Traumatic brain injury: progress and challenges in prevention, clinical care, and research

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.Table 1Key messages and recommendationsKey messagesRecommendationsSection 1Worldwide, TBI is a leading cause of injury-related death and disability, with devastating effects on patients and their familiesContinue concerted efforts to address this vast global health problem and focus on better prevention, improved access to care, and promotion of clinical research to improve treatment standardsSection 1More than 90% of patients presenting to hospital with TBI have so-called mild TBI (GCS 13–15), but evidence to inform treatment of patients with mild TBI is scarceIncrease public health interest and establish a research focus on mild TBISection 1In HICs, older patients (≥65 years) who are mostly injured by falls account for 30–40% of hospital admissions for TBI. Frailty and alcohol abuse contribute to falls causing TBI in older peopleTarget fall prevention for older citizens in HICsSections 1, 2People in LMICs are disproportionately affected by TBI, with most injuries caused by road traffic incidents. Substantial disparities in care exist, with little infrastructure available for emergency pre-hospital care and very little access to post-acute careDeliver on implementation of road safety goals, described in WHO's Decade for Action on Road Safety plan launched in 2021. Improve emergency pre-hospital care and develop an infrastructure for post-acute careSection 2Disparities in care also exist in HICs and relate to: older people injured by low-energy mechanisms (falls); access to rehabilitation for patients with moderate to severe TBI (GCS ≤12); and follow-up in patients with mild TBIAddress disparities through close collaboration between policymakers and clinicians; Approaches to consider include: critical appraisal of triage tools used in emergency settings; involvement of rehabilitation services at an early stage of the in-hospital treatment for TBI; and establishment of structured follow-up after mild TBI as good practiceSections 2, 4Use of blood-based biomarkers is on the verge of a breakthrough for diagnostic and prognostic use in TBI, but few assay platforms have been approved for clinical use and substantial variability exists between platformsStimulate the development, validation, and approval of clinical-use platforms, and facilitate cross-platform harmonisation of biomarker assaysSection 3Older patients often have co-morbidities, but very little evidence exists to inform their treatmentStimulate a research focus on older patients with TBISection 3Access to rehabilitation services is inconsistent and no protocols for treating long-term problems existImprove access to rehabilitation services and develop evidence-based treatments for long-term problems—including fatigue, and cognitive and behavioural changesSection 4Substantial advances have been made towards individualised management with improved characterisation and understanding of disease processes in TBI, but physicians are not yet sufficiently able to match therapies to subgroups of patientsStimulate research to identify subgroups of patients who would be most likely to benefit from specific interventionsSection 5Around 50% of patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health and wellbeing by 6 months after injuryImplement care pathways to ensure structured follow-up of patients with mild TBI, and stimulate research to identify patients with mild TBI at high risk for incomplete recovery, which would allow timely evaluation and treatmentSection 5Outcome in women after TBI is poorer than in menFacilitate research to help explain this sex and gender difference and inform intervention strategiesSection 6Prognostic models have been developed and extensively validated for moderate and severe TBI. No well-validated models exist for mild TBI, nor do models exist that are applicable across all ranges of TBI severityInitiatives should be stimulated to develop models applicable across the range of TBI severity. Availability of such models would constitute a huge step forward and facilitate implementation into clinical practiceSection 6Quality indicators developed for TBI are restricted to the ICU setting and are not yet ready for translation into practiceResearch should be stimulated to refine, validate, and implement quality indicators for TBISection 7Costs of data curation and deep harmonisation in preparation for sharing research data are underestimated and can amount to up to 20% of a study budgetFor completed studies, mechanisms should be developed to facilitate maintenance of the data and to provide guidance to external researchers wishing to analyse the data. For new studies, inclusion of an appropriate budget to prepare data for sharing should be foreseen in the grant awardSection 7TBI is often characterised by both an acute mental incapacity of patients to provide informed consent for participation in research and an emergency situation. Although GDPR recognises the issue of absence of capacity to provide consent, no provisions are included that are relevant to patients with an acute absence of capacity or to emergency situationsDevelop better regulatory guidance. Consider mandating that researchers obtain objective proof of mental capacity of the study participant, who might have been temporarily mentally incapacitated, before requesting informed consent.Section 7Data sharing and analyses across different datasets do not necessarily require data transfer and can be done on a federated platform. Use of a federated platform facilitates broad use of data and reduces the risks for violation of data security and privacy regulationSupport is required for the development of platforms for federated analysis, particularly for development and implementation of machine-learning techniques on such platformsTBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation. Open table in a new tab TBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation.