Gender Differences in Neurological Emergencies Part II: A Consensus Summary and Research Agenda on Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There is strong evidence that gender and sex play an important role across the spectrum of TBI, from pathophysiology to clinical care. In May 2014, Academic Emergency Medicine held a consensus conference “Gender-Specific Research in Emergency Care: Investigate, Understand, and Translate How Gender Affects Patient Outcomes.” A TBI working group was formed to explore what was known about the influence of sex and gender on TBI and to identify gaps for future research. The findings resulted in four major recommendations to guide the TBI research agenda.

Traumatic brain injury (TBI) is a common problem threatening U.S. public health. According to the Centers for Disease Control and Prevention (CDC), each year there are approximately 2.4 million U.S. hospital emergency department (ED) visits, hospitalizations, or deaths resulting from TBI. In addition, between 2007 and 2009 there was a yearly average of 1.1 million office-based visits and 84,000 outpatient department visits with TBI-related diagnoses either alone or in combination with other injuries.¹ It is estimated that there are at least 3.5 million TBI victims in the U.S. annually. The estimated cost (both direct and indirect) is between $60 and $221 billion per year, with up to 5 million persons living with disabilities related to TBI.¹ Historically, TBI has disproportionately affected young males, due to their high-risk behaviors. Among persons aged 20 to 24 years, the mortality rate after TBI in males is four times higher than in females.² However, the epidemiology of TBI is changing; falls now replace motor vehicle collisions as a primary documented mechanism of injury. In addition, more women than ever before are involved in sports, military combat, and other high-risk activities associated with TBI, leading to a rise in the proportion of female TBI victims.^3–5

METHODS

After evaluating the current literature, the authors (all emergency medicine researchers) proposed an agenda for future research. The proposed research questions were then discussed and voted on by participants in the 2014 Academic Emergency Medicine consensus conference neurological emergencies working group (see footnote for list of participants; please refer to the executive summary for details⁶).

TRAUMATIC BRAIN INJURY

Genotypical and phenotypical sexual differences are well described in nature, but the profound effects of gonadal hormones and their metabolites on the human brain have only recently been recognized. In 2001, the Institute of Medicine acknowledged the important influence of sex on brain function.⁷ Several brain-related disorders have been observed to vary in risk and prevalence by sex. For example, there is a fourfold greater risk of dyslexia and a 10-fold greater risk of attention deficit disorder in males when compared to females, while major depression is associated with a twofold greater risk and anorexia nervosa a 13 times greater risk in females when compared to males. Baseline norms in brain physiology and anatomy are also different between males and females.⁸ Sex differences have been described for cognitive (e.g., learning, memory, executive functioning, speed of processing, attention) as well as emotional domains, in both the injured and the uninjured brain. Sex differences have been notable for the effects on recovery following TBI.^9,10

Sexual Dimorphism in TBI

Sexual dimorphism is the result of genetically coded differences on the gonadal chromosomes (XX/XY), hormonal exposure throughout development, and environmental influences. These interactions are complex, but are important to consider in research and patient care. Chromosomal and/or selective genetic expression lead to changes at the proteomic and cellular level that can influence both the underlying mechanisms of injury and responses to treatment. The sex of the patient can have significant effects on enzyme activity, receptor density, protein binding, pharmacokinetics, metabolism, and the outcomes of the injury cascade. As with any other observed genetic effect, inattention to sex differences in planning drug development and failure to account for such sex differences in clinical trials could result in erroneous results and forfeiture of potentially important treatments.

What is meant by “sex difference” (beyond that which may be superficially obvious)? McCarthy et al.⁸ propose operational definitions for the different types of sex differences. In this classification system, Type I “sexual dimorphism” comprises traits observed almost exclusively in one sex or the other, such as courtship behaviors. Type II, or “sexual difference,” is expressed along a continuum, with one sex having more of the trait than the other (e.g., pain thresholds, fear, and anxiety). Type III is “sex convergence and divergence.” In this category the behavior of males and females appears the same at some point, either converging from dissimilarity toward similarity, or the reverse, but in either case the underlying mechanisms driving that behavior are different. Such differences can result in different functional responses and outcomes in response to an individual’s history, disease conditions, and environmental demands (e.g., problem-solving strategies, response to stress, disease, or injury).

