Synopsis of the 10th International Neurotrauma Symposium: from bench to bedside in neurotrauma translational research

Abstract

The 10th International Neurotrauma Symposium was held in Shanghai, China, on 27–30 April 2011. This meeting marked the 20th anniversary of International Neurotrauma Symposia. The vision of the International Neurotrauma Society is to unite clinicians and scientists to discuss and present the latest in translational clinical and basic science research related to neurotrauma. The Shanghai meeting brought together 1000 delegates from over 70 countries. Key areas discussed included current guidelines of neurotrauma management, the latest advances in neuroimaging, the latest concepts in cell death mechanisms after neurotrauma, the role of decompressive techniques for cranial and spinal neurotrauma, advances in biomarkers for CNS injury, and the future of clinical management and research in neurotrauma.

Keywords::

• biomarkers
• CNS inflammation
• CNS regeneration
• decompressive craniectomy
• neuroimaging
• neurotrauma
• spinal cord injury
• TBI

The 10th International Neurotrauma Society (INTS) meeting marked the 20th anniversary of International Neurotrauma Symposia, with the first being held in Fukushima, Japan in 1991. The recent meeting was hosted by the INTS President David Hovda (University of California, Los Angeles, CA, USA). The Chair of the local organizing committee was Ji-yao Jiang. The local organizing institutions included Renji Hospital, Shanghai Jiaotong University School of Medicine and the Shanghai Institute of Head Trauma. The meeting brought together 1000 delegates from over 70 countries across the world and allowed the sharing and dissemination of the latest research findings and the discussion of hot and controversial topics in the clinical and translational/basic science arenas of neurotrauma and spinal cord injury (SCI).

The 10th INTS was comprised of six plenary sessions and eight break-out sessions, as summarized in Tables 1 & 2. In addition to these, there was also a round table discussion on the indications and techniques for decompressive craniectomy in the setting of traumatic brain injury (TBI).

Highlights of the meeting

The clinical aspects of TBI

Andrew Maas (Antwerp University Hospital, Edegem, Belgium) opened the meeting and plenary session 1 by discussing the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) head injury research consortium, which has undertaken a pool analysis of several large trials in TBI [1,2]. Maas emphasized the importance of comparative effectiveness studies in neurotrauma and articulated the position that such an approach had numerous advantages over prospective randomized controlled trials, which tended to be narrower in scope and had limited generalizability. One of the major innovations of IMPACT has been the development of a sliding dichotomous Glasgow outcomes scale. This is felt to have greatly enhanced sensitivity to detect meaningful changes in outcome in individuals with TBI.

Maas’ lecture was followed by a plenary address by G Manley (University of California, San Francisco; San Francisco General Hospital, CA, USA), who discussed the development and implementation of guidelines for TBI [3]. Manley reviewed the guidelines for closed and penetrating TBI and discussed the challenges in managing pediatric neurotrauma. A major focus of Manley’s lecture was the need for more accurate pathophysiological classifications of TBI and the importance of unified and validated methods of prospective data collection.

In plenary session 4, a spirited discussion occurred relating to the role of decompressive craniectomy in TBI. Jamie Cooper (The Alfred Hospital, Prahran, Victoria, Australia) presented the results of the Early Decompressive Craniectomy in Patients with Severe Traumatic Brain Injury (DECRA) trial, which examined the role of early decompressive craniectomy for patients with severe TBI and refractory intercranial hypertension [4,5]. This landmark prospective, randomized clinical trial, which has recently been published in the New England Journal of Medicine[6], found that decompressive craniectomy did not improve outcome and might be harmful in patients with diffuse TBI (with no focal lesion) and refractory intercranial hypertension. Peter Hutchinson (Wolfson Brain Imaging Center, University of Cambridge, Cambridge, UK) discussed an ongoing clinical trial related to decompressive craniectomy and TBI [7]. Hutchinson’s trial is felt be complementary to the DECRA trial in that patients with focal brain injuries will be included. These lectures were followed by a round table discussion on the technique. Despite the DECRA trial, it was felt that a role still exists for decompressive craniectomy in selected patients who failed maximal medical management.

