Sex & Gender in Acute Care Medicine

Sex & Gender in Acute Care Medicine Chapter 7: Gender Differences in Cerebrovascular Emergencies

Chapter 7: Gender Differences in Cerebrovascular Emergencies Tracey Madsen Karen Furie

Opening Case • A 63-year-old woman presents to the Emergency Department with a severe, persistent right-sided headache • Associated with right-sided weakness that lasted for 30 minutes before resolving • She had a history of right-sided “migraines,” although she had never experienced numbness or weakness in the past

Opening Case • On exam, she was neurologically intact • She denied any symptoms other than headache • As her weakness had resolved and her headache seemed similar to prior episodes, she was treated symptomatically • Discharged home with primary care follow-up

Introduction • Cerebrovascular emergencies are among the most life-threatening and time-sensitive conditions that Emergency Medicine (EM) physicians encounter in the acute care setting • In the US, 795,000 people experience their first stroke each year • Stroke is the leading cause of disability and the third-leading cause of death

Introduction • It is essential that physicians are aware of the sex and gender differences in the epidemiology, pathophysiology, and course of these conditions • In this chapter, “sex” will be used to discuss differences between men and women that are due to biologic or physiologic processes

Introduction • “Gender” will be used to discuss differences between men and women that may be influenced by “socially constructed roles, behaviors, activities, and attributes” (WHO definition)

Ischemic Stroke • Compared to men, women have a higher lifetime risk of both ischemic and hemorrhagic stroke • But a lower age-specific incidence of stroke because women have longer life expectancies and are approximately 5 years older at the time of their initial stroke • Multiple sex differences in stroke risk factor prevalence should be considered

Ischemic Stroke • Women are more likely to have hypertension and atrial fibrillation as risk factors for stroke • Men are more likely to have large artery atherosclerosis, diabetes, and myocardial infarctions • ED providers should also be aware that both diabetes and metabolic syndrome increase the risk of stroke more dramatically in women

Ischemic Stroke • There are known sex differences in the utility of antithrombotic medications for primary stroke prevention • Aspirin is effective at preventing stroke in women but not in men • It is imperative that women receive antiplatelet therapy for primary prevention of stroke

Ischemic Stroke • Older women have a greater prevalence of atrial fibrillation than older men • As a result, they have more cardio-embolic strokes when compared to men • In spite of this risk, women are less likely to be started on anticoagulant therapy • EM providers should be especially vigilant in identifying atrial fibrillation in patients with stroke and initiating anticoagulation therapy

Ischemic Stroke • Stroke risk factors specific to women include pregnancy and its complications, hormonal contraception, and hormone replacement therapy (HRT) • Stroke causes approximately 12% of deaths during pregnancy • The greatest risks occur during the third trimester and the peri-puerperal period

Ischemic Stroke • Conditions associated with increased risk of stroke include: • Preeclampsia • Eclampsia • Hypertension of pregnancy • Gestational diabetes • Women with a history of preeclampsia or eclampsia have almost twice the odds of stroke in the 10 years following pregnancy

Ischemic Stroke • Women using exogenous hormones are also at increased risk for primary stroke • Migraine with aura is another important risk factor • Migraine headaches are three times more common in women than men • Among all patients with migraines, the risk of stroke is more pronounced in women

Sex Differences in Stroke • Estrogen is known to be neuroprotective • In animal and cell models, estrogen down regulates inflammation, decreases disruption of the blood brain barrier, and causes vasodilation of cerebral vessels • These mechanisms have not been confirmed in humans • There has not yet been research investigating estrogen as a potential treatment for humans with acute ischemic stroke

Sex Differences in Stroke • In models of cerebral ischemia without the influence of sex hormones, novel treatments designed to decrease inflammation seem to have more effect in male cells • Future research should investigate estrogen as a possible ED treatment for acute stroke • Current and future ED therapies for ischemic stroke may have sex-specific benefits

Clinical Manifestations • Women are more likely to have nontraditional symptoms of stroke • Including pain, change in level of consciousness, and non-neurologic symptoms • Women are also more likely to have stroke mimics • In one study of patients admitted with acute stroke, women were 42% more likely to report at least one nontraditional symptom

Clinical Manifestations • Since both intravenous and intra-arterial therapies for stroke are time sensitive, delay to ED presentation is a critical issue for men and women • Some studies have shown gender difference in time to ED arrival but other data conflict • Living alone and having an unwitnessed onset of symptoms are associated with longer pre-hospital delays

