Neurologic Disease in Women - part 6 ppsx

Eclampsia is a significant risk factor for stroke dur-ing pregnancy in the first 6 weeks postpartum 40 and accounts for about half of the case-related strokes 41.. A recentstudy of strok

NEUROLOGIC DISEASE IN WOMEN 232

Breast-feeding is, in general, encouraged for women

with epilepsy taking AEDs The benefits of

breast-feed-ing are believed to outweigh the risks associated with

fur-ther exposure of the neonate to AEDs (96,98) Exceptions

to this recommendation are made when the infant

appears lethargic or irritable, or if there is feeding

diffi-culty or poor weight gain Further discussion regarding

the concentrations of individual AEDs in breast milk is

provided in Chapter 5

Concerns are mounting that exposure to AEDs in

utero may confer long-lasting neurodevelopmental or

neurocognitive deficits Fetal head growth retardation

and low intelligence (89,99) has been associated with the

maternal use of AEDs Although prospective trials are

lacking, retrospective studies show that children exposed

in utero to valproate in monotherapy or polytherapy are

more likely to require special educational resources (100)

Prospective studies are under way to better define the

neu-rodevelopmental risks of AED exposure to the

develop-ing brain

Recent efforts by the American Academy of

Neu-rology (96) and the American College of Obstetric and

Gynecologic Physicians (97) to highlight those issues

rel-evant to the care of women with epilepsy will enhance

clinician familiarity with these diverse health concerns

These professional efforts, as well as a large-scale

pro-fessional and public initiative by the Epilepsy Foundation

of America, provide the medical professional with

infor-mation and educational resources to enhance the

com-prehensive care of women with epilepsy

RESOURCES AVAILABLE FOR HEALTH CARE

PROVIDERS AND WOMEN WITH EPILEPSY

Epilepsy Foundation of America

4351 Garden City Drive

Landover, MD 20785-2267

Telephone: 800-EFA-1000

Web site: www.efa.org

The Antiepileptic Drug Pregnancy Registry

Genetics and Teratology Unit

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47 Webber MP, Hauser WA, Ottman R, Annegers JF

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51 Dansky LV, Andermann E, Andermann F Marriage and

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NEUROLOGIC DISEASE IN WOMEN 234

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66 Farquhar et al 1994.

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96 American Academy of Neurology Quality Standards Subcommittee Practice parameter: management issues for women with epilepsy (summary statement).

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97 American College of Obstetric and Gynecologic Seizure

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99 Gaily E, Kantola-Sorsa E, Granstrom ML Intelligence

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oxemia of pregnancy (preeclampsia,

or toxemia gravidarum) is a drome that is characterized by preg-nancy-induced hypertension (PIH),proteinuria, and edema after week 20 of pregnancy

syn-Although this complex disorder can involve a number oforgan systems, its clinical presentation varies Patients maypresent with multisystem failure that results in oliguria;

disseminated intravascular coagulation (DIC); rhages into the liver; Hemolysis, Elevated Liver enzymesand Low Platelets (HELLP) syndrome; pulmonary edema;

hemor-and a number of neurologic problems The neurologic sentation frequently includes confusion, headaches, visualhallucinations (from which the name eclampsia arises), andblindness With the appearance of seizures or coma, thepatient’s condition is that of eclampsia No constant rela-tionship exists, however, between the various neurologicmanifestations and the severity of preeclampsia Seizuresand ischemic events, for example, may appear with fewheralding signs of preeclampsia (1)

pre-Worldwide, preeclampsia and eclampsia are majorcauses of perinatal morbidity and death (2) In the UnitedStates, 6 to 8% of pregnancies have preeclamptic complica-tions (3) This affects 5 to 10% of whites, 15 to 20% of blackprimigravidas, and up to 30% of twin pregnancies (4) Theincidence of preeclampsia also has other demographic dif-ferences It is most frequently seen in poorly nourished, nul-liparous woman, multiparous women over the age of 35

with extrauterine pregnancies, and women with multiplepregnancies or hydatidiform mole The American College ofObstetricians and Gynecologists proffers criteria forpreeclampsia-eclampsia shown in Table 16.1 (5)

CLINICAL CHARACTERISTICS

Hypertension

Preeclampsia is characterized by hypertension Althoughblood pressure values may vary, guidelines suggest a sys-tolic pressure of 140 mm Hg or above; or 90 mm Hg orabove, diastolic (5) A blood pressure above 160 to 180

mm Hg systolic, or 110 mm Hg diastolic during bed restsignals severe preeclampsia in the presence of proteinuria

of (.5 g/24 h), or 3+ to 4+ by dipstick (5) The diagnosis

is usually established by elevation in blood pressure on twooccasions separated by 6 hours, but not infrequently,eclamptic seizures supervene over a shorter period and mayoccur in the absence of edema or proteinuria

Edema

Normal pregnancy frequently results in edema of the legs.The edema of preeclampsia, however, is more marked indegree and affects not only the legs but also the handsand face

NEUROLOGIC DISEASE IN WOMEN 236

Proteinuria

Proteinuria in preeclampsia is defined as the

accumula-tion of more than 300 mg of protein in a 24-hour urine

collection, whereas severe preeclampsia induces >5 g/24h

proteinuria (3+ to 4+ by dipstick)

Seizures

The exact nature of eclamptic seizures remains unclear,

but increasing evidence suggests that focal neuronal

excitability arises from cortical damage produced by a

number of neuropathologic changes in preeclampsia and

eclampsia These include vasospasm with ischemia,

hem-orrhages of various sizes, and cerebral edema; these are

discussed later Epileptic seizures usually remit with

delivery of the baby, treatment of the hypertension, or

the use of magnesium sulfate Focal seizures from a

vari-ety of etiologies may secondarily spread, resulting in a

generalized tonic-clonic seizure Because of the other

neurologic abnormalities that may appear during

preg-nancy that may also result in seizures, consideration

should be given to the differential diagnosis of

peripar-tum seizures (Table 16.2)

Seizures in eclampsia may be focal or generalized

tonic-clonic Although they usually appear before

birth, they frequently occur during or shortly after

child-birth In some patients, seizures occur more than a week

postpartum, and there are case reports of seizures

occur-ring up to 26 days postpartum (6,7) One series noted that

44% of eclampsia cases occurred postpartum; 12%

within 48 hours, but 2% more than a week postpartum

(8) In another series, late postpartum seizures (thoseoccurring >48 hours postpartum) accounted for up to16% of cases of eclampsia (9) whereas others reported a48% incidence for the same period (4) Late onset eclamp-sia may present without the heralding features ofpreeclampsia such as edema, proteinuria, or even hyper-tension (10,11) If untreated, approximately 10% ofwomen with eclampsia have further seizures (12)

