|Year : 2021 | Volume
| Issue : 3 | Page : 172-178
Advances in traumatic brain injury research in 2020: A review article
Revanth Goda, P Sarat Chandra
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||28-May-2021|
|Date of Acceptance||15-Jun-2021|
|Date of Web Publication||30-Aug-2021|
P Sarat Chandra
Room 7, 6th Floor, CN Center, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Perhaps in no other area of neurosurgery, has a greater research been done as in traumatic brain injury (TBI). Despite this, TBI remains one of the biggest killers around the world and especially in India. Decompressive craniotomy still remains one of the mainstay paradigms in the management of TBI. The following article explores several new modalities of treatment, and these include the role of beta-blockers for TBI, updates on decompressive craniotomy, the results of DECRA and RESCUEicp trials, diagnostic and prognostic biomarkers in TBI, vascular dysfunction, neuroimaging, and role of neuroinflammation in TBI.
Keywords: Evidence, research, traumatic brain injury, treatment, trials
|How to cite this article:|
Goda R, Chandra P S. Advances in traumatic brain injury research in 2020: A review article. Apollo Med 2021;18:172-8
| Introduction|| |
Traumatic brain injury (TBI) is usually defined as a disturbance in brain function or evidence of brain pathology caused by blunt or sharp injury to the head. The annual incidence of TBI is estimated to be around 50 million cases worldwide, thus approximately affecting half of the population once during their lifetime. In low- and middle-income countries, TBI is the most leading cause of morbidity and mortality in the population below 40 years of age. Owing to the establishment of extensive neurointensive care units (ICUs) and updated protocols in intensive care management of TBI, there is a significant improvement in outcome following TBI in first-world countries. In developing countries like India, severe TBI has a mortality rate of more than 30% and can cause significant morbidity in 60%–70% of the cases. Intracranial injury is a product of primary and secondary insult. Although decompressive craniectomy (DC) following TBI is the most performed therapeutic procedure to reduce intracranial pressure (ICP), it does not deal with the mechanism of primary brain injury leading to secondary insult caused by trauma and it is imperative to understand the pathophysiology of TBI and develop targeted effective therapies for secondary brain injury to further reduce the morbidity rates following TBI.
This update will focus on the advancements in the management and research of TBI published in 2020 and will be discussed in three key concepts – (a) neurointensive care and protocolized therapies in TBI, (b) update on DC in severe TBI, and (c) research on TBI made in 2020 to develop targeted therapeutics and improve outcome.
| Update of Neurointensive Care and Protocolized Therapies in Traumatic Brain Injury|| |
In the acute phase of severe TBI, treatment of raised ICP is crucial to the management of patients. After trauma, hemorrhage and cerebral edema leads to increase in intracranial volume which further leads to herniation, and if left untreated can result in compartment syndrome impeding the flow of blood to the brain leading to hypoxia, ischemia and permanent disability. International guidelines have been developed to protocolize the intensive care management of TBI. This includes standardized neurointensive care, the use of ICP monitoring, neurospecific monitoring, and the necessity of neurosurgical intervention.
The Brain Trauma Foundation (BTF) was established in 1986 with the sole aim to develop research in TBI and improve the outcome of TBI by providing evidence-based guidelines and standardizing the treatment protocols in severe TBI. The BTF maintains and revises several guidelines in a 5-year cycle since its first edition in 1995 (second edition in 2000, third edition in 2007, and fourth edition in 2017). These guidelines address the important topics in the management of TBI patients with Glasgow Coma Scale (GCS) of 3–8. Since the publication of the fourth edition of BTF guidelines in 2017, there have been not many advancements in the standardized neurointensive care and protocolized therapies in severe TBI. The research studies with good class of evidence (Class I or II) published in 2020 regarding the intensive care management and therapeutic strategies in TBI will be discussed in this section.
| Beta-Blocker Therapy in Severe Traumatic Brain Injury: A Prospective Randomized Controlled Trial|| |
The regular administration of beta-blocker as a part of standard treatment protocol in severe TBI is still debatable and is not recommended as a part of BTF fourth edition guidelines. The advantage of early beta-blockade on outcome has been demonstrated in several observational studies and Lund concept guidelines developed by Lund University Hospital in Sweden. This randomized controlled trial (RCT) published in 2020 was conducted to examine the effects of propranolol on outcome in severe TBI. This effect of beta-blockers is based on the hypothesis that adrenergic storm (sympathetic stimulation) due to primary brain insult, often referred to as paroxysmal sympathetic hyperactivity, can worsen the secondary brain injury due to cerebral vasoconstriction and ischemia.