Differences in hormone levels throughout the cycle of development from birth to old age are among the most fundamental distinctions between the sexes. During development, exposure to estrogens, progesterone, testosterone, or other gonadal/hypothalamic hormones shape the phenotype of gender. There is clear evidence that hormones also play an essential role in brain development, maturation, and aging. As the fetus grows, the hormonal milieu organizes the regions of the brain that ultimately control sexual, emotional, and cognitive behavior; these varied levels of hormone expression result in both transient and permanent differences in neural circuitry and function. Further influences occur during puberty and adolescence. Later in life, the ebb and flow of hormones continue to influence cellular function and human behavior. Importantly, a growing body of evidence shows that hormones also play role in injury susceptibility, as well as recovery. For example, almost 200 publications describe the potent neuroprotective effect of progesterone when administered after neuronal injury.¹¹ The final reports from two human phase III clinical trials examining progesterone’s effectiveness as a treatment for acute TBI are pending.

The external environment has also been found to play a role in observed sex differences. For example, females and males often respond differently to stressful stimuli. In turn, stress can result in the release of hormones and other stress reactants that temporarily, or in some cases permanently, alter neuronal circuitry and behavior. As an example, posttraumatic stress disorder and anxiety are well-described neuropathologies influenced by sex and gender. Societal approaches to gender can also influence treatment and outcome. Treatment disparities, such as decreased admission rates post-TBI for black females compared to black males and their white counterparts, have been documented.¹²

Despite prior basic science research and growing awareness in the medical and public health spheres, there remains significant ambiguity about sex differences in clinical TBI. Furthermore, the relative advantage of sex in TBI morphology, response to treatment, outcome, and recovery is only beginning to be studied. In this article we will provide recommendations for future investigation based on current knowledge gaps in evidence-based research and the perceived importance of the role of sex in TBI. We will limit our scope to non–sports-related injuries, as TBI sustained during athletic competition is discussed by another article in this issue.¹³

Recommendation 1: Encourage the Inclusion of Both Sexes in Basic Science TBI Research and Promote the Exploration of Sex Differences as a Part of the Standard Rubric for Preclinical Evaluation of Therapeutics

After years of clinical research and huge resources expended, no therapeutic agent has translated from the preclinical phase into successful treatment for TBI. Over 50 phase III multicenter clinical trials have failed, despite promising and successful animal studies.¹⁴ While numerous reasons have been postulated, differences in sex may play an important role in response to treatment. Differences in metabolism, pharmacokinetics, receptor distribution and activity, enzyme activity, and ongoing hormonal interactions may affect whether a particular intervention exhibits important neurological properties. The National Institute of Mental Health concluded in a report in 2011 that there are profound sex differences in the brain and a paucity of research examining the effect of these sex differences.¹⁵ The NIH has recently proposed that scientists and clinicians consider incorporating the effects of gender into their programs of basic and clinical research. Despite the recognition that sex plays an important role in brain-related diseases and injury, strikingly little sex difference research currently exists.

Historically, the study of an investigational agent for TBI has focused on one sex (most often male animals). Of the hundreds of compounds studied as a potential treatment for TBI, most have not undergone rigorous evaluation for sex-specific interactions; however, fluctuations in hormonal levels can directly influence drug metabolism and pharmacokinetics.

Most preclinical studies of TBI are in rodents using a mechanical device to directly impact or penetrate the exposed brain parenchyma. This model is thought to simulate injuries that occur in blunt impact injury, motor vehicle collision, or fall from height. Although most of the earliest experiments ignored sex, TBI research is now beginning to include both male and female animals in experiments. Efforts include using ovariectomized female animals to reduce the potential effects of circulating sex hormones on functional and morphological outcomes.