Visual Problems

Visual symptoms are common They may involve ent parts of the visual axis from the retina to the occipi-tal cortex There may be hypertension-induced retinalarteriolar dilatation, papilledema, occlusion of the cen-tral retinal artery, and vasospasm (13) Retinal edema,hemorrhages, and exudates (Figure 16.1) as well as reti-nal detachment can occur Although some permanentvisual changes may occur, most symptoms resolve withcontrol of hypertension or in the postpartum period Inthe posterior visual pathway, there may be microinfarc-tions, microhemorrhages, and edema of the visual cor-tex with cortical blindness (14) (Figure 16.2)

differ-Other Clinical Features

Other problems with severe preeclampsia include a fall inurine output to below 400 mL/day; cyanosis or pulmonaryedema and ARDS, upper abdominal quadrant pain,thrombocytopenia, or hemolysis (HELLP syndrome)

TABLE 16.1

Clinical Manifestations of Severe Disease in

Patients with Pregnancy-Induced Hypertension

Blood pressure 160–180 mm Hg systolic, 110 mm

Hg diastolic

Proteinuria 5/g/24 h (normal ,300 mg/24 h)

Elevated serum creatinine

Grand mal seizures (eclampsia)

Pulmonary edema

Oliguria ,500 mL/24 h

Microangiopathic hemolysis

Thrombocytopenia

Hepatocellular dysfunction (elevated alanine

aminotransferase, aspartase aminotransferase)

Intrauterine growth retardation or oligohydramnios

Symptoms suggesting significant end-organ

involve-ment: headache, visual disturbances, or epigastric or

right-upper quadrant pain

Adapted with permission from the Committee on Terminology of

the American College of Obstetricians and Gynecologists, ACOG

technical bulletin, #219, January 1996, p 2.

TABLE 16.2

Causes of Seizures around Pregnancy

Epilepsy Central stimulants (e.g., Toxins amphetamines cocaine);

theophylline Metabolic Hyponatremia, hypocalcemia, problems hypoglycemia, hyperglycemia Cerebrovascular Cerebral infarction

problems Cerebral edema

Cerebral hemorrhage Cerebral venous sinus thrombosis Subarachnoid hemorrhage Infections/ Bacterial

infestations Viral

Parasitic infestations HIV

Space-occupying Benign and malignant tumors lesions Arterovenous vascular

malformations Cerebral abscess

ECLAMPSIA 237

PATHOPHYSIOLOGY

Myriad pathophysiologic mechanisms have been invoked

to explain the changes in preeclampsia-eclampsia, and it is

probable that a number of these mechanisms contribute to

the symptom complex (15–17) (Table 16.3) Some derive

from the physiologic changes that occur during pregnancy,

with changes in immunologic tolerance between maternaltissues and paternal elements in the fetus, morphologic arte-rial changes in the uteroplacental bed, vasodilatation fromprostaglandin secretion, and abnormalities of platelet aggre-gation Particular fetal or uterine factors are not essential forthe appearance of preeclampsia because it may occur fol-lowing extrauterine or molar pregnancies Data suggest thatthe vascular damage in the preeclamptic period arises fromthe interactions of neutrophils and activated macrophages,T-cell lymphocytes, and the interaction between comple-ment, coagulation systems, and platelets Endothelial dam-

FIGURE 16.1

Fluorescein retinal angiography in eclampsia showing

sub-retinal leakage (Reproduced with permission from Oliver M,

Uchenk D Bilateral exudative retinal detachment in

eclamp-sia without hypertensive retinopathy Am J Ophthalmol

1980;90:794 Copyright by Ophthalmic Publishing Company.)

FIGURE 16.2

The occipital poles of a brain showing multiple cortical petechial

hemorrhages that may cause cortical blindness (Reproduced

with permission from Sheehan HL, Lynch JB Pathology of

tox-aemia of pregnancy Edinburgh: Churchill Livingston, 1973.)

TABLE 16.3

Mechanisms Suggested as Possible Etiologies for Preeclampsia

Abnormal Placentation

Abnormal trophoblast invasion Increased trophoblast mass Abnormal uteroplacental location

Immunologic Dysfunction

Primarily a disease of primigravida Immunologic complexes in placenta and various organs

Immunologic complexes in maternal serum Multisystem involvement

Coagulation Abnormalities

Abnormal prostaglandin metabolism Disseminated intravascular coagulopathy Platelet activation and consumption Low antithrombin III

Essential fatty acids deficiency

stein PJ, Stern BJ, (eds.) Neurological disorders of pregnancy, 2nd

ed Mount Kisco, NY: Futura Publishing Co., Inc., 1992.

NEUROLOGIC DISEASE IN WOMEN 238

age may be produced by platelet consumption and increased

platelet aggregation (18) and hypertension

Pregnancy-induced hypertension appears to be a

multifactorial process No single mechanism can account

completely for the rise in blood pressure; however,

multi-organ vasospasm associated with endothelial dysfunction

appears to be a significant contributor Additionally, the

increased vascular responsiveness to catecholamines and

angiotensin adversely affect renal function, with

conse-quent proteinuria, hypoalbuminemia, edema, and

hyper-tension A shrinking intravascular volume may result in

decreased cardiac output and renal function, adversely

affecting utero-placental profusion Multi-organ,

includ-ing central nervous system (CNS) morbidity, may arise

from the HELLP syndrome, consisting of a number of

clinical abnormalities, including hemolysis, elevated liver

enzymes, and low platelets

With the invasion of the muscular layer of the uterus

by the endovascular trophoblast during the first trimester,

deactivation of autonomic innervation of the spiral

arter-ies occurs; these result in vascular changes in the inner third

of the myometrium (19,20) The spiral arteries then

trans-form into uteroplacental arteries, which release nitric oxide

(NO) (21,22) Nitric oxide produces a pressure,

low-resistance, uteroplacental circulation In preeclampsia,

however, an impaired transformation of the spiral

arter-ies of the nonpregnant uterus to uteroplacental arterarter-ies

occurs, only the decidual layers of the uteroplacental

arter-ies are involved in the transformation, and fewer arterarter-ies

are produced (23) There is failure of NO production,

immunologic maladaptation of nondilating spiral arteries,

increasing inactivation of NO, and further

vasoconstric-tion from oxygen free radicals and lipid peroxides The

balance is shifted between the vasoconstrictor and

platelet-aggregation promoting effects of platelet-derived

throm-boxane-A2 (TXA2) (24), and the vasodilator and

platelet-aggregation inhibiting effects of prostacyclin (PGI2)

elaborated in the maternal vascular walls Decreases in

PGI2 and NO decrease platelet activation and the

pro-duction of circulating serotonin Mild increases in

sero-tonin in mild preeclampsia may restore vascular PGI2 and

NO release, in turn improving uteroplacental perfusion by

increasing perfusion pressure Thus, an increase in

mater-nal blood pressure satisfies the vascular needs of the fetus

Further increases in serotonin result in increased

vaso-constriction and platelet aggregation, however,

worsen-ing the pathologic process Other abnormalities include

the renin-angiotensin-aldosterone system (25,26) and the

prostacyclin-thromboxane-A2 systems (15)

