Rehabilitation Considerations in Women with Traumatic Brain Injury

This review highlights the physiological, hormonal, and hematological changes following traumatic brain injury (TBI) in women. Younger women may experience worse outcomes due to higher cerebral pressures, while hormonal changes during menstruation, pregnancy, and menopause further influence TBI recovery. Postmenopausal women face higher risks of osteoporosis and fall-related TBIs. Psychological impacts include higher rates of depression, anxiety, and posttraumatic stress disorder. Social challenges and sexual dysfunction are prevalent, impacting community and vocational reintegration. Tailored rehabilitation addressing these gender-specific factors is crucial for improving outcomes for female patients with TBI across their lifespan.

Key points

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The physiologic/anatomic differences between men and women impact symptomatology, prognosis, and functional outcome following traumatic brain injury (TBI).
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Hormonal fluctuations over a woman’s lifetime can impact TBI susceptibility/outcomes.
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Women have a higher prevalence of post-TBI depression, anxiety, and posttraumatic stress disorder compared to men.
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Women with TBI encounter unique challenges in regards to social/sexual intimacy, self-esteem, and relationships highlighting the necessary social support for successful reintegration into the community.
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It is important to consider domestic violence in the diagnosis and management of TBI in female individuals.

Introduction

Traumatic brain injury (TBI) poses a significant public health concern with unique challenges in both diagnosis and treatment. Female TBI survivors face distinct challenges and barriers, compared to their male counterparts, given the anatomic, hormonal, socioeconomic, and cultural differences. The goal of this study is to enhance the understanding of, and provide guidance for, a more effective/tailored approach to treatment and rehabilitation for the female TBI population.

Physiologic/hormonal changes

Numerous physiologic changes occur after TBI, many of which may impact certain populations more than others. It has been postulated that estrogen has neuroprotective effects through the reduction of neuroinflammation and maintenance of the blood–brain barrier. In a study by Khaksari and colleagues, exogenous estrogen administered after TBI decreased inflammation through reduction of proinflammatory cytokine tumor necrosis factor-alpha. In turn, reduced 17b-estradiol has been shown to contribute to increased brain damage. Following TBI, women have higher levels of testosterone, which suggests an impaired conversion to estrogen. Men, who lack estradiol receptors, tend to show worse outcomes after TBI.

Like estrogen, progesterone and its metabolites may have neuroprotective effects. Progesterone protects glial cells from brain edema, necrosis, apoptosis, and inflammation. ^, Nevertheless, women of childbearing age, when progesterone peaks, tend to have the worst outcomes compared to women of other age groups. The significant changes in progesterone levels during a woman’s menstrual cycle have been implicated as an explanation. The dramatic drop in progesterone following TBI, in addition to the luteal phase of menstruation, causes a noteworthy drop in progesterone leading to worse outcomes, known as the “withdrawal hypothesis.” From this, estrogen and progesterone appear to be influential in neuroprotection after TBI.

The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment double-blinded multicenter clinical trial presented exogenous progesterone to patients with moderate–severe TBI in an effort to improve outcomes. At 6 months after injury, there was no significant benefit in outcome identified with the use of the Glasgow Outcome Scale-Extended (GOSE), Disability Rating Scale, and/or patient mortality rates.

Given the fluctuation of hormone levels throughout the female lifespan, it is crucial to consider the timing of TBI. In a study by Wunderle and colleagues, reproductive-aged female individuals presenting to the emergency department within 4 hours after a mild TBI (mTBI) endorsed greater postconcussive symptoms 3 months after injury, suspected to be related to the disruption of endogenous sex hormone production. Injuries during the luteal phase of menses showed worse quality of life scores at 1 month compared to women injured during the follicular phase or on oral contraceptives (OCP). Women with high levels of progesterone during and after injury (taking OCPs) had outcomes that were similar to those injured during the follicular phase.

