Sex and Gender Differences in the Presentation and Treatment of Cerebrovascular Emergencies

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Chapter 7 Sex and Gender Differences in the Presentation and Treatment of Cerebrovascular Emergencies


Tracy Madsen and Karen Furie



Opening Case


EL is a 63-year-old woman with a history of migraine, hypertension, and hyperlipidemia who presented to the Emergency Department with a persistent, severe, right-sided headache and right-sided weakness that had lasted 30 minutes before resolving. EL had frequently experienced right-sided “migraines,” although she had never experienced numbness or weakness with her migraines in the past. On exam, EL was neurologically intact and denied any symptoms other than her headache. As her weakness had completely resolved and her headache seemed similar to prior episodes, EL was treated symptomatically and 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 are expected to diagnose and treat in the acute care setting; it is essential that physicians are aware of the sex and gender differences in the presentation, diagnosis, and treatment of these emergent conditions. In the United States, there are 795,000 new strokes each year, and stroke is the leading cause of disability and the fifth-leading cause of death.1 Headaches, which may be the primary presenting symptom of subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH), account for 3 million Emergency Department (ED) visits in the United States;2 there are many sex and gender differences in the epidemiology, pathophysiology, and course of these conditions. Seizure, a complication of cerebrovascular disease, also shows sex and gender differences relevant to ED providers. The frequency with which ED providers treat patients with neurovascular emergencies as well as the high morbidity and mortality of these illnesses make it essential that EM physicians understand how sex and gender affect disease risk, presentation, management, and outcomes. In this chapter, the term “sex” will be used to discuss differences between men and women that are due to biologic or physiologic processes; “gender” will be used to discuss differences between men and women that may be influenced by social and cultural roles and expectations.



Discussion



Ischemic Stroke



Disease Risk and Prevention


Compared to men, women have a higher lifetime risk of stroke (both ischemic and hemorrhagic) but a lower age-specific incidence of stroke because women have longer life expectancies and are approximately five years older at the time of their initial stroke.3 EM physicians routinely perform risk assessment during the diagnosis and disposition of suspected stroke patients; multiple sex differences in stroke risk factor prevalence should be considered. 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.47 ED providers should also be aware that both diabetes and metabolic syndrome increase the risk of stroke more dramatically in women than in men.3,8 In addition, 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; consequently, it is imperative that women receive antiplatelet therapy for primary prevention of stroke.


Older women have a greater prevalence of atrial fibrillation than older men; therefore, they have more cardio-embolic strokes when compared to men.6,911 It is particularly concerning that in spite of the increased incidence of cardio-embolic strokes in women, women with stroke and atrial fibrillation are less likely to be started on anticoagulant therapy.7,1215 Multiple studies have also shown that women are less likely to be discharged on aspirin after suffering a stroke.1315 EM providers should be especially vigilant in identifying atrial fibrillation in ED stroke patients and appropriately initiating anticoagulation therapy.


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, and the greatest risks occur during the third trimester and the peri-puerperal period.16 Complications of pregnancy lead to a dramatically increased stroke risk during the pregnancy itself; however, the risks can persist for up to 30 years after delivery.17 Conditions associated with increased risk of stroke include preeclampsia, eclampsia, hypertension of pregnancy, and gestational diabetes. For example, women with a history of preeclampsia or eclampsia have almost twice the odds of stroke in the 10 years following their pregnancy.17 Women using exogenous hormones, primarily estrogen, are also at increased risk for primary stroke. Two randomized controlled trials studying estrogen for primary stroke prevention, the Women’s Health Initiative (WIH) Study and the Women’s Estrogen Stroke Trial (WEST), found estrogen to be of no benefit for stroke prevention; women on estrogen in the WIH study were actually at increased risk of stroke.18


Migraine with aura is another important risk factor for stroke in women. Migraine headaches are three times more common in women than in men, and among all patients with migraine, the risk of stroke is more pronounced in women.19 Migraine will be discussed in more depth in the “Migraines/Headache” section of the chapter.