In the closing session (plenary session 6), Ian Roberts (Antwerp University Hospital, Edegem, Belgium) discussed the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 trial, which is a large multicenter, randomized clinical trial examining the role of antifibrinolytic treatment in TBI [8]. The initial results of this trial appear to be promising and Roberts indicated the need to recruit additional centers into the trial. Ross Bullock (University of Miami, FL, USA) closed the INTS symposium with an overview lecture on the future of head trauma in the world. Bullock emphasized the need to develop more accurate classification systems for TBI [9], and to link this enhanced clinical methodology with state-of-the-art imaging and biomarker-based strategies. The potential of neuroprotective treatments and the impact of regenerative neuroscience were also discussed.

Clinical issues in traumatic spinal cord injury

Michael Fehlings presented on the guidelines for the treatment for traumatic SCI in opening plenary session 1. The important contribution of vascular mechanisms to the secondary injury was emphasized. While methylprednisolone continues to be a topic of controversy, Michael Fehlings advocated the continued use of the National Acute Spinal Cord Injury Study (NASCIS)-2 protocol in patients with cervical SCI and incomplete thoracic lesions. Ongoing clinical trials, including Phase I trial of a sodium glutamate antagonist (riluzole) being undertaken by the North American Clinical Trials Network, emergent studies using neural stem cells (e.g., the Phase I Geron trial) and emerging regenerative therapeutics including Cethrin^® and anti-Nogo were also discussed [10]. The author also presented a lecture on the global experience in SCI in closing session 6. It was emphasized that due to the lack of standardized prospective international registries, it is likely that both the incidence and prevalence of traumatic SCI are underestimated. The need for international efforts at data collection was emphasized. Results of the Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) trial related to the role and timing of surgical intervention in traumatic SCI were discussed [11]. This study has shown promising beneficial effects of early decompressive surgery (performed within 24 h) in individuals with a traumatic cervical SCI. Based on these promising data, the opportunity was presented to develop best-practice standards for early medical and surgical management of traumatic SCI on a global level. The opportunity for large, global, multicenter trials of promising neuroprotective drugs such as riluzole was also discussed. Finally, the need to achieve global consensus on how to move forward with potential clinical trials of autologous stem cells was emphasized.

Neuroimaging

David Brody (Washington University School of Medicine, MO, USA) opened the second plenary session with interesting findings from a study of US military personnel showing symptoms of blast-related TBI, which is difficult to detect using ordinary MRI techniques. They used an advanced MRI technique known as diffusion tensor imaging to examine the hypothesis that traumatic axonal injury is a process that contributes to blast-related TBI [12]. Brody reported that areas consistent with traumatic axonal injury were found in a significant number of the patients examined, suggesting that this technique is useful for assessing and diagnosing blast-related MRI, as well as potentially aiding therapeutic development and triage decisions.

Charles Gasparovic (Mind Research Network and University of New Mexico, NM, USA) discussed the benefits of using MRI – specifically magnetic resonance spectroscopy – in analyzing metabolic changes in patients with mild TBI whose cognitive deficits are not detectable by clinical measures [13]. His findings that higher estimated preinjury intelligence was related to a quicker return to normal metabolism within the brain, and his suggestion that this may indicate that biological factors underlying intelligence may also predict better recovery from brain injury, were intriguing. Furthermore, the metabolic changes associated with mild TBI were found to be different to the changes reported for more severe TBI, supporting the need for techniques and diagnoses specific to these milder traumatic brain events.

Finally, Minoru Shigemori (Kurume University, Kurume City, Japan) reported on the progress being made by the Japan Society for Neurotraumatology and the Asia Oceania Neurotrauma Society in developing guidelines and consensus for the treatment and management of severe TBI with reference to the importance of imaging techniques in diagnosis [14].

CNS inflammation

Discussions on inflammation in the CNS are inevitably complex as inflammation has been shown to have both positive and negative effects on outcomes after injury.

Phillip Popovich (Center for Brain and Spinal Cord Repair, Ohio State University, OH, USA) was the first to speak in the break-out session focused on inflammation and neurotrauma [15]. He tackled the seemingly contradictory roles of macrophages in both cell death and in axonal regrowth and regeneration. He spoke of evidence that the microenvironment around a lesion and CNS macrophages can be manipulated so that inflammation continues, but favors tissue repair without the accompanying cell death.

Peter Hutchinson (Wolfson Brain Imaging Center, University of Cambridge, Cambridge, UK) next spoke of the potential of using microdialysis in order to monitor the inflammatory response in vivo[16].