Increasing evidence suggests a mitochronidal defect

that impairs cytotrophoblastic differentiation and

inva-sion (27) This involves the mitochondrial mutation of the

nuclear or mitochondrial genomes, resulting in mutant

mitochondria in the daughter cells These impaired

mito-chondria in syncytial tissues are subject to high metabolic

demands The mitochondrial defects are thought toimpair normal placentation in pregnancy Higher inci-dences of the disease exist in immediate blood relatives,especially in a line from mother to daughter (28,29) Suchlack of concordance could be explained by differing pro-portions of wild-type and mutant DNA segregating totwins or siblings, thus engendering different cytoplasmicphenotypes (30) These genetic differences are linked tochanges in function and morphology, with loss of cristae

in the mitochondria, indicating a systemic metabolic function associated with a decrease in cytochrome oxi-dase (31) The same chromosomal locus for pregnancy-induced hypertension is found for the mitochondrialproduction of endothelial NO synthetase (32)

dys-More recent work by Redman and colleaguesunderscores the probable contribution of an intravas-cular inflammatory response to the preeclamptic process(33) Excessive inflammatory stimulation proportional

to placental size (in keeping with the finding thatpreeclampsia is more frequently seen in multiple gesta-tions and increasing placental size near term), is thought

to activate leukocytes and stimulate proinflammatorycytokine production In this fashion, the increasing pla-cental size, with its concomitant proinflammatory role,generates signals that may stimulate a more generalizedinflammatory response in the mother This balance maydecompensate possibly from excessive placental stimu-lus or excessive maternal response As part of the nor-mal pregnancy process, inflammatory response is shared

in the states of normal pregnancy and preeclampsia, andthe pathophysiologic processes are thought to reflectexaggerated responses in an otherwise normal preg-nancy The problem lies, therefore, not with pre-eclamp-sia per se, but the physiology of pregnancy itself Inter-current toxic, genetic, septic, or other factors may impairthe normal downregulation of particular components ofthe immune activation system that normally keep theinflammatory reactions in check This dynamic repre-sents the normal maternal-fetal “genetic conflict” (34).Hypertension, which accounts for many of the neu-rologic features seen with the resulting hypertensiveencephalopathy and vasospasm, however, is not univer-sally present in all patients with eclampsia Hence, thereliance placed by a clinician on hypertension to make thediagnosis might result in a delay in management, even withpatients manifesting other signs of preeclampsia, but with-out significant increase in blood pressure HELLP syn-drome, with its associated coagulopathy, may result inmajor neurologic sequelae and intracranial hemorrhagewithout hypertension (35) or indeed, proteinuria or edema

Cerebral Pathology

A major contributing factor to the cerebral pathology inpreeclampsia-eclampsia is cerebral edema supervening

ECLAMPSIA 239

when the cerebral blood pressure exceeds the limits of

cerebral autoregulation Cerebral autoregulation is

main-tained by the modulation of cerebral arteriolar resistance

in the face of the arterial pressure of the blood supply to

the brain This mechanism maintains the independence of

cerebral perfusion pressure from the systemic arterial

blood pressure With the relative hypertension seen in

preeclampsia, the autoregulation of the cerebral

circula-tion is impaired, resulting at one extreme in

hyperten-sion and encephalopathy and at the other extreme in

cere-bral hypoperfusion (36,37) The ensuing damage to

precapillaries and capillaries, disruption of the “tight

junctions,” and the extravasation of red cells and proteins

in the perivascular spaces contribute to the blood–brain

barrier disruption at particular areas of risk, which are

the border zones between the larger cerebral arteries

There is local vulnerability to cortical petechiae,

microin-farctions, and pericapillary brain hemorrhages Some of

these changes are due to the regional differences in the

control of cerebral blood flow (38), with regions of

alter-nating arteriolar dilatation and constriction resulting in

capillary breakdown, extravasation of blood elements,

increased platelet consumption, and the triggering of

coagulation with fibrin deposition (39) When the

pro-tective precapillary arteriolar vasoconstriction fails, the

increase in blood pressure exerts a direct effect on the

cap-illary bed, resulting in hemorrhages

The neurologic manifestations of

preeclampsia-eclampsia, although sudden, may be transient Progressively

severe headache lasting days may occur with visual

distur-bances, hallucinations, or even the perception of “flashing

lights” (from whence the name eclampsia is derived) Even

the occipital blindness can be reversible The pathologic

processes may progress, presenting clinically with focal

neu-rologic deficit, confusion, seizures, or even coma The visual

system may be affected by retinal arteriolar dilatation or

spasm, retinal hemorrhages and exudates, or even retinal

detachment Papilledema may result from raised

intracere-bral pressure The posterior cortical watershed zones, less

protected by sympathetic vasoconstrictor tone, are

partic-ularly subject to microhemorrhages and infarctions, as well

as to subcortical gray–white zone edema Any part of the

cerebral hemisphere can be involved, however, resulting, for

example, in aphasia or pareses

Eclampsia is a significant risk factor for stroke

dur-ing pregnancy in the first 6 weeks postpartum (40) and

accounts for about half of the case-related strokes (41)