Sex Differences in the Biology and Physiology of Stroke


The etiology of sex differences in stroke is multifactorial, but estrogen is thought to play a major role in the brain’s response to injury. During acute ischemia, in preclinical models, estrogen acts as a neuroprotectant through its actions on neurons, glial cells, and endothelial cells. In animal and cell models, estrogen down regulates inflammation, decreases disruption of the blood-brain barrier, reduces cell death, and causes vasodilation of cerebral vessels; however, these mechanisms have not been confirmed in humans.20 Estrogen’s effects on inflammation and apoptosis are altered in the setting of specific genetic polymorphisms as well, making the pathophysiology even more complex.2023 Despite preclinical knowledge that estrogen acts as a neuroprotectant, there has not yet been research investigating estrogen as a potential beneficial treatment in the acute setting for humans with ischemic stroke. Other preclinical data have revealed additional genetic differences between male and female cells that contribute to different responses to injury and ischemia, even in the absence of sex hormones.20,24 In preclinical models of cerebral ischemia without the influence of sex hormones, novel treatments designed to decrease inflammation seem to have more effect in male cells, suggesting additional mechanisms for sex differences in the brain’s response to injury.20,24,25 For example, in animal models, kappa opioid receptor agonists thought to decrease nitric oxide production in acute ischemic stroke reduce brain infarct volume in males but not in females, even in the absence of endogenous sex hormones.24 Future research should (a) investigate estrogen as a possible ED treatment for acute ischemic stroke and (b) consider that current and future ED therapies for ischemic stroke may have sex-specific benefits and responses.



ED Presentation/Clinical Manifestations


As has been described in acute coronary syndromes, women are more likely to have nontraditional symptoms of stroke including pain, change in level of consciousness, and non-neurologic symptoms.26,27 Women are also more likely to have stroke mimics.2830 There are no known consistent gender differences, however, in the frequency of traditional symptoms including hemiparesis and unilateral sensory changes. In one study that surveyed patients admitted with acute stroke, women were 42% more likely to report at least one nontraditional symptom.27 ED physicians should be aware of the frequency of atypical symptoms in stroke to minimize potential diagnostic and treatment delays.


Since both intravenous (IV) as well as intra-arterial (IA) therapies for ischemic stroke are time sensitive, delay to ED presentation is a critical issue for both men and women. Some studies have shown gender differences in the time between symptom onset and ED arrival, but other data conflict, likely because of methodological differences across studies.3136 Living alone and having an unwitnessed onset of symptoms are associated with longer pre-hospital delays and may be contributors to gender disparities in treatment; these factors affect women more often than men because of women’s longer life expectancies.4,37 Future ED-based research should investigate methods to decrease pre-hospital delays for those living alone or with unwitnessed stroke.



Diagnosis


A non-contrast CT scan is the initial imaging modality of choice for patients presenting with stroke symptoms. Studies of gender disparities in stroke care show that women are less likely to receive rapid brain imaging, which is defined by the American Heart Association and American Stroke Association as non-contrast CT within 25 minutes of arrival.38,39 In a large study of patients in a national stroke registry, women were 15% less likely to have initial brain imaging completed within 25 minutes in unadjusted analysis and 7% less likely to have rapid brain imaging in adjusted analysis.38 Studies have also found that women wait longer for physician evaluation, but these findings have not been replicated consistently.32,40


In addition, 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 but in the past have been less directly relevant to ED providers as compared to neurologists. Relevance to ED providers will increase, however, as ED physicians assume care for patients in TIA observation units.3



Acute Management


In addition to being aware of gender disparities in diagnostic imaging, ED providers should be aware of gender disparities in the use of standard ED stroke treatments. In multiple observational studies, women were less likely to receive IV tissue plasminogen activator (tPA) for acute ischemic stroke.7,31,33,4143 In one meta-analysis of 18 studies, women were between 19% and 30% less likely to receive IV tPA.42 In some populations, gender disparities in the use of IV tPA are attenuated after adjusting for variables including age, National Institutes of Health Stroke Scale (NIHSS), and other eligibility criteria, but these factors do not completely explain the treatment differences.42 Other contributing factors to the discrepancy in the use of tPA may include delays to ED arrival, delays to CT scan, and women’s presentation with nontraditional symptoms; however, the literature suggests that these factors do not completely explain the disparities. Future researchers should investigate the current status of gender disparities in the use of IV tPA. Recent data from national stroke registries have shown increasing rates of tPA use over time, but it is unknown whether gender disparities remain or whether the use of organized stroke care has reduced these disparities.44,45


In addition, there may be gender disparities in the use of intra-arterial therapies in the acute treatment of stroke.45 This area of research is not as well developed as research on IV tPA, but one large study of patients from a national US database revealed that women were 36% less likely than men to receive cerebral angiography.45 This study was limited by a lack of data on the specific intra-arterial procedures performed. Further investigation is necessary to evaluate the presence of disparities in specific intra-arterial therapies including intra-arterial tPA and mechanical thrombectomy.