The pregnant woman experiences hormonal and hematologic changes such as reduced progesterone and increased clotting factors. In addition, pregnancy leads to physiologic alterations including vasodilation, hemodilution, increased cardiac output, and greater oxygen demand, in an effort to support the growing fetus. Following TBI, pregnant women must be monitored for miscarriage, premature labor, and additional complications including deep vein thrombosis with careful use and consideration of medications.

Menstrual irregularities are well recognized after TBI; however, it remains unclear if hormonal changes play a role in the potential trauma and stress response. In a study of 30 participants, 60% with severe TBI, there was a significant increase in missed cycles and dysmenorrhea after injury compared to preinjury. Although TBI severity had no correlation with amenorrhea duration, there was a significant correlation with posttraumatic amnesia (PTA). For every 1 day increase in PTA, there was a 2% increase in the duration of amenorrhea. Duration of amenorrhea was associated with worse Short Form 12-item Health Survey, GOSE, and Mayo-Portland Adaptability Inventory participation subscale scores (114–344 days) when controlling for severity of injury, age, and time after injury. Prolonged amenorrhea was associated with lower quality of life, global outcome, and community participation. There was no difference in preinjury and postinjury fertility; however, only 4 patients became pregnant.

There is scarce literature on female fertility and pregnancy complications despite the known dysfunction of the gonadal pituitary axis. Anto-Ocrah and colleagues identified a lower incidence of pregnancy among concussed female individuals 2 years after injury compared to orthopedic-injured controls, in addition to lower incidence of pregnancy in patients with menstrual disruption following TBI. Colantonio and colleagues reported a lower percentage of attempted/successful pregnancy after severe TBI compared to matched controls but also monitored premenopausal women age 5 to 12 years after moderate–severe TBI and found no significant difference in fertility between women with TBI and controls. However, women with TBI had fewer children overall. This demonstrates the gap in knowledge of TBI’s effects on fertility.

Interestingly, patients with TBI had higher rate of induction, use of operative vaginal deliveries, unplanned and elective cesarean sections, and were more likely to use epidural and spinal pain-reducing agents. ^, Patients with previous TBI had slightly increased preterm and low birth weight infants, thus putting the infants at risk for requiring intensive monitoring. Adams and colleagues found women with TBI were at a higher risk of placental abruption, infants large for gestational age, and a drastically higher risk of stillbirth. Additionally, there were postpregnancy complications such as pain, fatigue, depression, and cognitive disorder. These findings highlight the need for identifying history of TBI in a female’s obstetric and gynecologic visits as crucial information could significantly impact pregnancy and deliveries. Research is needed to focus on long-term menstrual restoration, fertility, and other menstrual abnormalities, with differentiation between the stress response and direct trauma to the pituitary gland.

Perimenopausal and menopausal women may be at higher risk of detrimental effects after TBI compared to their younger counterparts. Blaya and colleagues observed worse somatic/cognitive symptoms after TBI in women aged 35 to 49 years compared to younger female individuals. This is possibly due to the loss of ovarian function with age causing a decline of estrogen and progesterone levels with resultant increase in chronic low-grade inflammation. Perimenopause is thus an inflammatory state predisposing an exacerbation of neurologic symptoms and worsening secondary injury. Elderly female individuals have hormonal levels near that of male individuals, thus the difference in TBI outcomes in this age group is likely attributable to other factors, such as the increased risk of frailty and osteoporosis secondary to decreased estrogen after menopause.

In addition to hormonal fluctuations, it has been found that cerebral blood flow and neuroinflammation also differ based on sex and age following TBI. In a study by Wagner and colleagues, women had fewer cerebrospinal fluid markers of excitotoxicity compared to male individuals. It was also noted that older women had higher markers of oxidative stress compared to younger women suggesting higher susceptibility to secondary brain damage. Women aged under 50 years had higher intracerebral pressures, brain swelling, and increased mortality at 6 months after injury compared to female individuals aged over 50 years.

