A military veteran who survived a gunshot wound to the head suffers from frequent seizures and memory problems. A motorcycle crash survivor experiences chronic depression and is unable to hold a job. A 7-year-old boy who fell down the stairs as a toddler now has behavioral problems and difficulty focusing at school.
What do these people have in common? All these individuals are all afflicted with the long-term effects of traumatic brain injuries, or TBI.
The brain is housed inside the skull and is suspended in a substance called cerebrospinal fluid, which serves to protect it from many everyday impacts. When a TBI occurs, the blow is so hard that it either penetrates the skull, as in a gunshot injury, or causes the brain to collide with great force into the skull, damaging brain cells as well as the arteries that supply them with blood. There are many causes of TBI, such as falls, assaults, sports injuries, and military combat. In the United States, TBI accounts for 2.5 million emergency department visits and 56,000 deaths every year.
At the time of the injury, people with a TBI can experience headache, nausea and vomiting, seizures, weakness, and a change in consciousness. However, inside the brain, a chain of events is beginning to unfold that leads to further brain damage, known as secondary injury. The brain cells that were damaged by the initial injury begin to release toxic substances that can harm surrounding cells. Neuronal axons, which connect different brain areas to one another, can be damaged, affecting parts of the brain that are far from the initial site of injury. All of these secondary injuries can happen within minutes to months of the primary insult.
Unlike our muscle and bone tissue, which are typically capable of self-repair, the brain isn’t very good at healing itself from injury. For this reason, the effects of TBI can be long lasting and even permanent. Long-term problems include changes in cognitive processes such as memory and attention, psychiatric problems such as depression and anxiety, and physical complaints including headaches and balance problems. These changes can last for years and can dramatically impair patients’ quality of life.
Clinical trials for TBI
Because TBI is so common and has such a profound effect on the quality of life, many investigational drugs have been developed in hopes of treating these injuries. Treatments have been designed to target both the original brain injury, as well as some of the secondary complications.
“However, despite promising results from preclinical and stage II trials, none of these trials have identified a successful TBI treatment so far.”
When new drugs are invented, they must pass through several test stages before they can be prescribed to patients. The initial stage is the preclinical stage, in which the drugs are tested in laboratory animals. Stages I and II are carried out in people and are designed to test the safety of drugs and to gather preliminary data to determine if the treatments might work. Finally, stage III trials are performed to determine the effectiveness of the treatment in a large group of patients. These trials are randomized and controlled, meaning that a group of patients with a particular disease are randomly assigned to receive either the drug or an inactive placebo.
Over 100 randomized controlled trials have been conducted for potential TBI treatments. However, despite promising results from preclinical and stage II trials, none of these trials have identified a successful TBI treatment so far. Some of the recent treatments that have failed in clinical trials include:
- progesterone, a reproductive hormone that was shown to reduce brain damage in animal models
- hypothermia, a method of cooling the body following injury to prevent tissue damage
- dexanabinol, a humanmade substance with properties similar to marijuana
- citocoline, a naturally-occurring compound with neuroprotective properties
- erythropoietin, a protein that regulates the production of red blood cells
Physical rehabilitation and occupational rehabilitation are thus the only treatments at this time.
Understanding trial failures
Why have so many treatments that initially showed promise in preclinical studies failed at the clinical stage?
One major problem is that animal models, which are used to predict what drugs might be effective, can be very different from human TBI patients. Whereas animal models are designed to have specific and well-controlled injuries, human patients show a spectrum of injury types and severities, and no two cases will be identical. TBI patients often present with comorbidities—other medical conditions that are present alongside their brain injuries. These comorbidities can include oxygen deprivation, injuries to other parts of the body, and other chronic diseases, such as diabetes. Lastly, drug doses that are designed in one species do not always work in another. The dose and timing of drug administration may need to be optimized for humans.
Fun fact: fresh brains are mushy. They seem harder in science class because they're preserved with formaldehyde. pic.twitter.com/68HSH16OvH
— Daniel Toker (@daniel_toker) September 6, 2017
“Moving forward, trials designed to evaluate new TBI treatments should incorporate measurements related to the patient’s quality of life.”
Another possible reason for trial failure is that researchers simply aren’t making the right measurements for assessing recovery. Clinical trials for TBI typically assess the survival and death rates, rates of major disability, and the Glasgow Coma Scale (GCS) and its extended version (GOS-E), which measure changes in the level of consciousness (5). These instruments tell physicians if patients have stayed alive or died, but do little to illuminate if patients’ day-to-day function has been affected.
Moving forward, trials designed to evaluate new TBI treatments should incorporate measurements related to the patient’s quality of life. These measures might be more sensitive for detecting small improvements and differences between patients.
Novel tools for TBI assessment
New tools are being developed to better evaluate patients’ day-to-day functioning and quality of life following TBI. Many of these tests will use modern technologies such as computerized testing and smartphone compatibility.