PATHOLOGY

Pathologic changes affect various parts of the neuraxis

(14) Aside from cerebral edema, hemorrhaging may occur

in the subarachnoid, subcortical, and intraparenchymal

areas Small- to medium-sized infarctions can occur in the

cerebral cortex, corona radiata, basal ganglia, and stem Metabolic and hypertensive encephalopathy are alsoseen Although damage predominantly affects the water-shed zones in the parieto-occipital regions, vascularchanges may also affect the parietal and frontal lobes.Many of these processes may be a source of seizures.Subarachnoid hemorrhages may occur in circum-scribed areas of cerebral cortex, whereas larger hemor-rhages can be seen in the hemispheres, basal ganglia, andpons (14,42) Hemorrhages in the gray matter may thenerupt into the ventricles or subarachnoid spaces (14).Smaller hemorrhagic areas, in the form of sulcal petechiaeand microinfarctions appear in the precapillary and cap-illary areas as well as around arterioles (14,42–43) Theseresult in splitting of the elastic fibers, necrosis of the arte-rial wall, and edema Deep-seated hemorrhages in thecorona radiata, basal ganglia, and brainstem may be seenalong with larger cortical hemorrhages (14,43) A recentstudy of stroke in pregnancy, with eclampsia given as aleading cause, showed the incidence of intraparenchymalhemorrhages and ischemic strokes to be similar (hemor-rhages usually account for approximately 15% of strokes),suggesting that pregnancy increases the risk of cerebralhemorrhage (44) Diffuse cerebral edema is associated with

brain-a rise in cerebrospinbrain-al fluid pressure brain-and pbrain-apilledembrain-a (45)

On postmortem, there may be marked central or verse herniation as well as gyral flattening (14,42)

trans-A number of organ systems can be damaged because

of the pathologic vascular changes that occur inpreeclampsia and eclampsia Platelet consumption andactive coagulopathy may occur in various organs There

is an increasing literature of angiographic and nial Doppler studies attesting to the vasospastic compo-nent in cerebral pathology (46–48) (Figure 16.3)

transcra-DIAGNOSIS

Preeclampsia is characterized by variable weight gain,pregnancy-induced hypertension, and edema An exces-sive weight gain is defined as more than 2 pounds perweek Pathologic edema is that which involves the handsand face However, seizures may appear before the edema,weight gain, or proteinuria (10,11,49) Standard defini-tions of preeclampsia and hypertension are given in Table16.1 The proteinuria may appear late in the course ofpreeclampsia Neurologic features frequently includeheadache and photophobia, pain in the upper abdomi-nal area, and brisk reflexes (Table 16.4)

LABORATORY STUDIES

Preeclampsia-eclampsia is a clinical diagnosis Someaccompanying laboratory abnormalities are the raised

NEUROLOGIC DISEASE IN WOMEN 240

serum creatinine and uric acid that occur in

approxi-mately 60% of patients In approxiapproxi-mately one-third or

fewer patients, a fall in platelets below 150,000 per mm3

may occur; hemolysis from disseminated intravascular

coagulation; and elevation of liver enzymes (HELLP

syn-drome), an entity that is associated with significant

mater-nal morbidity (49,50)

IMAGING

In most cases of eclampsia, particularly those without

focal neurologic findings, computed tomography (CT)

head scans are usually normal, but magnetic resonance

imaging (MRI) may still show T2-weighted

abnormali-ties in watershed zones Patients with focal neurologic

findings and atypical cases warrant investigation to

address neurologic complications Various series of CThead scans have shown abnormalities in 29% to 75% ofeclamptic patients (51) These changes include cerebraledema; hemorrhages in the brain stem, subependymalregions, subarachnoid spaces, and parenchymal areas;and infarction (52) Other large series have reported noabnormalities (12,53) MRI scans have documentedhypodensities in the basal ganglia, border zone ischemia,and focal cerebral edema, which usually resolve on sub-sequent scanning (49, 54,55) (Figure 16.4) In eclampsia,there may be the characteristic multifocal curvilinearabnormalities at the gray–white junction of the poste-rior watershed zones Such reversible angiopathy hasbeen further documented using angiography (Figure16.5), single photon emission computerized tomography(SPECT), and transcranial Doppler ultrasound (TCD)(46,48,54–57)

Most patients under obstetric care with eclampsia

do not get head MRI or CT scans, and it is only after focalneurologic findings appear that a neurologic consult andimaging are requested Women with focal neurologic find-ings warrant further investigation, but without it, clinicaldiagnosis usually leads to treatment with magnesium sul-fate and expeditious delivery of the baby

FIGURE 16.3

Left common carotid artery injection shows spasm of

periph-eral branches of left anterior and middle cerebral arteries.

Arrows point to beaded appearance of these vessels Paucity

of peripheral branches is shown (Reproduced with

permis-sion from Trommer BL, et al Cerbral vasospasm and

eclamp-sia Stroke 1988;19:326–329.)

TABLE 16.4

Clinical Features Preceding Eclampsia

Clinical Features Percent of Patients

MRI scan Hyperintense areas in the posterior parietal area

on a higher section (Reproduced with permission from

Raroque HG, Orrison WW, Rosenberg GA Neurology

1990;40:167–169.)

ECLAMPSIA 241

ELECTROENCEPHALOGRAPHY

Electroencephalography is usually abnormal (49) There

may be diffuse or focal slowing, and/or focal or

general-ized epileptiform activity (58,59)

THE MANAGEMENT OF ECLAMPSIA

The treatment of mild, moderate, or even severe

eclamp-sia is usually handled by obstetricians, and only rarely are

neurologists consulted for management More frequently,

neurologists are involved with the appearance of seizures,

focal neurologic deficits, or coma The treatment goal is

the rapid delivery of a viable baby, with preservation of

maternal health Therapeutic strategies are directed at

decreasing blood pressure to the autoregulatory range,

preventing seizures or their recurrence, and preventing or

minimizing cerebral edema Preeclampsia and eclampsia

represent a spectrum of neuropathologic change, and

management should be directed at the process as a whole

Treatment of Hypertension

Cerebral edema may rapidly resolve when hypertension

is lowered to within the boundaries of cerebral perfusion

autoregulation, usually a fall in 20 to 25% of the mean

arterial pressure Antihypertensive agents used have

included diazoxide, sodium nitroprusside, nitroglycerin,

and hydralazine (60–62) Nifedipine and labetalol are

currently favored agents (61) (Table 16.5)

Hydralazine 5 mg IV; repeat in 10

min-utes; then 10 mg IV every 20 minutes until stable blood pressure (140–150/90–110

mm Hg) achieved Labetalol 5–15 mg IV push; repeat

every 10–20 minutes by bling dose to a maximum of

dou-300 mg total Sodium nitroprusside a,b Controlled infusion 0.5–3.0 (best used for refractory mg/kg/min, not to exceed 800 hypertension) mg/min

Nifedipine b 10 mg sublingual, repeat in

30 minutes; then 10–20 mg

PO every 4–6 hours Nitroglycerine Should be used only by prac-

titioners thoroughly familiar with its use in obstetrics

monitor-ing.

result.