Psychological and cognitive changes

Human behavior is a complex, multifaceted phenomenon that is impacted by nature and nurture. Following TBI, structural alterations to the brain, damage to the limbic system, changes to neurotransmitters (serotonin, dopamine, gamma-aminobutyric acid [GABA], glutamate, acetylcholine, and norepinephrine), and the psychological response to injury, place both men and women at an increased risk for neuropsychiatric disorders.

Men and women experience unique clinical outcomes following TBI as a result of differing hormones, anatomy, and functionality of the brain at baseline. ^, Women tend to have more “bilateral representation of verbal abilities and performance IQ than men.” Despite these biologic/structural differences, women also tend to have a unique “growing environment, neurodevelopment, and sociologic attributes” leading to specific neuropsychological outcomes. While gene expression can alter cell protein production through neurotransmitter signal cascades, our environment also has the capability to alter gene expression through the activation/silencing of histones in a phenomenon known as epigenetics.

Mood Disorders

Depression in the general population has a prevalence of 8% to 10%, with a 70% increased likelihood of depression in women compared to men. ^, This higher risk of depression in women has been attributed to “gonadal hormones, early life stressors, reductions in brain volumes, and/or history of abuse in early life.” Of note, the (Diagnostic and Statistical Manual of Mental Illnesses 5 [DSM5]) used to diagnose neuropsychiatric disorders has also been postulated to be better geared toward detecting the depressive symptoms expressed by women.

Within the first year following TBI, 25% to 65% of patients are diagnosed with depression. As this population faces new challenges and adapts to changes in professional life, family life, and the community, the apparent obstacles cause a rise in stress and depressive symptoms. Along with depression comes the increased risk for social isolation, hostility, and cognitive decline that are only amplified by brain injury. Almost a quarter (21-22%) of TBI survivors experience suicidal ideation (SI) placing them at an increased risk for suicide. Data suggests that following a severe TBI, patients have a 3 to 4 time higher relative risk of suicide compared to the general population. Decreased brain-derived neurotrophic factor functioning as well as serotonin/norepinephrine dysregulation has been hypothesized to play a role in depression/suicidality following TBI.

Women with TBI are also more likely to have higher levels of depressive symptoms, perceived stress, and motor/cognitive/somatic symptoms, compared to men following a mild/moderate brain injury. ^, Women not only tend to report depressive symptoms more frequently than men following TBI but also report differing concerns to health care providers. Women report psychosomatic symptoms, including pain and sleep disturbance, whereas men tend to present with cognitive difficulties including concentration issues. ^,

Many differences have been attributed to the unique gender responsibilities and expectations of women. Women with TBI often endorse challenges including an “altered sense of self, issues with power, control, and isolation, as well as an alteration in caring and gender roles.” Many women report feeling vulnerable and share a fear of feeling stigmatized.” Fabricius and colleagues discuss the consequences of no longer being able to “do gender” the way that they performed preinjury. There is “guilt and shame” of inadequately performing gender roles. This study also highlights difficulty in “navigating the health care system from a subordinate social position undermining self-advocacy and patient credibility.” Despite these challenges, Oyesanya and colleagues report that many women continue to care for themselves with little to no assistance, and often, receive poor self-care. Many women have poor long-term outcomes including return to work (RTW) with only 51% of women returning to work compared to 66% of men.