Cristina Morganti-Kossman and Nicole Bye (National Trauma Research Institute, Alfred Hospital, and Department of Medicine, Monash University, Victoria, Australia) presented complementary talks on their research, which has provided evidence that suppression of inflammation does not increase neurogenesis; however, neuroprotection can be achieved with low-level suppression of inflammation as with a low dose of minocycline over a longer time period [17,18]. Minocycline was also shown to improve functional recovery after focal TBI in mice.

Carmen Chan (Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, Japan) added to the voices stressing that inflammation in SCI has a role to play in both neurogenesis and cell death and that combinatorial therapies may be the way forward to maximize recovery and neuroprotection.

Eric Thelin (Karolinska Institute, Stockholm, Sweden) discussed the potential benefits of monitoring levels of S100B in serum following TBI in order to predict outcome [19], while Jennie Ponsford (The Alfred Hospital, Victoria, Australia) discussed sleep disturbances in patients after TBI and the likelihood that some of this is due to mechanical damage to the brain [20].

Biomarkers

Ronald Hayes and Kevin Wang (Banyan Biomarkers Inc., FL, USA) presented complementary talks on the topic of biomarkers [21,22]. Hayes outlined the numerous clinical trials and feasibility studies indicating that biomarkers, in particular UCH-L1, GFAP and SBDP150, are useful in identifying acute injury, as well as sports concussion and brain injury due to overpressure after blast-exposure, in addition to helping predict outcomes. Wang went on to delineate proteomic and systems biology methods of discovering potentially useful biomarkers that can then be validated in both animal models and in humans. Shu-Yuan Yang (Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin, China) discussed how induced overexpression of Hes1 was shown to enhance functional recovery after fluid percussion injury in mice, neatly representing a biomarker that can be indicative of better outcomes.

CNS regeneration

Min Zhao (University of California, Davis, CA, USA) reported on the potential of exploiting endogenous electric fields, as well as applied electric fields, to guide the migration of neural stem cells to the site of damaged tissue and thus potentially assist in tissue repair [23]. Jungfeng Feng (University of California, Davis, CA, USA) elaborated on this and described work in vitro characterizing the migration of human neural stem cells derived from human embryonic stem cells in small applied electric fields.

Rutledge Ellis-Behnke (MIT, MA, USA) described a scaffold technology, called RADA4, which has been successful in facilitating the regeneration of axons and functional recovery in hamsters. Promising results with robust migration of cells, growth of axons and blood vessels, and repair of the spinal cord have also been seen in rats with this self-assembling peptide [24].

Thomas Reeves (Virginia Commonwealth University, VA, USA) discussed the differential effects of drugs on myelinated axons compared with unmyelinated ones post-injury [25,26]. Neither drug tested – CsA or FK506 – was able to prevent suppression of compound action potentials in unmyelinated axons, but they were able to in myelinated ones, emphasizing the importance of taking differences in fiber type into account when developing therapeutic strategies.

Deborah Shear (Walter Reed Army Institute of Research, DC, USA) presented findings from her ongoing work to assess the neuroprotective effects of progesterone and dextromethorpan in a rat model of a penetrating ballistic-like brain injury [27,28]. Findings indicated both were effective in reducing neurological and motor deficits when applied postinjury, but only dextromethorpan showed efficacy in improving performance on the Morris Water Maze task. The work to establish the dose–response curve for both treatments is ongoing.

The final speaker in the break-out session on CNS regeneration and repair was Krieg Sandro (Technical University Munich, Munich, Germany), who presented work on a novel strategy to help prevent secondary damage caused by brain edema formation [29]. His team investigated the role of arginine vasopressin in the formation of brain edemas in a mouse model and found that the administration of an arginine vasopressin va1 receptor antagonist reduced edema formation and contusion growth. The overall results suggest that central inhibition of these receptors could act as a treatment for TBI.

Closing comments & summary

The 10th International Neurotrauma Symposium in Shanghai, China featured the latest advances in clinical science and cutting-edge translational research related to traumatic brain and SCI. This meeting clearly showed that neurotrauma is an exciting, dynamic and interdisciplinary field. The next decade will witness major changes in neurotrauma management, which will be of great benefit to patients and to society.