Reproduced with permission from Repke JT A longitudinal

Gynecol-ogy and obstetrics Hypertension and preeclampsia 1993;

29:463–477.

NEUROLOGIC DISEASE IN WOMEN 242

With the appearance of intracranial hemorrhage,

management should follow the guidelines for the

moni-toring and acute management of raised intracranial

pres-sure Intubation with hyperventilation, diuresis, and

occa-sionally intracranial pressure monitoring in an intensive

care setting may all be warranted

Treatment of Seizures

The pathophysiologic changes underlying seizures and

eclampsia remain unclear Seizure activity arises from the

abnormal excessive neuronal excitability and its

subse-quent spread, but the changes that precipitate neuronal

excitability have been the subject of much discussion In

preventing epileptogenesis, management is directed both

at treating the underlying cause of cerebral damage and

at preventing the precipitation and spread of seizure

activ-ity In the United States, the camps have been divided

between the emphasis placed by obstetricians on

magne-sium sulfate as an “anticonvulsant,” and the position

taken by neurologists that the principal cause of

epilep-togenesis is the hypertensive encephalopathy and

associ-ated cerebrovascular abnormalities—with the seizures

remaining a problem that is best treated by known

anti-convulsants Some evidence suggested that the aggressive

treatment of hypertension diminished eclamptic seizures,

but the controversy remained over how best to treat

impending seizures and preeclampsia and prevent

recur-rence of seizures in eclampsia The evolution of this

con-troversy led to large multicentered trials that have

answered the question of which treatment is best in

pre-venting eclamptic seizures or their recurrence before the

clear underpinnings or rationale for this treatment had

been clearly established In part motivated by the

con-troversies regarding magnesium sulfate in eclampsia

(63–65), a large multicenter trial in 1,680 women with

eclampsia demonstrated that 4 g intravenous (IV)

mag-nesium sulfate over 5 minutes, followed by 5 g

intra-muscular (IM) in each buttock and 5 g every 4 hours was

superior to a loading dose of phenytoin 1 g or diazepam

10 mg IV over 2 minutes repeated if seizures recurred,

fol-lowed by 40 mg in 50 mL of normal saline over 24 hours

(66) Patients who received the magnesium sulfate

treat-ment had a 67% lower risk of recurrent seizures than

those who received phenytoin, and a 52% lower risk than

those who were treated with diazepam (Figure 16.6)

Some criticism could be leveled at this study for the

absence of phenytoin levels and data showing only mean

blood pressures in defining the diagnosis of eclampsia in

both treatment arms A subsequent multicenter trial that

examined 2,138 patients with preeclampsia, however,

clearly showed the superiority of magnesium sulfate at 10

g IM and 5 g every 4 hours to treatment with 1 g

pheny-toin (67) In this paper, none of the 1,049 patients who

were given magnesium sulfate went on to have

eclamp-tic seizures, whereas 10 of the 1,089 patients treated withphenytoin had seizures Phenytoin levels in nine of the tenwomen with seizures, however, were documented to be

in the lower therapeutic range (,13.1 mg/mL) Morerecent data from the Magpie Trial, in over 10,000 preg-nant women with hypertension, showed a decrease inmaternal death (68) For a protocol for the administra-tion of magnesium sulfate and advice on monitoringpatients, see Tables 16.6 and 16.7

The cellular and vascular mechanisms underlyingeclamptic seizures are still unresolved, but some evidencesuggests that the N-methyl D-asparate (NMDA) subtype

of the glutamate receptor, which can be blocked by nesium ions, is involved in neuronal firing thresholds(69,70) Magnesium blocks these receptors, thus pre-venting neuronal damage that would in turn lead toseizures Animal models have shown that magnesium sul-fate suppresses neuronal burst firing and interictal EEGspike generation (71), but other investigators using thesame model failed to support these findings and revealedthat the decrease in neuronal firing was a decay phe-

mag-70 60 50 40 30 20 10 0

11

11

36

14 9

1 5

11

29

22 8

FIGURE 16.6

A study of 1,680 women with eclampsia showed a 52% lower risk of recurrent seizures with magnesium sulfate compared with diazepam, and a 67% lower risk compared with phenytoin.

(Reproduced with permission from Lancet 1995;45:1455–1463.)

ECLAMPSIA 243

nomenon (72) In vivo studies in animals and humans

do not show evidence suggesting that magnesium sulfate

infusion controls or prevents seizures When given to

rodents subjected to electroshock and pentylenetretazol,

which are rodent models for epilepsy, magnesium sulfate

had little effect in preventing seizures (73) Seizures

out-side the setting of eclampsia, in renal failure or porphyria,

have occasionally been prevented by magnesium sulfate

infusion, whereas in other situations it is either tive (74,75) or has not been tried However, magnesiumsulfate might act as a calcium antagonist, preventing cere-bral vasoconstriction and the subsequent cortical injurythat leads to seizures Curiously, dietary supplementationwith calcium decreases the incidence of preeclampsia inhigh-risk patients (76)

ineffec-Magnesium sulfate is not without side effects Thehigher serum levels of magnesium sulfate suppress patel-lar reflexes at 6 mEq/L, and at higher levels of 8 to 10mEq/L it results in lethargy and respiratory depression,with cardiac arrest occurring at levels above 12 mEq/L.There are reports of women with eclampsia havingseizures refractory to magnesium sulfate (12,60), and up

to one-third of patients may have recurrent seizures(12,77) Phenytoin has been used with good effect(78–80) and may also control seizures that are resistant

to magnesium sulfate (81)

Rapid Control of Seizures

Intravenous diazepam can rapidly control ongoing longed seizures, usually with minimal effect on the fetus.Diazepam may, however, result in neonatal hypothermia,lethargy, apnea, hypotonia, and poor sucking effort.Although phenobarbital is an effective antiepileptic drug,

pro-it is less often used because of pro-its sedating effects

SUMMARY

Neurologists can make an important contribution to themanagement of eclampsia When consulted by theirobstetric colleagues, they can provide input into the man-agement of seizures and the intracerebral vascular eventsthat occur with eclampsia and the peripartum period(Table 16.5) Much remains to be done in elucidating thepathophysiology of preeclampsia and eclampsia, partic-ularly with regard to the vascular and antivasospasticeffects of treatments such as magnesium sulfate on thecerebral circulation The most recent studies have shown

a benefit of magnesium sulfate over phenytoin in the vention of seizures in preeclampsia and the prevention

pre-of recurrent seizures in eclampsia A need exists for morebasic and clinical research from both obstetric and neu-

TABLE 16.6

Magnesium Sulfate Administration

for Seizure Prophylaxis

Intramuscular

10 g (5 g deep IM in each buttock)

5 g deep IM every 4 hours alternating sides

Made up as 50% solution

Intravenous

6 g bolus over 15 minutes

1 to 3 g/h by continuous infusion pump

May be mixed in 100 mL of crystalloid; if given as

intravenous push, make up as 20% solution;

push at maximum rate of 1 g/min

40 g Mg SO47H2O in 1000 mL Ringer’s lactate;

run at 25 to 75 mg/h (1 to 3 g/h)

Reproduced with permission from Repke JT A longitudinal

Gyne-cology and obstetrics Hypertension and preeclampsia 1993;

Respiratory rate 12 breaths per minute

Monitor pulse for arrhythmia

Watch for O2desaturation

Watch for widening QRS or prolonged QT intervals on

Reproduced with permission from Repke JT A longitudinal

approach In: Moore TR, Reiter RC, Rebar RW, et al., (eds.)