Women, regardless of TBI history, are 4 fold more likely than men to have an anxiety disorder. Generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD) are more commonly seen in the TBI population compared to the general public. Anxiety disorders following TBI have a prevalence of 19% to 50% and tend to emerge earlier following TBI than mood disorders. Albicini and colleagues reported that children who endured moderate/severe brain injuries, particularly female individuals, were more likely to experience psychological effects later in life compared to young male individuals with mild injuries. In this study, patients with a childhood TBI not only had a 5 fold increased likelihood of anxiety disorder later in life but also a 4 fold increased chance of panic attacks, specific phobias, and depression. Anxiety in patients with TBI has been linked to poor social interpersonal functioning, decline in independent living, and is a positive predictor of depression. Anxiety disorders frequently coincide with depression (75% of the time) as well as substance abuse, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, pain disorders, and sleep disorders. ^,

PTSD following TBI is a consequence of the co-occurring psychological trauma of the injury rather than by the biomechanical force to the brain. TBI is a risk factor for the development of PTSD with a rate of 12% to 30% in mild, 15% to 27% in moderate, and 3% to 23% in severe TBI. Patients with mTBI have an increased risk of PTSD by a factor of 1.23, and patients with moderate/severe TBI have an increased risk factor of 1.71. Other risks include lower education, black race, and young age. The lifetime prevalence of PTSD is 10% to 12% in women and 5% to 6% in men. Women seem to have higher subcluster scores for PTSD than men, which could be due to variations in the hypothalamuc-pituitary-adrenal (HPA) axis and oxytocin levels.

Postinjury mania “elevated/expansive or irritable” mood with at least 4 of the following: “inflated self-esteem/grandiosity, increased goal directed activity or agitation, risk taking, decreased need for sleep, distractibility, pressured speech, and racing thoughts” is a less common mood disorder appearing in TBI approximately 1.7% to 9% of the time. While mania is due to excess monoamine transmitters, both depression and mania can occur simultaneously.

Affective Disorders

Affective disorders involve “emotional dyscontrol” and are “brief, discrete episodes of abnormal emotions” that last seconds to minutes. Emotional dyscontrol includes pseudobulbar affect (PBA), affective lability, and irritability. PBA is a form of emotional dyscontrol with “brief, stereotyped, intense, and uncontrollable episodes of laughing or crying.” The prevalence of PBA in TBI has been reported to be 21.4%, 17.5%, and 15.5% at 3, 6, and 12 months, respectively, after injury. Women, and those with left-sided lesions, more commonly present with pathologic crying, whereas pathologic laughing may be more prevalent in men and those with right-sided lesions. Affective lability, becoming “overcome by intense emotions in reaction to stimuli of personal or social import,” has been seen in 28% of mTBI and 33% to 46% early postinjury, and 14% to 62% later postinjury in severe TBI. Irritability, becoming “impatient, annoyed, easily angered,” increases following a TBI with approximately 63%, 69%, and 71% of patients with moderate to severe experiencing this at 3, 6, and 12 months.

Cognition

In general, women perform better than men on verbal memory and perceptual motor speed tasks, whereas men tend to perform better in visual-spatial, mental rotation, and quantitative problem-solving tasks. Following TBI, there is an increased risk of cognitive dysfunction including, but not limited to, attention, processing speed, verbal/working memory, and language/communication. Worsening cognitive abilities result in an increased likelihood of worse social, emotional, physical, and mental health function. Pre-existing conditions including learning disabilities, ADHD, and prior brain trauma may contribute to these cognitive impairments following brain trauma.

Liossi and colleagues reported that women were significantly more impaired in verbal and visual memory following TBI than men. Hui-Ling Hsu and colleagues provided objective fMRI evidence of hypoactivation of the working memory circuit in women, compared to men, following mTBI. Women may have more ongoing working memory issues following TBI compared to men. Women in the study also had more difficulty performing the total digit span compared to men following brain injury. Ma and colleagues reported that men with TBI more commonly had better recovery of verbal tasks while women with TBI showed quicker advances in spatial positioning.

Sleep

In the discussion of mental health following TBI, the bidirectional impact of sleep on psychological/cognitive function is paramount. Following TBI, there is a 46% prevalence in sleep disturbance. Following an mTBI, there is an increased prevalence of insomnia (29%), sleep apnea (25%), hypersomnia (28%), and narcolepsy (4%). Patients with TBI are noted to have a longer sleep onset latency, shorter sleep duration, increased nighttime awakenings, and decreased rapid eye movement (REM) sleep. This poor quality/quantity of sleep leads to increased fatigue and worsened cognitive function/behavioral outcomes.

