (WBA) can detect poor platelet response and to elucidate its clinical significance for tICH patients. METHODS: We prospectively enrolled patients with isolated tICH between 2018 and 2020. Demographics, medical history, injury characteristics and patient outcomes were recorded. Platelet function was determined by VerifyNow and WBA testing at the time of arrival to the trauma bay and 6 hours later. RESULTS: A total of 221 patients were enrolled, including 111 patients on no antiplatelet medication, 78 on aspirin, 6 on clopidogrel and 26 on aspirin and clopidogrel. In the trauma bay, 29.7% and 67.7% of patients on no antiplatelet medication had poor platelet response on VerifyNow and WBA, respectively. Among patients on aspirin, 72.2% and 82.2% had platelet dysfunction on VerifyNow and WBA. Among patients on clopidogrel, 67.9% and 88.9% had platelet dysfunction on VerifyNow and WBA. Patients with non-responsive platelets had similar in-hospital mortality (3 [3.0%] vs. 6 [6.3%], p = 0.324), tICH progression (26 [27.1%] vs 24 [26.1%], p = 0.877), ICU admission rates (34 [34.3%] vs 38 [40.0%), p = 0.415) and length of stay (3 [IQR 2-8] vs 3.2 [IQR 2-7], p = 0.818) to those with responsive platelets. Platelet transfusion did not improve platelet response or patient outcomes. CONCLUSIONS: Rapid platelet function testing detects a highly prevalent poor platelet response among patients with tICH, irrespective of antiplatelet medication use. VerifyNow correlated fairly with whole blood aggregometry among patients with tICH and platelet responsiveness detectable by these tests did not correlate with clinical outcomes. Additionally, our results suggest that platelet transfusion may not improve clinical outcomes in patients with tICH. LEVEL OF EVIDENCE: level I, Diagnostic Tests.

10.
Neurocrit Care ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518968

RESUMO

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

11.
ACS Chem Neurosci ; 12(19): 3588-3597, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34506125

RESUMO

Traumatic brain injury (TBI) induces a pathophysiologic state that can be worsened by secondary injury. Monitoring brain metabolism with intracranial microdialysis can provide clinical insights to limit secondary injury in the days following TBI. Recent enhancements to microdialysis include the implementation of continuously operating electrochemical biosensors for monitoring the dialysate sample stream in real time and dexamethasone retrodialysis to mitigate the tissue response to probe insertion. Dexamethasone-enhanced continuous-online microdialysis (Dex-enhanced coMD) records long-lasting declines of glucose after controlled cortical impact in rats and TBI in patients. The present study employed retrodialysis and fluorescence microscopy to investigate the mechanism responsible for the decline of dialysate glucose after injury of the rat cortex. Findings confirm the long-term functionality of Dex-enhanced coMD for monitoring brain glucose after injury, demonstrate that intracranial glucose microdialysis is coupled to glucose utilization in the tissues surrounding the probes, and validate the conclusion that aberrant glucose utilization drives the postinjury glucose decline.


Assuntos
Lesões Encefálicas , Animais , Encéfalo , Dexametasona , Glucose , Humanos , Microdiálise , Ratos
12.
J Neurosurg Spine ; : 1-12, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34560634

RESUMO

OBJECTIVE: Circumferential minimally invasive spine surgery (cMIS) for adult scoliosis has become more advanced and powerful, but direct comparison with traditional open correction using prospectively collected data is limited. The authors performed a retrospective review of prospectively collected, multicenter adult spinal deformity data. The authors directly compared cMIS for adult scoliosis with open correction in propensity-matched cohorts using health-related quality-of-life (HRQOL) measures and surgical parameters. METHODS: Data from a prospective, multicenter adult spinal deformity database were retrospectively reviewed. Inclusion criteria were age > 18 years, minimum 1-year follow-up, and one of the following characteristics: pelvic tilt (PT) > 25°, pelvic incidence minus lumbar lordosis (PI-LL) > 10°, Cobb angle > 20°, or sagittal vertical axis (SVA) > 5 cm. Patients were categorized as undergoing cMIS (percutaneous screws with minimally invasive anterior interbody fusion) or open correction (traditional open deformity correction). Propensity matching was used to create two equal groups and to control for age, BMI, preoperative PI-LL, pelvic incidence (PI), T1 pelvic angle (T1PA), SVA, PT, and number of posterior levels fused. RESULTS: A total of 154 patients (77 underwent open procedures and 77 underwent cMIS) were included after matching for age, BMI, PI-LL (mean 15° vs 17°, respectively), PI (54° vs 54°), T1PA (21° vs 22°), and mean number of levels fused (6.3 vs 6). Patients who underwent three-column osteotomy were excluded. Follow-up was 1 year for all patients. Postoperative Oswestry Disability Index (ODI) (p = 0.50), Scoliosis Research Society-total (p = 0.45), and EQ-5D (p = 0.33) scores were not different between cMIS and open patients. Maximum Cobb angles were similar for open and cMIS patients at baseline (25.9° vs 26.3°, p = 0.85) and at 1 year postoperation (15.0° vs 17.5°, p = 0.17). In total, 58.3% of open patients and 64.4% of cMIS patients (p = 0.31) reached the minimal clinically important difference (MCID) in ODI at 1 year. At 1 year, no differences were observed in terms of PI-LL (p = 0.71), SVA (p = 0.46), PT (p = 0.9), or Cobb angle (p = 0.20). Open patients had greater estimated blood loss compared with cMIS patients (1.36 L vs 0.524 L, p < 0.05) and fewer levels of interbody fusion (1.87 vs 3.46, p < 0.05), but shorter operative times (356 minutes vs 452 minutes, p = 0.003). Revision surgery rates between the two cohorts were similar (p = 0.97). CONCLUSIONS: When cMIS was compared with open adult scoliosis correction with propensity matching, HRQOL improvement, spinopelvic parameters, revision surgery rates, and proportions of patients who reached MCID were similar between cohorts. However, well-selected cMIS patients had less blood loss, comparable results, and longer operative times in comparison with open patients.