One such tool is the National Institutes of Health (NIH) Toolbox, a collection of testing tools designed to evaluate patients’ thinking abilities, motor function, psychological well-being, and more. These assessments include both objective measures (such as tests of motor function—how well an individual can perform specific movements) and self-reported measures (such as tests for emotional health). The following are examples of some of the motor tests in the toolbox (13):
- Standing Balance Test: this test evaluates a patient’s balance under 6 different testing conditions (i.e. feet together with eyes open vs closed)
- Four-minute Walk Test for gait speed: this test of walking speed is administered on a straight course in two trials, one “at usual pace” and one “as quickly as possible.”
- Two-minute Walk Test for endurance: measures the distance walked on a 50-foot course in two minutes.
These tests can be administered using the NIH toolbox iPad Application.
Another recent NIH development is the Patient Reported Outcomes Measurement Information System (PROMIS), a system of patient-reported measures across several health domains: physical health (e.g., fatigue and fine motor function), mental health (e.g., anxiety and cognitive function), and social health (such as social participation). This tool was designed to test patients with any of a variety of diseases, and the tests were developed using individuals in the general population.
One aspect of the PROMIS system is the use of Computerized Adaptive Testing (CAT). The questions asked in the assessment will be modified or “adapted” for an individual patient based on his or her response to the previous question. The PROMIS computerized adaptive test creates a profile for each patient that gauges their function across nine areas of health.
NIH also introduced the Neuro-Quality of Life assessment (Neuro-QOL) assessment, which is similar to the PROMIS system but specific for neurological disease. A similar assessment called the TBI-QOL is currently under development. The TBI-QOL further improves upon the Neuro-QOL because calibration testing was conducted in TBI patients, rather than in the general population (12).
Ecological momentary assessment is another new approach that may be useful for assessing the behavioral and psychiatric problems that occur in TBI patients. Ecological momentary assessments require patients to report specific information regarding their symptoms in real-time in their everyday environments. For example, a patient with social anxiety might report on their symptoms each time they engage in a social interaction during the day. In a recent study, a smartphone application for conducting ecological momentary assessments, was found to be useful for the long-term monitoring of mood in TBI patients.
Researchers are also developing new methods for administering these tests to patients. Such methods include geofencing of testing (an app becomes activated when a particular location is entered), autoenrollment, and the integration of patient assessments into hospital electronic health systems, such as SmartHealth IT.
By integrating these new tests, clinical trials may be more successful at detecting the effects of new treatments on the quality of life of TBI patients. Just like how the microscope allowed scientists to have a more intricate understanding of the world than with just the human eye, better quality of life tools with mobile apps change the way we understand patients with TBI. In doing so, these tests may increase the number of positive outcomes in clinical trials, advancing the progress of much-needed new treatments for the millions of patients with TBI.
- Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic Brain Injury–Related Emergency Department Visits, Hospitalizations, and Deaths — United States, 2007 and 2013 CDC Surveillance Summaries / March 17, 2017 / 66(9);1–16
- Xiong Y, Zhang Y, Mahmood A, Chopp M. Investigational agents for treatment of traumatic brain injury. Expert Opin Investig Drugs. 2015 Jun; 24(6): 743–760.
- Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49(4):391–402.
- Xiao G, Wei J, Yan W, et al. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61.
- Samadani U and Daly SR. When Will a Clinical Trial for Traumatic Brain Injury Succeed? AANS Neurosurgeon 2016 25:3.
- Juengst SB, Graham KM, Pulantara IW, et al. Pilot feasibility of an mHealth system for conducting ecological momentary assessment of mood-related symptoms following traumatic brain injury. Brain Inj. 2015;29(11):1351-61.
- Andrews PJ, Sinclair HL, Rodriguez A, et al. Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. N Engl J Med. 2015 Dec 17;373(25):2403-12.
- Maas AI, Murray G, Henney H 3rd, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006 Jan;5(1):38-45.
- Zafonte RD, Bagiella E, Ansel BM, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT). JAMA. 2012 Nov 21;308(19):1993-2000.
- Adelson PD, Wisniewski SR, Beca J, et al. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol. 2013 Jun;12(6):546-53
- Nichol A, French C, Little L, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet. 2015 Dec 19;386(10012):2499-506.
- Tulsky DS, Kisala PA, Victorson D, et al. TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury. J Head Trauma Rehabil. 2016 Jan-Feb;31(1):40-51.
- Reuben DB, Magasi S, McCreath HE, et al. Motor assessment using the NIH Toolbox. Neurology. 2013 Mar 12; 80(11 Suppl 3): S65–S75.
- NIH PROMIS, Qolty 2017
- NIH Neuro-QoL, Qolty 2017
- Tulsky, Kisala, et al. TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury J Head Trauma Rehabil. 2016 Jan; 31(1): 40–51.
- Smart – An App Platform for Healthcare.