Treatment Response


Disparities in the use of IV tPA 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 their usual daily activities at 90 days when compared to those receiving placebo, while no such treatment response was found in men.46 Other small studies are supportive of this finding, including one small retrospective study that found that women receiving tPA were more likely to have vessel recanalization on post-stroke imaging.47 There has been speculation that women’s improved response to treatment with tPA may be related to variations in fibrinolysis, but the differences in response to tPA and the factors causing those differences need to be confirmed. If there are in fact genetic, hormonal, or other biologic differences between women and men 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


Gender differences in mortality from stroke vary across age categories, but because of women’s longer life expectancies, the total number of stroke deaths is higher for women than for men. There are no consistent gender differences in case fatality from stroke after adjusting for factors such as age and stroke severity.3


Data on functional outcomes in ischemic stroke are clearer: Women consistently fare more poorly than men. Specifically, women are more likely to be disabled three months after stroke and have limitations in activities of daily living (ADLs) and lower health-related quality of life scores one year after a stroke when compared to men.4,6,12,48,49 Women are also less likely to return home after stroke and more likely to be discharged to chronic care facilities.5,12 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. Some of the factors that may contribute to worse functional outcomes for women may include older age and more comorbidities at the time of the stroke, although these do not completely explain the difference. In the future, investigations of ED diagnostic tools such as prognostic biomarkers or clinical decision rules may help ED providers identify both women and men at risk for poor outcomes.



Hemorrhagic Stroke



Disease Risk/Prevention


Spontaneous intracerebral hemorrhages (ICH) represent only a small portion of strokes overall; approximately 10% to 15% of new strokes are spontaneous hemorrhagic strokes,50 and the incidence of ICH has been estimated to be 246 per 100,000 person-years.51 In one study of 266 patients in China, ICH was twice as common in men as compared to women.52 In a meta-analysis across multiple countries, however, there were no differences in the incidence of ICH between men and women.51 Risk factors for ICH include hypertension, diabetes, and use of caffeine, tobacco, and alcohol. 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 a group of 18- to 49-year-olds.53


Another potential risk factor for ICH that differs by gender is the use of stimulant substances, including ephedrine, a weight-loss supplement used twice as frequently by women.54 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 finding. Its results did, however, suggest an increased ICH risk with higher doses of ephedrine.55 The dose-dependent association between ephedrine and ICH needs to be confirmed in a larger sample of ephedrine users. Similarly, cocaine use is associated with spontaneous ICH, but its use is more common in men. In a small study of patients with ICH, however, there were no gender differences in the proportion of patients who had used cocaine prior to their ICH.56


Finally, preclinical data suggest that certain genetic mutations that increase patients’ risks for poor outcomes after ICH may have sex-specific effects. For example, polymorphisms in apolipoprotein E (APOE), a gene that influences brain injury and inflammation in ICH, have sex-specific effects on the outcomes of ICH in rodents.57



Management/Treatment Response


Few studies have focused on differences in responses to specific treatments for ICH by gender, including blood pressure control and surgical intervention. Despite this lack of data, inferences based on surrogate measures demonstrate that women are more likely to have limitations in care after having an ICH. For example, in one study, women with ICH were more than three times more likely to have do not resuscitate (DNR) orders initiated within 24 hours of diagnosis as compared to men, even after adjusting for factors such as age and volume of hemorrhage.58 In the same study, women were more likely to be admitted to the floor for comfort care and were less likely to be admitted to the intensive care unit.