Clinical Manifestations • These factors affect women more often than men because of their longer life expectancies • Future ED-based research should investigate methods to decrease pre-hospital delay in people living alone or with unwitnessed stroke

Diagnosis • Non-contrast CT is the initial imaging modality of choice for patients with stroke symptoms • Studies of gender disparities in stroke care show that women are less likely to receive rapid brain imaging • Defined by the American Heart Association and American Stroke Association as a non-contrast CT within 25 minutes of arrival

Diagnosis • Women are less likely to have echocardiography and carotid ultrasound performed during their stroke evaluation • These are both important tools in the evaluation of stroke etiology • Relevance to ED providers will increase as ED physicians assume care for patients in TIA observation units

Acute Management • ED providers should also be aware of gender disparities in the use of stroke treatments • In multiple observational studies, women were less likely to receive IV tissue plasminogen activator (tPA) for acute ischemic stroke • In one meta-analysis, women were between 19% and 30% less likely to receive tPA

Acute Management • In some populations, gender disparities in the use of tPA are attenuated after adjusting for age, NIHSS, and other eligibility criteria • But these factors do not completely explain the treatment differences • Recent data from national stroke registries have shown increasing rates of tPA use over time but it is unknown whether gender disparities remain

Treatment Response • Disparities in tPA use have been especially notable in light of data suggesting that IV tPA is more beneficial to women than men • A 2006 pooled analysis of patients from tPA clinical trials showed that women treated with tPA were 10% more likely to be able to carry out daily activities at 90 days compared to those receiving placebo • No such treatment response was found in men

Treatment Response • There has been speculation that women’s improved response to tPA may be related to variation in fibrinolysis but this needs to be confirmed • If there are sex differences that impact the effectiveness of tPA, it is imperative that these be identified so ED therapies can be used with greater specificity and efficacy

Clinical Outcomes • There are no consistent gender differences in case fatality from stroke after adjusting for factors such as age and stroke severity • However, data on functional outcomes in ischemic stroke are clearer • Women consistently fare more poorly than men • Specifically, women are more likely to be disabled 3 months after a stroke

Clinical Outcomes • Women have lower health-related quality of life scores 1 year after stroke compared to men • They are less likely to return home and more likely to be discharged to chronic care facilities • Studies of gender differences in functional outcomes after stroke typically include both treated and untreated patients and do not consistently adjust for use of tPA

Hemorrhagic Stroke • Spontaneous intracerebral hemorrhages (ICH) represent only a small portion of strokes overall • Approximately 10% to 15% of new strokes are spontaneous hemorrhagic strokes • In a meta-analysis across multiple countries, there were no differences in ICH incidence between men and women

Disease Risk/Prevention • Risk factors for ICH include hypertension, diabetes, and use of caffeine, alcohol and tobacco • These factors may increase risk differentially in men versus women • For example, both hypertension and excessive alcohol use increased the risk of ICH in men more significantly than in women in one study

Disease Risk/Prevention • Another potential risk factor that differs by gender is the use of stimulants, including ephedrine, a weight-loss supplement used twice as frequently by women • Multiple case series suggest that ephedrine use is associated with ICH • But one large retrospective study of more than 700 ICH patients did not confirm this

Disease Risk/Prevention • Its results did suggest an increased ICH risk with higher doses of ephedrine • This dose-dependent association needs to be confirmed in a larger sample of ephedrine users • Similarly, cocaine use is associated with ICH but its use is more common in men

Management/Treatment Response • Few studies have focused on differences in response to specific treatments by sex or gender • Inferences based on surrogate measures show that women are more likely to have limitations in care after having an ICH • In one study, women were more than 3 times as likely to have do not resuscitate orders initiated within 24 hours of diagnosis as compared to men

Management/Treatment Response • In the same study, women were more likely to be admitted for comfort care and less likely to be admitted to the ICU • Blood pressure management is a mainstay of therapy for ICH • It is unknown whether there are gender differences in the treatment of blood pressure in the setting of acute ICH

Outcomes • ICH is a condition with high morbidity and mortality • No consistent evidence shows whether there are true gender differences in outcomes • In studies that include patients with sub- or supratentorial hemorrhages, women are more likely to have cerebellar hemorrhages, death within seven days, and worse functional outcomes