Interest in hormones as a treatment for TBI was initially sparked by Attella et al.,¹⁶ who observed improved functional outcomes and decreased edema in pseudopregnant rats after TBI (when compared to normal-cycling females rats with similar injuries). The investigators speculated that the observed difference could be attributed to higher levels of progesterone in the pseudopregnant state. Follow-up studies by Roof et al.^17–21 confirmed that administration of progesterone could attenuate cerebral edema and improve functional outcomes in both male and female rats subjected to TBI, thus providing a framework for future research.

A growing body of literature demonstrates that there may be important sex differences in the inflammatory cascade, genomic and proteomic signaling mechanisms, recovery profiles, response to stressors, and treatments in the preclinical arena.^22,23 It is becoming more apparent that sex differences in TBI outcomes require careful attention when evaluating new pharmacological or even physical rehabilitation treatments. Sex differences have been described on both the baseline and the postinjury performance of neuropsychiatric tests, quality-of-life measures, and other outcome measures (females score better on some and males on others), and in the case of females, menstrual phase at time of injury remains an important area of clinical investigation.^23,24 In one recent study of TBI patients, increased levels of estradiol and testosterone in both men and women were related to increased mortality and worse global outcomes.²⁵ In addition, protracted symptoms post-TBI, such as chronic headache and depression, have also been shown to be higher in females. Still, given the limited number of papers on the topic, clinical studies of the influence of sex on TBI mortality tend to be ambiguous. Most of the data come from secondary analyses of existing databases and retrospective reviews, resulting in inconclusive and conflicting conclusions. Given the overwhelming number of preclinical studies focusing only on males, more prospective research is needed to delineate whether sex, hormonal state, or environmental issues play a role in sex differences in brain injury outcome and repair.

Many questions remain at both the basic science and the clinical level. Preclinical research should be conducted with attention to the potential influence of sex on pathophysiology and treatment.

Preclinical and Clinical Questions

1. What are the cellular mechanisms for sex differences in response to treatment (e.g., genetic, metabolic, hormonal)?

2. If different pathophysiological and recovery mechanisms exist, can they be exploited to provide novel treatments for acute TBI?

3. Does sex influence current and future therapies (metabolism, dose/pharmacokinetics, response to treatment, safety, sociology)?

4. Are there sex differences in response to combination therapies for TBI?

Recommendation 2: Promote, Facilitate, and Conduct Research Examining Sex-specific Risk Factors, Mitigation Strategies, and Interventions for TBI

Identifying risk is a key part of injury prevention and mitigation. Risk factors for TBI differ between the sexes. Males are more likely to engage in high-risk behaviors such as extreme sports and are involved in motor vehicle collisions to a greater degree than their female counterparts. However, the sports concussion literature suggests that after controlling for the sport played, concussion rates may actually be higher in female athletes.²⁶ These data suggest that preinjury characteristics and behavior patterns may at least somewhat explain the observed epidemiological differences between sexes in mild TBI. Phenotypical factors such as female stature, neck strength, and body habitus have been hypothesized to increase risk for TBI related to sports.^27,28 Outside of sport-related TBI, behavior patterns that have been associated with gender may also be associated with injury. For example, females tend to be passengers in motor vehicles more often than males, and their location in the vehicle can play an important role in the risk and severity of injury.²⁹

Most prior research evaluating recovery after mild TBI has focused on epidemiological descriptions of postconcussive complications and the development of prediction algorithms to eventually mitigate or prevent those risks. Only recently has the relationship of premorbid, sex-specific characteristics been investigated as risk factors in mild TBI. Sports concussion data indicate that even prior to head injury, women report greater symptoms associated with concussion (headache, fatigue, sleep difficulty, irritability, sadness, nervousness, feeling more emotional, feeling slowed down, and difficulty concentrating).³⁰ Observational studies of ED patients with mild TBI found that women are more likely to report headache symptoms prior to as well as after head injury.³¹ Preinjury emotional disorder, high intelligence quotient (IQ), and posttraumatic stress disorder are also associated with increased likelihood of developing postconcussion syndrome at 3 months (odds ratio = 5.76).³² These findings suggest that the higher rate of acute postconcussion syndrome symptoms found in women may be due to premorbid sex characteristics rather than differences in trauma-related outcomes.