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, but some data suggest a difference between women and men in the response to lowering blood pressure. In one study of more than 100 patients, a more rapid decrease in blood pressure in the first 24 hours after ICH was more strongly associated with increased mortality in men as compared to women.59



Outcomes


ICH is a condition with high morbidity and mortality; in-hospital mortality rates can reach 25%, and 30-day mortality rates are often as high as 50%.50,52 No consistent evidence shows whether there are true gender differences in outcomes after ICH. 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.58,60,61 In another study that included only patients with supratentorial bleeds, men and women had the same mortality rates.62 Some data even suggest lower mortality in women.63 Diversity in the populations, as well as other confounding factors, may help explain the conflicting findings in the relationship between sex and ICH outcomes. One study of these outcomes revealed a significant interaction between sex and age, with women older than age 70 having a higher risk of poorer outcomes.64 There are large knowledge gaps in the area of gender and ICH, and future research relevant to the acute care of ICH patients should focus on differences in risk factors, presentation, management, and prognosis.



Subarachnoid Hemorrhage (SAH)



Disease Risk/Prevention


The prevalence of both unruptured intracranial aneurysms (UIA) and subarachnoid hemorrhage (SAH) are higher in women than men; women older than age 50 are two to three times more likely to have SAH when compared to men.6567 Furthermore, ruptured intracranial aneurysm is the most common etiology of SAH, and after the sixth decade of life, women are twice as likely to have an UIA.65 The reason for the increased prevalence of both SAH and UIA in women is unclear. One hypothesis is that estrogen protects against the development of aneurysms by increasing vessel collagen deposition and strength, and postmenopausal women lose this protective effect.67 This is supported by data showing that HRT reduces SAH risk.6769 Conversely, the use of combined oral contraceptives increases the risk of SAH, but this is not true across all studies.68,70 The risk of SAH has not been found to be elevated during pregnancy.68


SAH has many risk factors in addition to sex, including hypertension, advanced age, non-white race, family history of SAH, autosomal dominant polycystic kidney disease, smoking, and alcohol use. The risk of SAH is greater for women who smoke than for men who smoke.69,71 In one study, cigarette smoking increased the risk of SAH by a factor of nine in women but only by three in men.69 ED providers must be aware of these risk factors when evaluating patients with symptoms suggestive of SAH and should include the risk of SAH in their counseling message to smokers.



Natural History


The risk factors for rupture of an UIA include aneurysm size, patient age, and smoking. Between 20% and 50% of cerebral aneurysms will rupture; the annual risk of rupture of UIA ranges from 0.05% per year to 1.5% per year.72,73 No published data address the influence of sex on the natural history of unruptured aneurysms. An increased prevalence of aneurysms in women is likely the major contributor to the increased incidence of SAH.67 Of those with SAH, women are more likely to have multiple aneurysms and internal carotid aneurysms, but the size of the ruptured aneurysm does not differ by sex.67



Clinical Manifestations/ED Presentation


Symptoms of SAH include thunderclap headache, exertional onset, emesis, syncope, meningismus, and photophobia.72 It is unknown whether there are gender differences in the presenting symptoms of SAH, although data suggest that the frequencies of coma and decreased Glascow Coma Scale (GCS) are similar in men and women.67,74 One small study showed no difference in rates of sentinel headaches between men and women with SAH.75 Overall, women with headaches are more likely to use the ED, but it is not known if this is true in patients with UIA or SAH. In addition to having an increased incidence of SAH, women have higher rates of migraine and chronic headache, making the diagnosis of SAH potentially more difficult. In studies of SAH misdiagnosis, though, where the most common incorrect diagnoses were migraine and tension headache, women were not more likely to be misdiagnosed.76



Diagnosis


The diagnostic standard for identifying SAH is a non-contrast CT scan followed by a lumbar puncture and neurosurgical consultation.72 It is not known whether there are gender differences in the use of either CT or spinal tap as diagnostic approaches in patients with suspected SAH. Small datasets suggest no gender differences in sentinel headaches, but this should be confirmed with future research, given the risk of missed SAH diagnosis if CT and lumbar puncture are not performed.75,76 Additional recommended imaging for those with suspected SAH includes CT angiography and/or MR angiography. There are no sex-specific recommendations in use of imaging, and it is unknown whether gender differences exist in the use of these imaging modalities. This is an important direction for future research, as there are known differences in prevalence of SAH between men and women.65