Outcomes • In another study that included only patients with supratentorial bleeds, men and women had the same mortality rates • Some data even suggest lower mortality in women • Diversity in the populations, as well as other confounding factors, may help explain conflicting findings with regard to outcomes

Subarachnoid Hemorrhage (SAH) • The prevalence of both unruptured intracranial aneurysms (UIA) and SAH are higher in women than men • Women >50 are 2-3 times more likely to have SAH compared to men • Ruptured intracranial aneurysm is the most common etiology of SAH • After age 60, women are are twice as likely to have a UIA

Subarachnoid Hemorrhage • Reason for this increased prevalence of SAH and UIA in women is unclear • One hypothesis is that estrogen protects against aneurysm by increasing vessel collagen deposition and strength • Postmenopausal women lose this protection • This is supported by data showing that HRT reduces SAH risk

Subarachnoid Hemorrhage • Oral contraceptives have been shown to increase SAH risk but not across all studies • SAH has many other risk factors, including: • Hypertension • Advanced age • Non-white race • Family history • Autosomal dominant polycystic kidney disease • Alcohol and/or tobacco use

Subarachnoid Hemorrhage • The risk of SAH is greater for women who smoke than for men • In one study, smoking increased SAH risk by a factor of 9 in women but only 3 in men • ED providers must be aware of these risk factors when evaluating patients • ED providers should include the risk of SAH in smoking cessation counseling

Natural History • The risks factors for rupture of a UIA include aneurysm size, patient age, and smoking • Between 20% and 50% of cerebral aneurysms will rupture • No published data addresses the influence of sex on the natural history of unruptured aneurysms • Increased prevalence of aneurysm in women is likely the major contributor to increased incidence of SAH

Clinical Manifestations • Symptoms of SAH include: • Thunderclap headache, exertional onset, emesis, syncope, meningismus, photophobia • It is unknown whether there are gender differences in presenting symptoms • One small study showed no difference in rates of sentinel headaches between men and women

Clinical Manifestations • Overall, women with headaches are more likely to use the ED • It is unknown if this is true in patients with UIA or SAH • Women also have higher rates of migraine and chronic headache • Potentially making the diagnosis of SAH more difficult • However, in studies of SAH misdiagnosis, women were not more likely to be misdiagnosed

Diagnosis • The diagnostic standard for identifying SAH is a non-contrast CT scan • Followed by a lumbar puncture (LP) and neurosurgical consultation • It is not known whether there are gender differences in the use of CT or LP in patients with suspected SAH • Additional recommended imaging includes CT angiography and/or MR angiography

Diagnosis • There are no sex-specific recommendations in use of imaging • It is unknown whether sex difference exist in the use of these modalities • This is an important direction for future research

Acute Management • Management of ruptured aneurysm includes ICU admission, prevention of vasospasm, and definitive treatment with surgical or endovascular therapy • Men are less likely than women to receive early definitive therapy for SAH • Those with delayed treatment are more likely to have disability following SAH

Acute Management • The reason for the delayed therapy in men remains unclear • Higher rates of both internal carotid aneurysms and multiple aneurysms in women may contribute to the delay

Clinical Outcomes • Research has not demonstrated clear differences in mortality from SAH by sex • Age is a predictor of mortality and women with SAH typically older • Women do report a lower quality of life following SAH even after adjusting for SAH severity • This may be because more women live alone, a finding in other stroke types, although this has not been confirmed for SAH

Migraines/Headache • Women have a higher risk of most primary headache syndromes • Migraine, specifically, is 2-3 times more common in women than in men • Women are also at higher risk for many types of secondary headache syndromes, including: • Temporal arteritis, cerebral venous thrombosis, idiopathic intracranial hypertension, trigeminal neuralgia, and temporal mandibular disorders

Migraines/Headache • ED providers must also be aware that chronic headache syndromes increase the risks for other medical, somatic, and psychiatric conditions • Of note, migraine with aura has a stronger association with stroke, myocardial infarction, and death from cardiovascular disease than migraine without aura

Migraines/Headache • There are also sex differences in the comorbidities associated with migraine • One study found men with migraine were more likely to have comorbid medical conditions, include hypertension and diabetes • Women with migraine were more likely to have fibromyalgia, depression, and anxiety

Sex & Gender in Acute Care Medicine