Cortical spreading depolarizations are a novel mechanism independently associated with unfavorable clinical outcome in TBI Jed Hartings, PhD Department of Neurosurgery University of Cincinnati [email_address] 513-558-3567 COSBID
Developing new therapies is a challenge in TBI due to heterogeneity of the disease, in cause, severity, pathology, and outcome.
Imaging is the only tool to assess heterogeneous intracranial disease processes.
Neuromonitoring captures ICP and P ti O 2 , which are usually global measures of cerebral status.
Medical management is mainly supportive, aimed at maintaining adequate cerebral blood flow and oxygenation.
To advance treatment, a goal of translational research is to identify pathomechanisms that can be monitored and targeted for therapeutic intervention. This would enable application of therapies tailored to individual patients and their specific pathomechanisms , and optimize chances to detect significant treatment effects when they exist in clinical trials.
Spreading depolarizations Spreading depolarizations = class of pathologic waves characterized by near-complete sustained depolarization of neurons/astrocytes that propagate through gray matter at 1-5 mm/min
Discovered in 1944 by Leão in rabbit cortex
Occur spontaneously in animal models of focal cerebral ischemia and TBI (late 1970’s)
Principal mechanism of the penumbral expansion of cerebral infarction (1990’s)
First discovered in humans in 1996 by Mayevsky with a multimodal intraparenchymal research probe (1 of 14 TBI patients)
Demonstrated in >50% of patients with acute brain injury by Anthony Strong and COSBID using standard electrocorticography (2000’s)
Objective Study Aim To test the null hypothesis that depolarizations have no independent association with 6-month outcomes after TBI , after controlling for established prognostic factors in multivariate analysis
We previously reported that occurrence of depolarizations is significantly associated with 6-month outcomes after TBI (Hartings et al., Brain 134:1529-40, 2011)
Depolarizations may be a marker of injury severity, with no causal influence on recovery; known prognostic factors may account for this association
103 patients monitored for 72 hr (quartiles: 40,102)
surgery at 10 hr post-trauma (quartiles: 5, 26)
Depolarizations observed in 58 of 103 patients monitored (56%)
total of 1,328 depolarizations (average: 23 / patient)
ISD (n=20) CSD (n=38) None (n=45)
Results No differences in recording durations (p>0.50), timing of surgery (p>0.50), or prognostic scores (p=0.34). Significant difference in outcome between depolarization categories χ 2 , p<0.01 Poor outcome (dead, VS, severe disability) ISD CSD None Poor outcome More likely Less likely Prognostic scores
Results *p=0.26 ^p<0.001 Multivariate ordinal regression analysis Estimated common odds ratio 95% confidence interval p-value Prognostic Score 1.76 1.26 to 2.46 <0.001 Depolarization None 1.0 reference <0.001 CSD 1.56* 0.72 to 3.37 ISD 7.58^ 2.64 to 21.8 Depolarization No 1.0 reference 0.01 Yes 2.55 1.25 to 5.20
Late, in-hospital secondary insults may be confounding variables; they may co-vary with spreading depolarizations and mediate some of the association of depolarizations with outcome.
Depolarizations were scored into 2 simple categories, whereas patterns are complex and exist on a continuum. Prognostic value of ECoG may be increased with more refined quantification of depolarization ‘burden’.
Study subjects limited to those who undergo surgery. Do the same relationships exist in non-surgical patients?
Variable placement of electrode strip may impact detection of ISDs/CSDs. However, the effect would be to bias data toward a negative result.
Acknowledgments Ross Bullock – Miami, FL David Okonkwo – Pittsburgh, PA Lilian Murray – Glasgow, Scotland Gordon Murray – Glasgow, Scotland Martin Fabricius – Copenhagen, Denmark Andrew Maas – Edegem, Belgium Johannes Woitzik – Berlin, Germany Oliver Sakowitz – Heidelberg, Germany Bruce Mathern – Richmond, VA Bob Roozenbeek – Rotterdam, Netherlands Hester Lingsma – Rotterdam, Netherlands Jens Dreier – Berlin, Germany Ava Puccio – Pittsburgh, PA Lori Shutter – Cincinnati, OH Clemens Pahl – London, UK Anthony Strong – London, UK COSBID U.S. Army CDMRP PH/TBI Research Program, Contract No. W81XWH-08-2-0016