Acute Management


Management of ruptured aneurysms includes admission to an intensive care unit, prevention of vasospasm, and definitive treatment for the aneurysm with either surgical or endovascular therapy.72 Men are less likely than women to receive early definitive therapy for SAH, and those with delayed surgical and/or endovascular treatments are more likely to have disability following SAH.67,77 The reason for the delayed therapy in men remains unclear, although the higher rates of both internal carotid aneurysms and multiple aneurysms in women may contribute to the delay.67,77



Clinical Outcomes


Research has not demonstrated clear differences in mortality from SAH by sex, although the data remain conflicting.67,78 Age is a predictor of mortality, and women with SAH are typically older; this should be taken into account by ED providers. Women, however, report a lower quality of life following SAH as defined by difficulty performing daily activities, depression, and anxiety, even after adjusting for SAH severity.79,80 This may be because more women live alone, a finding in other stroke types, but the etiologies of these results have not been confirmed in studies of SAH.



Migraines/Headache



Disease Risk/Prevention


Women have a higher risk of most primary headache syndromes including migraine and tension headache.8184 Specifically, migraine is two to three times more common in women than in men, affecting 12% to 25% women versus 5% to 9% of men.8184 Women are also at higher risk for various types of secondary headache syndromes including temporal arteritis, cerebral venous thrombosis, idiopathic intracranial hypertension, trigeminal neuralgia, and temporal mandibular disorders.8587


ED providers must also be aware that chronic headache syndromes increase the risks for other medical, somatic, and psychiatric conditions that include stroke, cardiovascular disease, fibromyalgia, depression, and anxiety.83 Of note, migraine with aura has a stronger association with cardiovascular comorbidities including stroke, myocardial infarction, and death from cardiovascular disease as compared to migraine without aura.19,88 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 including hypertension and diabetes, while women with migraine were more likely to have fibromyalgia, depression, and anxiety.89 Another study, however, found that women with migraine with aura were more than twice as likely to have had an ischemic stroke, but no association was found between stroke and migraine in men.88 The exact pathophysiology of the association between migraine and ischemic events may be related to endothelial dysfunction that occurs with chronic migraine, but this needs association will require further confirmation.90 Finally, ED providers must be aware of constellations of stroke risk factors that occur in women: Women who have migraine, smoke cigarettes, and use oral contraception are 10 times more likely to have an ischemic stroke compared to those without migraine who do not use cigarettes or hormonal contraception.91



Natural History


Approximately 5% of patients with episodic or intermittent migraine will develop chronic or daily migraine, which leads to more frequent ED visits and more lost days of work and school.92 The rate of progression to daily headache seems to be similar in women and men.92


Other aspects of the natural history of migraine, however, differ between women and men because of fluctuating female sex hormones. Both elevated estrogen and hormonal fluctuations in estrogen trigger migraine.83 Menstruation is often a time when migraines are more frequent, more severe, and longer lasting; this increased frequency is seen more commonly in migraines without aura.83,93 Some women even suffer from “menstrual migraine,” headache present only during menstruation. In women who suffer from migraine without aura, migraines become less frequent during pregnancy and menopause, when sex hormone levels are more stable.94 In pregnant women presenting to the ED who have increased headache frequency or a new type of headache, alternate diagnoses including preeclampsia should be considered.



Clinical Manifestations/ED Presentation


Among migraine patients, the frequency of presentation to the ED differs by gender; women migraineurs visit the ED almost five times more frequently than men.2 Overall, some estimate that women account for 80% of US health care costs for migraine.2 Clinical aspects of migraine also differ by gender. Women report migraines that are more frequent and last longer and are more severe when compared to men’s reports.83 Women more commonly report a visual scotoma preceding the migraine, as well as more nausea, photophobia, and phonophobia.83,95 Migraines that mimic stroke are of special interest to ED providers. Hemiplegic migraines are about three times more common in women than men, but elucidating sex differences in other associated headache symptoms that may mimic stroke will require further research.96



Diagnosis


Migraine is primarily a clinical diagnosis. The ED evaluation of acute headache, however, often includes diagnostic testing to exclude other etiologies of headache including SAH and cerebral venous thrombosis. ED providers should consider the sex differences in prevalence of these alternative diagnoses when making a diagnosis of migraine.