14.
Surg Neurol Int ; 12: 331, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345472

RESUMO

Background: Thoracic intramedullary neurosarcoidosis is an uncommon but serious manifestation of spinal cord disease. Its concomitant occurrence with thoracic disc herniation can mislead the physician into attributing neurologic and radiographic findings in the spinal cord to disc pathology rather than inflammatory disorder. Here, we present such a rare case of concomitant thoracic disc and spinal neurosarcoidosis. Case Description: A 37-year-old male presented with progressive right lower extremity weakness and numbness. Magnetic resonance imaging (MRI) of the thoracic spinal cord revealed a T6-T7 paracentral disc eccentric to the right with T2 signal change extending from T2 to T10 level. This prompted acquiring a contrasted MRI that also depicted intramedullary enhancement around the T6-T7 disc bulge. Computed tomography scan of the chest showed mediastinal lymphadenopathy concerning for sarcoidosis. Lymph node biopsy confirmed the diagnosis of sarcoidosis, and high-dose steroid treatment was initiated. The patient had significant symptomatic improvement with steroids with full neurological recovery and improvement of his symptoms. Conclusion: While stenosis from thoracic disc disease could potentially suggest a mechanical etiology for the patient's symptoms, attention must be paid to the imaging findings as well as the degree and extent of cord signal change and intramedullary contrast enhancement. Appropriate and timely diagnosis is essential to avoid unnecessary invasive procedures.

15.
Expert Rev Neurother ; 21(9): 1051-1058, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34402352

RESUMO

OBJECTIVE: To determine minimally clinically important differences (MCIDs) for Disability Rating Scale (DRS), Fugl-Meyer Upper Extremity Subscale (FM-UE), Fugl-Meyer Lower Extremity Subscale (FM-LE), and Fugl-Meyer Motor Scale (FMMS) in patients with chronic motor deficits secondary to traumatic brain injury (TBI). METHODS: Retrospective analysis from the 1-year, double-blind, randomized, surgical sham-controlled, Phase 2 STEMTRA trial (NCT02416492), in which patients with chronic motor deficits secondary to TBI (N = 61) underwent intracerebral stereotactic implantation of modified bone marrow-derived mesenchymal stromal (SB623) cells. MCIDs for DRS, FM-UE, FM-LE, and FMMS were triangulated with distribution-based, anchor-based, and Delphi panel estimates. RESULTS: Triangulated MCIDs were: 1) -1.5 points for the Disability Rating Scale; 2) 6.2 points for the Fugl-Meyer Upper Extremity Subscale; 3) 3.2 points for the Fugl-Meyer Lower Extremity Subscale; and 4) 8.4 points for the Fugl-Meyer Motor Scale. CONCLUSIONS: For the first time in the setting of patients with chronic motor deficits secondary to TBI, this study reports triangulated MCIDs for: 1) DRS, a measure of global outcome; and 2) Fugl-Meyer Scales, measures of motor impairment. These findings guide the use of DRS and Fugl-Meyer Scales in the assessment of global disability outcome and motor impairment in future TBI clinical trials.

16.
World Neurosurg ; 155: e264-e270, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34418605

RESUMO

BACKGROUND: Proximal junctional kyphosis (PJK) and proximal junction failure are common and costly complications after long-segment adult spinal deformity (ASD) correction. Although much research has focused on the concept of "softening the landing" to prevent proximal junction pathologies, long-segment constructs largely deviate from the force-deformation curve of the physiologic spine. Our novel distributed loading technique for ASD correction is described using multimaterial, long-segment constructs to create a biomechanically sound, yet physiologic, decremental stiffness toward the rostral end. METHODS: Operative steps detail the custom-designed constructs of dual-headed pedicle screws and varied rod diameters and materials (cobalt chromium or titanium) for an initial 20 patients (mean 66.6 ± 4.8 years). Standing scoliosis films were obtained preoperatively and at regular intervals postoperatively to assess for PJK. RESULTS: No patient had evidence of PJK or proximal junction failure at latest radiographic follow-up (mean 17.9 months, range 13-25 months). Radiographic findings for sagittal vertical axis averaged 11.2 ± 5.6 cm preoperatively and 3.6 ± 2.3 cm postoperatively. Compared with preoperative parameters, postoperative reductions in pelvic incidence-lumbar lordosis mismatch averaged 28.7 ± 12.9 degrees, and sagittal vertical axis averaged 7.6 ± 5.2 cm while PJA was essentially unchanged. CONCLUSIONS: Preliminary results suggest that the distributed loading technique is promising for prevention of PJK with stiffness gradients that mimic the force-deformation curve of the physiologic posterior tension band. Our technique may optimize the degree of stress at the proximal junction without overwhelming the anterior column bony while remodeling and mature arthrodesis takes place.

17.
JAMA Neurol ; 78(8): 982-992, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34228047

RESUMO

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.

18.
JAMA Netw Open ; 4(7): e2116839, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34309670

RESUMO

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.

19.
JAMA Neurol ; 78(9): 1137-1148, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279565

RESUMO

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.

20.
Neurocrit Care ; 35(2): 335-346, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34309784

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Tronco Encefálico/diagnóstico por imagem , Escala de Coma de Glasgow , Humanos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
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