Gyne-cology and obstetrics Hypertension and preeclampsia 1993;

29:463–477.

NEUROLOGIC DISEASE IN WOMEN 244

rologic perspectives in the optimal management of

patients with eclampsia

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1213–1218.

troke continues to be the third ing cause of death and the leadingcause of disability in the UnitedStates In women, stroke is the sec-ond leading cause of death, with 102,892 women dying

lead-of stroke in 2000, accounting for 61.4% lead-of total strokedeaths (1) Interestingly, the overall rate of stroke amongwomen is lower than that in men but women are morelikely to die from stroke (1,2) Because women live longerand stroke rates increase with age, women have a higherincidence of stroke when over 85 years (2–4)

Furthermore, treatments geared toward the generalpopulation may not be applicable to women, becausewomen may have different risk factors and may appear

to respond differently to certain therapies For womenwho are premenopausal, the stroke rate is low exceptwhen associated with hormonal contraception; smokingalso clearly increases the stroke rate among women

Pregnancy does not increase stroke rates significantlyuntil the last trimester, although pregnancy can compli-cate pre-existing cerebrovascular disease Oral hormonereplacement used by menopausal women may increasethe stroke rate

This chapter reviews the statistics, epidemiology,stroke presentation, and treatments directed to women

Issues related to stroke and pregnancy, oral tion, and hormone replacement also are discussed

contracep-STROKE PRESENTATION, TREATMENT DIFFERENCES IN WOMEN

Stroke is a word that refers to acute neurologic damageand dysfunction from vascular causes Many types ofstrokes and etiologies exist It is generally preferable toavoid acronyms like CVA (cerebral vascular accident).Strokes are not always cerebral, not necessarily primar-ily vascular, and they are never an accident

Ischemic strokes are typically due to the

throm-boembolism of intra- or extracranial arteries This is due

to either local arterial disease with or without tion, hypercoagulable states, or from aorto/cardiacembolization, which results in bland ischemia and celldeath Treating the cause of thromboembolism conse-quently reduces the risk of recurrent ischemic strokes Suchischemic strokes are prevented by using antiplatelet agents

emboliza-or anticoagulation femboliza-or emboli arising from medium andsmall vessels, carotid endarterectomy (CEA) for a carotiddisease source, or anticoagulation for emboli of cardiacorigin The determination of etiology is important because

it defines treatment In general, those hypercoagulablestates that mainly affect the venous system cause strokes

by means of “paradoxical” emboli, which cross over fromthe right to the left side of the heart via anatomic deficitssuch as an atrial septal defect on a patent foramen ovale,often with an atrial septal aneurysm

NEUROLOGIC DISEASE IN WOMEN 248

Hemorrhagic strokes can occur because of the

hem-orrhagic transformation of a previous bland ischemic

infarct, and these have the same etiologies Hemorrhagic

strokes can occur due to cerebral venous thrombosis

(CVT) or venous strokes CVT causes strokes by

slow-ing exitslow-ing blood flow and increasslow-ing intracerebral

pres-sure This results in bland and hemorrhagic infarcts in

nonarterial vascular distributions The classic triad of

papilledema, seizures, and headache is a typical

presen-tation CVT is often caused by hypercoagulable states,

similar to those that predispose to deep venous

throm-bosis, such as smoking and oral contraceptive use, or

dehydration Structural lesions such as meningiomas or

congenital bony abnormalities can obstruct the venous

outflow and predispose to venous thrombosis Treatment

often includes anticoagulation, despite the presence of

hemorrhage

Primary central nervous system (CNS) hemorrhages

are often due to hypertension and can result in

hemor-rhages in the thalamus, basal ganglia, cerebellum, or

pons Treatment is mainly supportive and includes the

reversal of bleeding disorders Primary CNS hemorrhages

can also occur due to trauma, blood dyscrasias,

hyper-coagulable states, and structural vascular lesions such as

arteriovenous malformations, cavernous angiomata, or

cerebral aneurysms Structural vascular lesions are often

best treated using surgical or interventional radiologic

procedures

Acute Stroke Presentation

It is unclear why women die more often from stroke

than men do, while the stroke rate for men is higher

(Figure 17.1) One study showed that women may

experience a longer delay from arrival in emergency

rooms to the time they are evaluated for stroke

symp-toms (5) This may be due to a possible sex difference

in the reporting of acute stroke symptoms One study

looked at 1,189 admissions that ended with a validated

stroke diagnosis in emergency rooms The traditional

stroke symptoms of postural imbalance (men 20% vs

women 15%) and hemiparesis (men 24% vs women

19%) were more likely to be the presenting symptoms

for men than for women Women were more likely to

present with symptoms that were somewhat atypical

for stroke, including pain (men 8% vs women 12%)

and change in level of consciousness (men 12% vs

women 17%) Women reported nontraditional stroke

symptoms 62% more often than men did (6) That this

accounts for the gender difference in death from stroke

seems unlikely Although the use of intravenous for

acute stroke is potentially life-saving and is highly

time-dependent, a majority of active stroke centers probably

treat only about 1.8% of stroke patients with this

ther-apy (7)