Acute Management/Treatment Response


Men are three times less likely to seek treatment for headaches, 54% less likely to receive prescription medications for headache, and 37% less likely to use preventative medications for migraine.97 Reasons for these disparities are unclear but may be related to gender differences in response to pain or a greater frequency of undiagnosed migraines in men. There are clear gender differences in recommended headache treatments during pregnancy and during menstrually triggered headaches. Some of the medications used to treat acute migraine have possible teratogenic effects that must be considered before they are prescribed to pregnant patients with migraine. Acetaminophen and metoclopramide are first-line options for pregnant patients, although sumatriptan has also been used.98 Optimal treatment of menstrual migraine differs from that of typical migraine; if severe menstrual migraine is suspected, referral to a specialist and treatment with oral hormones to induce amenorrhea should be considered.99


Gender differences exist in the response to some medications used for acute headache in the ED, but more research is needed. For example, in one study women were more likely to have recurrent migraines following treatment with triptans for acute headache; nevertheless, this pattern of ostensible recurrence may have been a result of longer-lasting, more severe migraines in women.100 Both animal and human studies have shown that women experience less analgesia and more side effects from opiates including morphine. Narcotics for primary headache syndromes, however, should be avoided in both men and women.101,102



Clinical Outcomes


Functional outcomes differ by gender with women reporting more lost productivity and disability from their headaches. As reported by the World Health Organization, migraine is the 12th most common cause of disability in women but the 19th most common when the data for men and women were combined.83 On average, women with migraine miss 8.3 days of work per year compared to 3.8 days for men, and work-related disability as a result of migraine is worse for menstrual migraines than non-menstrual migraines.103,104



Seizure/Status Epilepticus


Many aspects of seizure disorders manifest sex and gender differences relevant to ED providers. Overall, the prevalence of seizure is higher in men than in women, probably because of higher prevalence of trauma, substance use, stroke, and central nervous system infection in men.105 Idiopathic generalized seizure disorder, a subtype of seizure with a purely genetic cause, however, is more common in women.105 In addition, psychogenic non-epileptic seizures, or pseudo-seizures, are more common in women than men and require different treatment strategies than true epileptic events.106


Hormones affect seizure frequency as many women experience exacerbation of their epilepsy during menstruation. Catamenial epilepsy is defined as a twofold increase in seizure frequency during menstruation or around the time of ovulation and is thought to occur in up to one-third of women with epilepsy.107 In addition to the typical seizure triggers such as sleep deprivation and alcohol use, hormonal fluctuation should be considered by ED providers treating women with seizures.


Status epilepticus, a sustained period of seizure activity and common ED emergency, requires urgent treatment. Status epilepticus is more common in men, as is mortality from it.105 The increased mortality probably results from the greater frequency of seizure triggers in men, including trauma, but it may also be related to the effects of sex hormones on the seizure threshold.105 Management of status epilepticus is similar in men and women, but ED physicians should consider how sex and gender might affect treatment response. Many antiepileptic medications (AEDs) are weight based, and there is a clear association between sex and weight. Inaccurate dosing may lead to continued seizure activity and/or oversedation with a need for acute airway protection. In addition, emergency providers must consider potential teratogenic effects of common AEDs.108 Finally, ED providers must counsel their women patients with epilepsy who are taking AEDs that these medications decrease the effectiveness of oral contraceptives as they stimulate the metabolism of both estrogen and progesterone. Drug interactions between AEDs and contraceptives can also lead to lower plasma concentrations of AEDs if they are taken concomitantly and thus to more seizures.109


The differential diagnosis of seizure and status epilepticus in pregnant women must include eclampsia. Women with a history of epilepsy are also more likely to have complications of pregnancy including eclampsia, placental abruption, and preterm labor.110,111 These women are more likely to have an increase in seizure frequency during pregnancy.112 Seizures from eclampsia must be considered in all pregnant women from week 20 of gestation up to 4 weeks postpartum, even in those without hypertension or other classic signs of preeclampsia such as headache and visual changes.113,114 Patients with suspected eclampsia should be managed with blood pressure control, magnesium, and AEDs.


Future research should investigate potential sex differences in the effectiveness of antiepileptic medications, particularly those used to manage status epilepticus. Further research also needs to focus on the possibility that AED dosing may need to be adjusted during times of hormonal fluctuation such as menopause.

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Feb 13, 2017 | Posted by in EMERGENCY MEDICINE | Comments Off on Sex and Gender Differences in the Presentation and Treatment of Cerebrovascular Emergencies

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