Table 1. Plenary sessions at the 10th International Neurotrauma Symposium.

Session	Title of session and speakers
Session 1	Guidelines for Neurotrauma Recommendations for Trials and Prognosis: The impact of IMPACT – Andrew Maas Development and Implementation of Guidelines for TBI – Geoffrey Manley Guidelines for the Treatment of Spinal Cord Injury – Michael Fehlings
Session 2	Neuroimaging Advanced MRI Detection of Blast-Related TBI – David Brody Recovery from Glutamate and Energy Metabolism Alterations after Mild TBI – Charles Gasparovic Neurotraumatology in Japan and Asia – Minoru Shigemori
Session 3	TBI-induced Neuronal Injury and Death Evidence for Neuronal Atrophy as well as Cell Death Following Diffuse Brain Injury – John Povlishock Mechanisms Underlying Cell Death After Brain Injury – Robert W Keane Guideline-Based Management of Severe Head Injury in Japan – Katsuji Shima
Session 4	Decompressive Strategies in TBI and SCI The European Experience in TBI – Peter Hutchinson Efficacy of Standard Craniectomy for Refractory Intracranial Hypertension with Cerebral Contusion – Ji-yao Jiang Early Decompressive Craniectomy for Patients with Severe TBI and Refractory Intracranial Hypertension (DECRA): A Prospective Randomized Clinical Trial – Jamie Cooper
Session 5	Biomarkers and Novel Approaches to Monitoring Clinical Studies of the Utility of Serum Biomarkers for Diagnosis, Prognosis and Management of TBI – Ronald Hayes Improvement on Spatial Learning in Morris Water Maze Following Recombinant Adenovirus Vector-mediated Hes1 in Adult Mice Hippocampus After Fluid Percussion Injury – Shu-Yuan Yang Neuroproteomics and Systems Biology-based Protein Biomarkers Discovery and Validation for Traumatic and Blast Brain Injury – Kevin Wang
Session 6	The Future of Neurotrauma CRASH2: Antifibrinolytic Treatment in TBI – Ian Roberts The Global Experience in Spinal Cord Injury – Michael Fehlings Future of Head Trauma in the World – Ross Bullock

CRASH: Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage; IMPACT: International Mission for Prognosis and Analysis of Clinical Trials in TBI; TBI: Traumatic brain injury.

Table 2. Summary of speakers at break-out sessions at the 10th International Neurotrauma Symposium.

Session	Title of session and speakers
Session 1	Experimental Therapeutic Approaches and the Future of Clinical Trials in TBI Andras Buki Bruce Lyeth Esthme Shohami Liang-Fu Zhou Hester Lingsma
Session 2	CNS Regeneration and Repair – session 2.1 John Houle Min Zhao Rutledge Ellis-Behnke Thomas Reeves Deborah A Shear Jungfeng Feng Krieg Sandro	DAI Revisited – session 2.2 Enoch Wei Doug Smith Junghoon Kim Edwin Yan Baiyan Liu Meiqing Lou Liying Zhang Surakrant Yutthakasemsunt	Clinical Management of TBI – session 2.3 Francis Lockie Deepak Gupta Virginia Newcombe Hitoshi Kobata Jin Hu Yumin Liang Lijun Hou Bob Roozenbeek Zhou Fei
Session 3	Glia in CNS Injury – session 3.1 Michael Sofroniew S Hellewell Stefania Mondello Elham Rostami Adel Helmy Yutaka Shigemori Masahiro Tado Zhiye Zhuang		Controversies in TBI Metabolism – session 3.2 David A Hovda Natalia Notkina Dong Sun Anthony Figaji Frances Corrigan Valeriya Tenedieva Tim Ham Elizabeth Moore
Session 4	Patient Management in CNS Injury – session 4.1 Nino Stocchetti Wai S Poon Dafin F Muresanu Ivan Timofeev Gourikumar Prusty Safi Ur Rehman		Inflammation and Neurotrauma – session 4.2 Philip Popovich Peter Hutchinson Cristina Morganti-Kossman Carmen Chan Eric Thelin Nicole Bye Jennie Ponsford

DAI: Diffuse axonal injury; TBI: Traumatic brain injury.

Acknowledgements

The authors would like to acknowledge the work done by the organizers of the meeting to make it such a success, as well as the contribution of all the speakers and those who presented posters.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.