Stroke Treatment in Women

Once the diagnosis of stroke in women has been made,how men and women are treated may be different (Table17.1) Management of stroke may differ based on pre-sumed differences in the efficacy of medications and pro-cedures In fact, this may be due to the comparativelygreater age of women with stroke Significant gender dif-ferences exist in the treatment of cardiac disease Womenare less likely to receive major diagnostic and therapeu-tic procedures for cardiac disease (8,9) Further, evidencesuggests that men with stroke are more likely to have sig-nificant comorbidities, such as a higher rate of ischemicheart disease (men 18.1% vs women 15.3%) and dia-betes (men 20.1% vs women 18.7%), but women havehigher rates of hypertension (women 33.8% vs men30.0%) and higher rates of atrial fibrillation (women12.9% vs men 10.2%) (3) This study also showed thatmen 85 years and older were more likely to receiveaspirin and ticlopidine for their strokes than did womenaed 85 and older, although both groups received war-farin at the same rate; these problems of therapy weresimilar at younger ages This may be because womenwith a lesser burden of cardiac disease or diabetes areless likely to have received preventive medications forthese two disorders, and these medications may also pro-tect against stroke

Aspirin is an effective medication for stroke tion in men and is most likely useful in stroke prevention

preven-in women Some studies suggest little benefit, but may lackpower to demonstrate efficacy, whereas others have shownbenefit (3) Present recommendations are to use aspirin

Pain

Cha

e

LOSe

uage

Faci

Droop

Vision

Dzi

ness

Uncla ifi

Neulo c

Nonsp ific

Men Women

CEREBROVASCULAR DISEASE IN WOMEN 249

A recent study showed that aspirin may be effective for

pri-mary prevention of stroke in women but not in men The

study suggets that while the data for aspirin use men has

been poor for primary prevention of stroke aspirin tends

to protect women from having their first stroke

Inter-estingly aspirin seems less effective at preventing

myocar-dial infarction than in men Presently women at risk for

having their first stroke need to consider aspirin for

pre-vention (3a)

Aspirin and dipyridamole in combination is a new

treatment and is available in a combination pill After the

analysis of the European Stroke Prevention Study, it was

found that women had lesser benefit from this

combina-tion therapy than men Men had a risk reduccombina-tion for

stroke of 49% compared to 41% for women Risk

reduc-tion for all vascular endpoints of the study showed a risk

reduction for men of 39% compared to 30% for women

The combination medication is effective for both sexes,

but seemingly less effective in women than in men (10)

Ticlopidine is an antiplatelet agent that is still in use,

but has largely been supplanted by clopidogrel because of

gastrointestinal and hematologic side effects In the dian American Ticlopidine Study (CATS) trial, ticlopidinewas found superior to aspirin 650 mg twice a day in bothsexes, with a nonstatistically significant trend towardgreater risk reduction in women for stroke or death (riskreduction of 27% for women; 19% for men over aspirin)(11) Other ticlopidine and clopidogrel trials have shown

Cana-no difference between sexes Both sexes had reductions

in stroke and vascular death at similar rates (12)

Warfarin is probably as effective in women as inmen It is the treatment of choice for antiphospholipidantibody syndrome and stroke from cardiac source.Abnormalities of protein C, protein S, antithrombin III,and factor V Leiden are treated with warfarin if they aresuspected to be the cause of stroke In general, these fac-tors lead to venous clots but may cause stroke whenassociated with right to left shunts, or a patent fora-men ovale with an atrial septal aneurysm A higher inci-dence of stroke occurs among women with coronaryartery disease and atrial fibrillation (13), however, pos-sibly giving women greater benefit from warfarin thanmen (3)

Carotid endarterectomy is an important treatmentfor the primary and secondary prevention of stroke inpatients with significant carotid stenosis Carotid disease

is more common in men than women A male to femaleprevalence ratio ranges from 3:2 to 8:1 (14) Studies lackcongruence as to whether women have a higher postop-erative stroke rate than men Studies show a higher rate

of postoperative complications in women: in one study,postoperative stroke was seen in women patients more

often (p=0.050), the urgency of intervention (p=0.026), and carotid reoperation (p=0.024) (15,16) Other pop-

ulation studies have found no difference in morbidityand mortality (17,18) Cited causes for the higher com-plication rate in women have been old age of patient atpresentation, presence of hypertension, and surgicalissues regarding the smaller size of carotid arteries inwomen (14)

Stroke Risk Factors Specific to Women

Some specific differences have been found between menand women that may predispose them to stroke (Table17.2) One study found that women with stroke had anelevated tissue plasminogen activator antigen, which was

an independent risk factor for stroke in nondiabeticwomen aged 15 to 44 years old It was suggested thatimpaired endogenous fibrinolysis might be a risk factorfor stroke in women (19) This does not seem to be a mod-ifiable risk factor

Another study showed that a significant proportion

of young women (13% of studied) have elevated totalhomocysteine serum levels, an independent risk factor forstroke and vascular disease Increased serum homocys-

TABLE 17.1

Workup/Treatment for Stroke by Etiology

Evaluate Size and Location of Stroke

• CT or MRI of brain strokes may not appear for 6–24

hours unless diffusion MRI is done

• Assess whether stroke is ischemic, hemorrhagic, or

primary CNS hemorrhage

• Assess whether stroke is in normal arterial vascular

distribution

Evaluate Location of Arterial Occlusion

• Evaluation of intra- and extracranial vessels

• MR angiography, CT angiography, transcranial

Doppler of intracranial vessels

• Warfarin may be required for high-grade

sympto-matic stenosis intracranially

• Carotid imaging with duplex, CT angiography, MR

angiography, or conventional angiography

• Symptomatic carotid stenosis 70% should be

treated surgically

Evaluate Possibility of Aortic or Cardiac Thrombus

Embolization

• Transthoracic echocardiography—LVEF, valvular

lesions, right to left shunts

• Transesophageal echocardiography—aortic

artherosclerosis, left atrial appendage clot

• Warfarin often required for cardiac source emboli

Evaluate Risk Factors and Treat

• Antiplatelet agents for small- and medium-vessel

disease

• Warfarin for hypercoagulable states

• Treat hypertension, diabetes, and

hyper-cholesterolemia

NEUROLOGIC DISEASE IN WOMEN 250

teine levels were correlated with increasing age, higher

serum cholesterol levels, alcohol intake (more than 7

drinks a week), and cigarette smoking Serum

homocys-teine levels were decreased in women who took daily

mul-tivitamins with vitamin B6, B12, and folate (20)

The drug phenylpropanolamine, commonly found

in cough remedies and appetite suppressants, was

asso-ciated with hemorrhagic strokes in women, but not in

men Most affected women were between the ages of 17

to 45 years The FDA has also received reports of 22 cases

of spontaneous intracranial hemorrhage in association

with phenylpropanolamine Most cases (16 patients)

occurred when the drug was used as an appetite

sup-pressant In the study, no men had used

phenypropanolamine as an appetite suppressant, and

there was no association between men and cold remedy

use of the drug and stroke These women were also more

likely to be African-American, to smoke, and to have

recently used cocaine Phenylpropanolamine appetite

suppressants should thus be avoided in women (21)