Further complicating comparisons between the sexes is research showing that women are more forthcoming with mild TBI symptoms and are more likely to seek medical care.³³ The reliance of self-report in mild TBI research leads to inherent selection bias in study designs and limits the generalizability of data results. Further study in this area is needed to identify and discriminate differences in gender-specific risk factors and mitigation strategies for TBI.

Risk, Injury Prevention, and ED Management Questions

1. What are the risk factors for experiencing TBI and risk factors for having a poor outcome after TBI, and how are these distributed by sex?

2. What ED-based interventions could be deployed to mitigate sex-specific TBI risk?

3. Does the changing epidemiology of TBI and the evolving risk profile among females require a change in prevention strategy, screening, and treatment?

4. Are the mechanisms and extent of injury and recovery the same between the sexes?

5. Are there sex differences, independent of socioeconomic and race for types and quantity of tests ordered, admission rates, and referral rates from the ED?

Recommendation 3: Define and Deploy Relevant Sex-specific Outcome Measures and Therapeutic Strategies

Clinical observational studies demonstrate conflicting results regarding the relationship between sex and outcome after TBI. A meta-analysis published in 2000 showed that females tend to do worse on a variety of brain injury outcomes (death, hospital length of stay, postinjury symptoms, development of postconcussion syndrome, lost work days) after TBI.³⁴ However, other studies illustrate that there is either no difference or improved performance.^35,36

In mild TBI studies, both sports and nonsports literature report a significant association between female sex, prolonged recovery,^37,38 and postconcussion syndrome^{10,34,39–43} after mild TBI. Other investigators have found no association between sex and postconcussive complications.^44,45 Moreover, even in studies where sex was predictive of worse outcome, important variables such as stress, anxiety, pain, antidepressant use, depression, and social support were significantly associated with similar brain injury outcomes. Discriminating between the effect of sex on postconcussion outcomes, in comparison to other dynamic and confounding variables is difficult; some authors conclude that women and men should be assessed differently after TBI.¹⁰

Neurocognitive outcome measures frequently used to evaluate treatments often have different baseline setpoints between sexes. Even simple outcome measures to assess memory, such as the Morris Water maze, are confounded by the different swim strategies of female versus male rodents. In humans, performance on neuropsychological tests is known to be different between sexes at baseline. Females tend to perform better on verbal memory tests and measures of attention, while males perform better on nonverbal and spatial tasks.³⁰ Recently, however, this assumption has been challenged by Zuckerman et al.⁴⁸ who reported no significant differences in neuropsychological outcomes at baseline or after mild TBI in male and female high school athletes.

Without the benefit of baseline assessments, the use of normative data from neuropsychological tests to diagnose and manage TBI patients is a loose approximation at best, biased by sex-specific differences in pre- and postinjury functional performance. Similarly, comparisons between the sexes using other outcome measures, such as the Glasgow Outcome Scale score, modified Rankin Scale, and composite postinjury symptoms scores (e.g., postconcussive symptoms checklist) are relatively blunt, nonspecific assessments of overall TBI recovery. Sex differences need to be taken into account and outcome measures need to be selected that either normalize across genders or can be adjusted appropriately between sexes.

Outcomes Questions

1. What outcome measures are influenced by gender? Do differences persist over time?

2. What ED assessment and monitoring tools should be tailored for sex differences?

3. Should hormonal status of the female be taken into consideration in determining most appropriate treatment and when evaluating postinjury functional outcomes?

4. Are there specific biomarkers (physiological or imaging) that may better predict pattern of injury and response to treatment between genders?

5. What sex-specific social support, rehabilitation, and environmental factors are important for improved recovery?

6. What is the frequency of male versus female patients seen and discharged from the ED for TBI that are referred to concussion and head injury-specific rehabilitation clinics?

