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Sex & Gender in Acute Care Medicine

Sex & Gender in Acute Care Medicine. 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

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Sex & Gender in Acute Care Medicine

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

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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

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