In this RCT, a total of 356 patients were enrolled and 222 were randomized after excluding 134 patients (not meeting inclusion criteria or declining to participate) and 102 patients were allocated to intervention group and received oral propranolol 20 mg every 12 hourly for 10 days and were followed for a duration of 6 months. This study concluded that the use of early propranolol led to improved survival and better functional outcomes at 6 months in patients with isolated head injury but did not show benefit in patients with polytrauma as summarized in [Table 1]. These findings that decreased in hospital mortality rates following propranolol were supported by other studies published in literature by Chen et al. and Alali et al. The main concerns regarding the usage of propranolol in severe TBI are the risk of hypotension and bronchoconstriction which can aggravate secondary brain injury due to ischemia and hypoxia, respectively, but none of the studies in the literature reported such adverse side effects and morbidity following propranolol administration.
|Table 1: Update on intensive care and protocolized therapies in traumatic brain injury|
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| Update on Decompressive Craniectomy in Severe Traumatic Brain Injury|| |
DC (the temporary removal of a large part of skull) has been the main part of surgical armamentarium in the treatment of TBI. It can be performed primarily or secondarily. Primary DC involves removal of bone flap early after trauma. Secondary DC involves performing surgery at a later stage after trauma for raised ICP refractory to medical treatment. Patient selection, timing, and surgical technical aspects regarding DC continue to be debated, and there has been a debate whether this procedure should be performed at all. In the fourth edition of the BTF guidelines published in 2017, the lead chapter provided two-level IIA recommendations regarding DC in severe TBI. This edition of the BTF guidelines is the first edition to provide guidelines regarding DC in severe TBI. Despite the publication of high-quality trials such as RESCUEicp (Trial of DC for Traumatic Intracranial Hypertension) trial and DECRA, (DC in Patients with Severe TBI) trial after the publication of fourth edition of BTF guidelines in 2017, the role of DC remains still controversial.
The recommendations for DC in the fourth edition of BTF guidelines are shown in [Table 1], [Table 2], [Table 3],[Table 4],[Table 5],[Table 6],[Table 7],[Table 8].
|Table 2: The Brain Trauma Foundation Fourth Edition Level IIA recommendations for decompressive craniectomy in severe traumatic brain injury|
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|Table 4: Updated Level IIA recommendations for decompressive craniectomy in severe traumatic brain injury|
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|Table 5: Future directions in the field of decompressive craniectomy in traumatic brain injury|
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|Table 6: Ongoing trials on decompressive craniectomy in traumatic brain injury|
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|Table 8: Ongoing trials on research in traumatic brain injury (launched in 2020)|
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The first recommendation of the fourth edition of the BTF guidelines for DC in severe TBI is solely based on the 6-month follow-up of DECRA trial published in 2011 and the second recommendation was based on two studies by Jiang et al. and Qiu et al.
| Updated Recommendations for Decompressive Craniectomy in Severe Traumatic Brain Injury (2020 Update)|| |
DECRA (12-month follow-up) and RESCUEicp trials are the high-quality RCTs which studied the secondary DC in the treatment of refractory raised ICP and are published after the fourth edition of BTF guidelines. These trials serve as an addition to the existing literature in providing the updated recommendations for DC in severe TBI. The key difference in the study protocols of DECRA and RESCUEicp trials is to investigate the effect of DC in early and late refractory raised ICP in patients with TBI, respectively. The comparisons between DECRA and RESCUEicp trial are summarized in [Table 3].
Incorporating the DECRA trial and RESCUEicp trial in the existing literature helps in updating the recommendations of DC in severe diffuse TBI. The first recommendation for DC in TBI published by the fourth edition of BTF guidelines was removed, the second was restated, and three new level IIA recommendations were provided [Table 1].