Recommendation 4: Promote the Standardization of Case Definitions for Mild TBI and Concussion and Facilitate the Utilization and Collection of Standard Data Measures to Improve Ongoing Surveillance and Meta-analysis Efforts

In 2003, the CDC Mild Traumatic Brain Injury Working Group called for more accurate estimations of the incidence, prevalence, and burden of mild TBI,⁴⁹ yet over a decade later, consensus on TBI definition, prevalence, and common data standards remain elusive. Systemic meta-analyses are often limited due to wide variability in study design, data collection elements, and outcomes. The overall complexity of TBI patients is further confounded by variability in age, Glasgow Coma Scale (GCS) scores, preexisting comorbidities, medication use, mechanism of injury, access and timing of care, and clinical management strategies. The lack of a standardized case definition of mild TBI or concussion makes cross-comparison of data sets nearly impossible.

“Concussion” is a term used most often in the sports medicine literature, but is also used interchangeably with mild TBI and “minor head trauma.” While all concussions are a form of mild TBI, not all mild TBIs are concussions. Mild TBI cases include patients with GCS scores of 13 to 15, while “concussion” is assigned to individuals with GCS scores of 15. This is a critical distinction because although still considered “mild” brain injury, patients with GCS scores of 13 or 14 after head injury have a higher risk for intracranial lesions, requirement for emergent neurosurgical intervention (9.5% vs. 0.8% in individuals with GCS 15),⁵⁰ and worse outcomes compared to individuals with GCS 15, leading some investigators to propose categorizing GCS 13 as “moderate” brain injury.”^51–54 Concussions represent a specific subtype of mild TBI in which gross neurological function remains intact or is impaired briefly but spontaneously resolves. Computed tomography is, by definition, negative for traumatic pathology. The indiscriminate use of “mild TBI” interchangeably with “concussion” leads to significant heterogeneity in cohort studies and has prevented cross-comparison of data outcomes screening tools.

Surveillance for mild TBI is likewise problematic. Current surveillance systems rely on ED visits and hospitalizations in parallel with acute care and ambulatory clinic presentations, with very little overlap between the two data sets. Further preclinical information, such as mechanism of injury (e.g., location in a vehicle) or environment condition (fall from a specific height), is often not available or not documented in the medical chart.

To assist with the standardization of diagnosis and injury surveillance, the CDC TBI Working Group has developed recommendations for “conceptual” and “operational” case definitions of mild TBI. These definitions are based on clinical presentation and abstracted health codes, respectively.⁴⁹ Additionally, the CDC commissioned a group of experts in 2002 to discuss “the future of TBI registries and data systems.” Among several recommendations, the group advocated for the development of “a common taxonomy for collection of key surveillance and follow-up data.”⁵⁵ Unfortunately, the translation of these recommendations into clinical research practices is lacking. The ultimate goal would be to operationalize expert recommendations based on the literature to further promote and facilitate epidemiological research.

Definitions Research Questions

1. How should “concussion” and “mild TBI” be defined and reported in future TBI research efforts? What are the most accurate and reliable measures of concussion and mild TBI?

2. What elements of an ED medical record are vital (e.g., key data points) for surveillance standards during data abstraction?

SUMMARY

Sex differences likely play an important role in traumatic brain injury, but are understudied and poorly understood. At the Gender-Specific Research in Emergency Care Consensus Conference 2014, the traumatic brain injury working group reviewed the literature, discussed the state of traumatic brain injury gender research, and made four major recommendations to guide future traumatic brain injury research: 1) encourage the inclusion of both sexes in basic science traumatic brain injury research and promote the exploration of sex difference as a part of the standard rubric for preclinical evaluation of therapeutics; 2) promote, facilitate, and conduct research examining sex-specific risk factors, mitigation strategies, and interventions for traumatic brain injury; 3) define and deploy relevant sex-specific outcome measures and therapeutic strategies; and 4) promote the standardization of case definitions for mild traumatic brain injury and concussion and facilitate the utilization and collection of standard data measures to improve ongoing surveillance and meta-analysis efforts. If these steps are taken, major advances could be made in traumatic brain injury research and improved care of our traumatic brain injury patients.