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Original Investigation
December 30, 2019

Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury

Author Affiliations
  • 1Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 2Department of Neurological Surgery, University of Miami, Miami, Florida
  • 3Division of Neurosurgery, Virginia Commonwealth University, Richmond
  • 4Department of Critical Care Medicine, King’s College London, London, United Kingdom
  • 5Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 6Department of Basic and Clinical Neuroscience, King’s College London, London, United Kingdom
  • 7Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 8Departments of Neurology, Experimental Neurology, and Neurosurgery and Centre for Stroke Research, Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 9Department of Public Health, Centre for Medical Decision Making, Erasmus Medical Centre, Rotterdam, the Netherlands
  • 10Department of Neurosurgery, University of Louisville School of Medicine, Louisville, Kentucky
  • 11Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 12Department of Mechanical Engineering, University of Cincinnati, Cincinnati, Ohio
  • 13Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
JAMA Neurol. 2020;77(4):489-499. doi:10.1001/jamaneurol.2019.4476
Key Points

Question  Does the measurement of spreading depolarizations provide clinically meaningful information that is independent of other assessments?

Findings  In this cohort study of 138 patients who underwent surgery for traumatic brain injury, the occurrence of repetitive spreading depolarizations (clusters) in 51 patients (37.0%) was associated with poor neurologic recovery during intensive care and was a factor independently associated with worse 6-month functional outcomes.

Meaning  Spreading depolarizations are a common mechanism of secondary injury that should be considered for monitoring and treatment targeting in traumatic brain injury.


Importance  Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery.

Objective  To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes.

Design, Setting, and Participants  This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures.

Interventions  A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care.

Main Outcomes and Measures  Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale–Extended score.

Results  A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg; P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively; P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively; P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65; P = .02) for worse outcomes.

Conclusions and Relevance  In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

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