The updated recommendations are shown in [Table 4]:
- NEW recommendation 1 reflects positive findings of RESCUEicp trial
- NEW recommendation 2 relates to the negative findings of DECRA trial and
- NEW recommendation 3 relates to the positive findings in both the trials.
| Lacunae in the Knowledge and Future Directions|| |
Although current evidence strongly supports DC to reduce ICP and that DC of inadequate size is associated with poor outcomes, there is a lot of knowledge gap and high-quality studies are required to study every aspect of DC in TBI. Some crucial knowledge lacunae are mentioned in [Table 5] which requires further high-quality studies.
| Update of Research in Traumatic Brain Injury in 2020|| |
The major goal of research in the field of TBI is to better understand the pathophysiology of TBI and develop targeted therapeutics to improve outcome following injury. Major advances were made in 2020 in the field of preclinical and clinical research in TBI to achieve the goal. The research conducted in 2020 will be discussed in the following sections.
Diagnostic and prognostic biomarkers in traumatic brain injury
Significant efforts by two large observational studies – Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) in the USA and Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) in Europe led to the development of diagnostic biomarkers in TBI. Czeiter et al. analyzed six serum neurological biomarkers within 24 h after injury (S100B, neuron-specific enolase, glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], neurofilament light, and t-tau) from 2867 patients of TBI in CENTRE-TBI study and studied their relation to predict the clinical severity scale of TBI and computed tomography (CT) abnormalities. They found that GFAP measured within 24 h can predict CT abnormalities surpassing the clinical characteristics. In patients with mild TBI, GFAP outperforms other markers and adds value to clinical characteristics in predicting the positive CT findings. They also found that combination of biomarkers did not provide any additional value as compared to GFAP alone. They also concluded that combining GFAP with UCH-L1 did not provide additional value in ruling out a CT scan among patients with mild TBI (GCS of 15) in whom a CT scan is felt to be clinically indicated, refuting the results of Evaluation of Biomarkers of TBI (ALERT-TBI) study published in 2018. The ALERT-TBI study also fails to establish the role of biomarkers in comparison with clinical characteristics to predict the CT positivity in mild TBI.
The results of CENTRE-TBI study on biomarkers in TBI support the development of novel CT guidelines combining GFAP and clinical characteristics for triaging patients with mild TBI in emergencies for CT scanning. The standardization of GFAP assay is necessary for widespread use, especially in resource-limited settings where CT scan is not accessible and TBI is highly prevalent.
Neurophysiological and neuroimaging biomarkers in traumatic brain injury
The failure of previous guidelines in improving the outcome of moderate-severe TBI led to the thought that new approaches are required [Table 3]. This change in the thought process changed the goal to implement a precisive personalized approach to patients whose conditions are likely to improve by identifying variations of pathophysiological process in TBI. Over the last decade, the use of multimodal intracranial monitoring for moderate-severe TBI has been increasing to characterize secondary brain injury mechanisms and provide precisive personalized treatment to optimize brain physiology. One such breakthrough in the clinical trials is the identification of the phenomenon of spreading depolarization, a direct measure of secondary brain injury.
Spreading depolarization waves are slow, pathological waves propagating through the cerebral gray matter, triggered by noxious stimuli such as trauma and ischemia. These waves lead to complete loss of electrochemical gradients in neurons and astrocytes in the affected region resulting in spreading depression of electroencephalography (EEG), cytotoxic edema. These waves are thought to be the major source of acute excitotoxic injury in the animal models of stroke.
multicentric, prospective, observational cohort study on 138 patients to study the prognostic value of spreading depolarizations in severe TBI in 2020 by Hartings et al, it was found that spreading depolarization waves can occur as sporadic events in one quarter of the patients, and more adverse, repetitive, and clustered events in one third of the patients. These clustered waves were associated with poor motor improvement and carried a high risk of poor functional outcome. In their study, they concluded that the clustered events of spreading depolarization can act as an independent prognostic biomarker apart from the conventional prognostic factors such as age, GCS at arrival, and pupillary reactivity. These waves can also be an important therapeutic target. They also concluded that EEG can be considered as an additional neuromonitoring method in patients with severe TBI for personalized management.
A larger clinical trial as a part of TRACK-TBI (NCT03379220) is ongoing to study the role of spreading depolarization in TBI and to standardize less invasive monitoring modalities like scalp EEG rather than using invasive intraparenchymal electrodes or subdural electrocorticography array so that nonoperative TBI patients can also be monitored in ICU.