Social and intimate relationships

Socialization

Due to the effects on cognition and communication, TBI during adolescence and adulthood can result in difficulties with social relationships, leading to isolation. Social intimacy is a fundamental need met via physical and sexual intimacy, friendships, self-conceptualization, and communication. TBI can lead to difficulty with the interpretation of emotions, tones of voice, social cues, emotional lability, impulsivity, inappropriate affect, and slowed or impaired speech all of which can decrease one’s ability to participate socially. Female patients with TBI report higher rates of loss of confidence, depression, anxiety, stress, and loss of trust leading to social isolation and increased risk of physical, sexual, and psychological abuse. There is evidence that female gender confers an emotional recognition advantage following TBI. Pediatric female patients with TBI perform better on facial affect-recognition tasks following injury and improve faster over time as compared to pediatric male patients with TBI. Adult female individuals with TBI significantly outperform adult male individuals with TBI in dynamic emotional recognition tasks; differences in performance were not seen in non-TBI control groups and were not correlated with location of lesions. This is bolstered by findings showing that women experience better social outcomes following TBI compared to men.

With social media use, many individuals with TBI are utilizing technology to build relationships and community. In related studies, participants aged under 65 years, especially those ages 18 to 29 years, were more likely to use social media. ^, There are benefits to incorporating social media and Internet education into therapies, to teach patients the nuances of Internet communication needed to build and maintain healthy social relationships online. Critically, gender-appropriate and developmentally appropriate training should be provided to patients and caretakers regarding online safety, privacy, cyberbullying, and overuse; this is especially important for girls and women with TBI who are at an increased risk of sexual exploitation through manipulative intimate relationships online.

In the care of patients with TBI, it is also important to acknowledge the value of both genetically related and chosen families for social, physical, and emotional connection and support. Challenges in the care of lesbian, gay, bisexual, transsexual, queer/questioning, intersex, and asexual (LGBTQIA+) populations with TBI may arise if sexual orientation or an intimate partner was not known to family prior to injury. Partnerships without an established legal relationship have issues with legal or medical decision-making, leading to increased financial and insurance-related stressors.

Sexual Dysfunction

The barriers to social communication following TBI also influence romantic and sexual relationships. Changes in fatigue, mood, mobility, sensation, and self-image can affect new or pre-existing intimate relationships. Approximately 80% of people resume sexual activity following TBI but 33% report reduced sexual frequency, desire, and function. Women are more likely to report sexual dissatisfaction, dysfunction, and lowered self-esteem as compared to men following TBI. ^, These women commonly report anorgasmia and men report reduced sexual desire. More men receive information about sexual activity after TBI compared to women, but there is no gender difference regarding interest in or perceived importance of sex and intimacy education. Ninety-seven percent of surveyed health care professionals reported that it is important to discuss sexual function following TBI, but only 36% addressed it with patients.

Health care providers should provide education regarding intimacy and sexual activity following TBI. Resources suggest the permission (P), limited information (LI), specific suggestions (SS), and intensive therapy (IT) (PLISSIT) model to assess sexuality in brain injury rehabilitation; this model is commonly used in the field of sex therapy and offers a framework to evaluate and address sexual concerns ( Fig. 1 ). In addition to specific concerns, providers can offer generalized education regarding anatomy, sexual function, sex and intimacy communication, sexuality, sexual and gender identity, relationships, and coping with changes and stressors. In patients reporting sexual dysfunction, consider causes such as medication side effects and physical impairments. Encourage patients to explore both solo and partnered sexual activity as they adjust to changes in mobility and sensation following TBI; women are more likely to be open to or have already tried sexual aids and toys at time of counseling.