There are currently no objective biomarkers for concussion, an invisible injury and form of mTBI, which often remains difficult to diagnose and treat. Although there are broad consensus guidelines, individual treatment decisions for this heterogeneous injury are largely left to the discretion of the physician. Previous studies have suggested a link between C-reactive protein (CRP), an inflammatory biomarker in the blood, and TBI, but the relationship is still under-explored. Because the underlying pathophysiology remains poorly understood, it remains challenging to create a treatment plan, noted Ayse Erdemir, clinical research coordinator at HSS, and first author of both studies.

“Currently there are no established pharmacological treatments for mTBI,” Erdemir noted. Standard treatment involves physical therapy, guided exercise, and lifestyle modifications, with some options for treating headache, head pressure, and insomnia, common symptoms that can impact recovery. While previous studies of amitriptyline in this population have been inconclusive, the team's research provides new data which may support its use in specific circumstances.

These studies, if further validated, have the potential to influence the treatment of mTBI, she added.

For the first retrospective study of 383 concussion patients, researchers focused on measurements of high sensitivity CRP (hsCRP), an inflammatory biomarker in the blood. Erdemir pointed out, “We found that higher levels of hsCRP were associated with more frequent reporting of symptoms like sadness and trouble falling asleep. Notably, patients with abnormal hsCRP took longer to recover compared to those with normal levels. These patients also tended to be older and have higher BMI.”

Additionally, she said "The findings suggest that hsCRP could potentially be a candidate for inclusion in biomarker panels for acute mTBI assessment, but more research is needed to understand its long-term role in tracking symptom resolution and recovery."

The results also offer a possible new insight into the pathophysiology of the disease, suggesting that, at least in some patients, the concussion may be characterized by low levels of inflammation in the brain that resolves with tailored treatment paradigms.

For the second study, the researchers analyzed data from the same group of patients, focusing on those who were prescribed amitriptyline. They found that patients who had received the drug more often had histories of depression, anxiety, and migraines, and also had more severe concussion symptoms than those who did not receive the medication. Even though their concussions appeared to be more complex and severe, patients in the amitriptyline group recovered at the same rate as more straightforward cases.

“Amitriptyline seems to play a supportive role in helping patients with more frequent and severe baseline symptoms to recover,” said Erdemir. “A tool to treat headache and insomnia in concussion patients doesn’t just improve quality of life throughout recovery; it may also facilitate and potentially expedite recovery. Restoring normal sleep and improving sleep quality is especially important to helping the brain heal from mTBI.”

While researchers believe patients with more severe concussions are more likely to benefit, the drug may still be prescribed in other patients to relieve symptoms.

More research is clearly needed to develop clinical applications. Researchers hope to follow up by analyzing longitudinal trends of hsCRP across recovery, to further support its use as a biomarker. Additional study of amitriptyline should include a randomized, controlled trial comparing the medication to placebo as well as other medications used to treat headache.

References:

High-sensitivity C-Reactive Protein (hsCRP): Retrospective Study of Potential Blood Biomarker of Inflammation in Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

Amitriptyline for Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

The researchers conclude their findings demonstrate a need for further interventions to reduce concussion rates, such as the required use of protective head equipment in women’s sports, the adoption of neck-strengthening exercises and other prevention training, and greater enforcement of rules to decrease levels of contact in men’s sports.

Concussions can occur in a wide range of sports, affecting not only professional athletes but youth athletes as well. There are approximately 1.7 million to 3.8 million sports concussions reported in the nation each year^1,2,3 as well as 1.1 million to 1.9 million pediatric recreation-related concussions.⁴

For the first paper, "Sex-Based Differences in the Incidence of Sports-Related Concussion: Systematic Review and Meta-analysis," first published on September 30, 2019, in the journal Sports Health, senior author Daphne Ling, PhD, MPH, a sports medicine epidemiologist at HSS, and colleagues conducted a meta-analysis of sex-based differences in concussion incidence in lacrosse, soccer, baseball/softball, basketball, track and field and swimming/diving. They found that the concussion incidence rates for females were statistically significantly higher compared to males in both soccer and basketball.

“While the causes are unknown, we suspect this sex difference in concussion incidence in soccer and basketball might be attributed to females having decreased head and neck strength, greater peak angular acceleration and increased angular displacement compared to males. Female athletes are also more likely to disclose their symptoms to coaches and parents. This is important for physicians to consider when treating patients who participate in these sports,” concluded Dr. Ling.

For the second paper, "Women Are at Risk for Concussions Due to Ball or Equipment Contact in Soccer and Lacrosse," published online ahead of print on October 17, 2019, in the journal Clinical Orthopaedics and Related Research (CORR), senior author Ellen Casey, MD, a sports medicine physician with the Women’s Sports Medicine Center at HSS, and colleagues conducted a meta-analysis of 10 studies published from January 2000 to December 2018. The studies reported concussion incidence for both male and female athletes who participated in the following sports: ice hockey, soccer, basketball, baseball/softball and lacrosse. The objective was to identify in which sports female athletes were less likely to experience concussions from player contact versus ball or equipment contact.

In female athletes, the main cause of concussions was contact with the ball or equipment in lacrosse, and heading the ball in soccer. Additionally, female hockey players were more likely than male players to experience concussions after contact with the ice surface. The researchers found no differences between male baseball and female softball players for ball/equipment-induced concussions. Similarly, there was no difference observed between male and female basketball players for surface or ball contact.

Furthermore, the pattern of the underlying concussion-causing mechanism was the same regardless of differences between the male and female versions of the sport. It is suggested that sex hormones; decreased neck strength in female athletes, which reduces their ability to withstand external forces; and increased neck and torso strength in male athletes, which allows them to better absorb impact in the upper body versus in the head alone, may play a role in the sex differences in concussion incidence.

To reduce their risk of concussion, Dr. Casey advises women to participate in exercises to enhance neck strength, stiffness and neuromuscular control, as females tend to have deficits in these areas relative to males. “Depending on the sport, exercises and training to optimize technique with high-risk movements, such as heading the ball in soccer, are also critical in reducing concussion risk."

Dr. Casey concluded, "If we truly want to reduce the impact of sports concussions, more research is needed on what causes concussions so that prevention measures can be put in place as well as better reporting of sex and gender differences across sports.”

Jennifer Cheng, PhD, Brittany Ammerman, BA, Kristen Santiago, BA, Bridget Jivanelli, MLIS, all from HSS, were co-authors for both manuscripts. Jo A. Hannafin, MD, PhD, and Emerald Lin, MD, from HSS were co-authors for the CORR and Sports Health publications, respectively.

References:

1) Daneshvar DH, Nowinski CJ, McKee AC, Cantu RC. The epidemiology of sport related concussion. Clin Sports Med. 2011;30:1-17.

2) Harmon KG, Drezner JA, Gammons M, et al. American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med. 2013;47:15-26.

3) Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21:375-378.

4) Bryan MA, Rowhani-Rahbar A, Comstock RD, Rivara F; Seattle Sports Concussion Research Collaborative. Sports- and recreation-related concussions in US youth. Pediatrics. 2016;138:e20154635.