In the field of neuroimaging in TBI, Jolly et al. defined distinct subnetworks in the brain that are activated during reasoning tasks and working memory which are the most affected cognitive domains following TBI. They combined diffuse-weighted magnetic resonance imaging (MRI), cognitive testing, and network analysis to identify these subnetworks. TBI causes dissociation of these networks leading to cognitive dysfunction, hence this approach can be particularly useful in identifying patients who are more likely to develop cognitive dysfunction following TBI to provide early cognitive rehabilitation of such patients.
Neuroinflammation in traumatic brain injury
Cognitive dysfunction due to chronic widespread nonresolving inflammation and microglial activation is the hallmark of TBI, and whether microglial activation is responsible for cognitive dysfunction is not understood.
In the acute phase of TBI, microglia rapidly respond to damage-associated pathways released because of injury and migrate toward the site of injury. The beneficial effect of migration is thought to be for the clearance of debris which is crucial in the wound healing process. In the chronic stage, many activated microglia retain their phenotypic appearance from the acute stage, and this chronic activation was thought to be detrimental and causes cognitive deficits. However, there is no direct evidence to support this hypothesis. Clearing the uncertainty regarding the role of microglia in TBI, two studies have been published in 2020 based on the well-defined mouse models of TBI.
Willis et al. conducted a study on repopulating microglia in mouse brain and summarized as – (a) removing microglia from the injured mouse brain did not alleviate cognitive deficits, (b) microglial turnover during the acute phase can stimulate neurogenesis (through interleukin-6-soluble receptor) and improve cognitive outcome following moderate-severe head injury, and (c) maintaining the microenvironment by microglia in the acute stage of injury is crucial for neurogenesis and attenuation of cognitive deficits, since the treatment in the chronic phase does not result in clinical improvement. They also suggested that microglia can be manipulated in the acute phase to adopt a pro-regenerative phenotype that can prevent cognitive dysfunction and these microglia can be a future precisive therapeutic target in TBI.
There are no treatment modalities for primary insult following TBI till date, and most of the guidelines are to prevent the spread of secondary insult to the brain. Sharma et al. in their study treated mice after TBI (contusion or diffuse axonal injury) with intravenous infusion of immunomodulatory nanoparticles (500 nm carboxylated poly[lactic-co-glycolic] acid) that destroys the monocyte-derived macrophages, which are thought to be the source of secondary brain injury. These nanoparticles administrated <3 h after injury depleted the number of macrophages, and this treatment resulted in the normalization of cellular architecture and visual and motor function in mice.
Vascular dysfunction in traumatic brain injury
Several human neuropathological studies showed that microvascular injury is common after TBI and can persist for several years after insult. More specifically, blood–brain barrier (BBB) disruption and leakage of serum proteins have been shown to play an important role in the pathogenesis of delayed complications following TBI, and this disruption of barrier has been recently suggested as a potential biomarker predicting outcome. Literature regarding the objective assessment of BBB disruption and its effect on outcome is negligible.
Veksler et al. in their study have used a modified dynamic contrast-enhanced MRI (DCE-MRI) to detect and track BBB disruption in a cohort of 42 American male football players exposed to repetitive head impacts. They found that these players had shown an increased slow-phase BBB impairment that reflects microvascular dysfunction which persisted for months and correlated with axonal injury on diffusion tensor imaging.,,, This disruption of BBB was region specific (white matter, midbrain peduncles, red nucleus, and temporal cortex), and these changes were not observed in the sex- and age-matched athletes of noncontact sports. Taking into consideration these findings, they suggested that DCE-MRI sequence which is a relatively simple sequence to perform with available software on all scanners can be used to identify microvascular injury following mild concussion injuries, and this disruption of BBB can also be a future potential target for therapeutic interventions.
| Conclusion|| |
Major advances in clinical and preclinical research in the field of TBI were made in 2020 taking one step ahead toward the goal of targeted therapeutics to improve outcomes. Still, there are lacunae in the knowledge understanding different concepts of pathophysiology and interventions in TBI which are expected to be filled by the ongoing trials. The research field in TBI is ideally positioned to better understand the pathophysiology and develop novel therapeutic strategies owing to the eminent efforts by TRACK-TBI and CENTER-TBI studies coupled with the ongoing preclinical trials.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]