For stroke and heart disease, the recognized risk

fac-tors of smoking, elevated cholesterol, a previous stroke,

and large artery atherosclerotic disease hold true for both

men and women Workup for new strokes should be

sim-ilar in both sexes and in the elderly Hypertension and

elevated cholesterol become more common in women asthey age Typically, cholesterol levels will increase afterthe age of 45, presumably due to the onset of menopause.Women should have routine checks of blood pressure andcholesterol after they become menopausal, even if previ-ously normotensive with normal cholesterol levels (22).Strategies for lowering cholesterol with statin medica-tions are similar for men and women

AUTOIMMUNE AND COLLAGEN VASCULAR DISEASE

Autoimmune disorders and collagen vascular diseases aremore common in women than in men; therefore, cere-brovascular diseases from these causes are also more com-mon The three major causes of stroke in women from col-lagen vascular diseases are from systemic lupus erythematosus(SLE), the antiphospholipid antibody (APLA) syndrome, andfrom large-, medium-, and small-vessel vasculitis

Systemic Lupus Erythematosus

Systemic lupus erythematosus can cause neurologic orders including psychosis, chorea, neuropathies, andstroke SLE is found in a ratio of men to women of 1:7;

dis-it predisposes to stroke and therefore is a significant riskfactor for stroke in women (23) Data regarding SLE andstroke are difficult to interpret because SLE is a systemicautoimmune disorder and may be associated withantiphospholipid antibodies, which cause a hypercoagu-lable state and lead to both venous and arterial disease.The presence of antiphospholipid antibodies with SLE isreferred to as a secondary antiphospholipid antibody syn-drome In one study of patients with SLE, stroke occurred

at an average age of 35 years, with the diagnosis of SLEbeing made on average 4.4 years previously; 86% of SLEpatients had active SLE at the time of their stroke.Headache was common at onset (24) The presumedmechanisms of stroke were coagulopathy, cardiogenicembolism, large cerebral vessel vasculitis, occlusive vas-culopathy, cervical arterial dissection, and premature ath-erosclerosis On evaluation of the patients, findingsincluded major intracranial or extracranial vessel occlu-sive processes from thrombus, dissection, fibromusculardysplasia or vasculitis, and atherosclerosis (24) A vas-culopathy is associated with SLE, but it is debatablewhether an actual small- and medium-vessel vasculitis isassociated with SLE, because autopsy studies have notfound evidence of true vasculitis Echocardiography stud-ies show that a significant number of patients with SLEhave Libman-Sacks endocarditis, which has the poten-tial to generate emboli to the cerebral circulation andcause stroke (25,26) The treatment of stroke associatedwith SLE mirrors the treatment of SLE flares Immuno-

TABLE 17.2

Work-up for Uncommon Causes of Stroke

in Selected Patients

Arterial Stroke

• MRI with MR angiogram evaluating Circle of Willis

• CT with either TCD, CT angiography, or

• Factor V Leiden, antithrombin III

• Phospholipid antibodies IgG/IgM

• Lupus anticoagulant

• Prothrombin gene mutation

• Can cause arterial stroke if right to left shunt present

CEREBROVASCULAR DISEASE IN WOMEN 251

supression is often required, and anticoagulation is

rec-ommended for occlusive events associated with

antiphos-pholipid antibodies (as discussed in Chapter 22)

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody represents a group of

autoantibodies that present with thrombo-occlusions

and include both anticardiolipin antibodies and the

lupus anticoagulant The syndrome of antiphospholipid

antibody (APLA) syndrome occurs when the antibodies

are found in the absence of SLE Presence of these

anti-bodies is an independent risk factor for stroke in young

women (28) and is associated with early fetal loss In one

series of 93 patients with vascular occlusions and APLA

syndrome, there occurred occlusions (59%), arterial

occlusion (28%), and both arterial and venous

occlu-sions (13%) (27) The Stroke Prevention in Women

study is a population-based case-control study in which

anticardiolipin antibody was found in 26.9% patients

with stroke and in 18.2% of nonstroke controls The

lupus anticoagulant was found in 20.9% of stroke

patients and in 12.8% of controls The presence of either

anticardiolipin antibody or lupus anticoagulant was

found in 42% of patients with strokes and in only 27.9%

of controls Thus, the presence of either antibody leads

to a relative odds ratio of stroke of 1.87 (1.25-2.83,

p=0.0027) (28).

The APLA syndrome may present with strokes,

death, cerebral vein thrombosis, or retinal occlusive

syn-dromes Diagnosis is made by finding elevations of

acti-vated partial thromboplastin time (aPTT) Confirmation

can be made by finding prolongation of the dilute Russell

viper venom time (dRVVT) (29) The presence of mildly

elevated anticardiolipin antibodies, especially IgM, does

not appear be associated with stroke, but elevations of

IgG, especially in range above 40 GPL, is associated with

stroke recurrence and death (30)

The treatment of APLA syndrome in patients with

prior stroke involves long-term anticoagulation with an

INR of 2.0 to 3.0 Low-dose aspirin is probably not

help-ful, and warfarin has been shown to be more effective

than aspirin alone (29,30) Low molecular weight heparin

or unfractionated subcutaneous heparin is used in

preg-nant women because warfarin is teratogenic (29,30)

Vasculitis

Takayasu’s arteritis was originally described in young and

middle-aged women It is a large-vessel vasculitis

affect-ing the aortic arch and the major branches The

major-ity of symptoms arise from the stenosis or occlusion of

these great vessels It causes stroke secondary to the

malignant hypertension from arterial stenosis and

steno-sis of the major arterial blood supply to the brain It

pre-sents with fever, malaise, anemia, and loss of peripheralpulses Treatment includes immunosuppression and sur-gical and nonsurgical treatment of large artery stenosis(31)

Polyarteritis nodosa (PAN) is a medium- and

small-vessel vasculitis that affects arteries PAN patients sents with fever, malaise, and weight loss The skin lesionsmay help to differentiate it from other vasculitides; lesionsare erythematous, purpuric, and nodular (32) Renalinvolvement occurs in over 70% of patients As withTakayasu’s arteritis, the long-term morbidity is due tohypertension affecting the heart and cerebral vessels.Stroke usually occurs later in the course of disease Fre-quent presentations of PAN include encephalopathy, mul-tifocal strokes of the brain and spinal cord, and sub-arachnoid hemorrhage It is treated by immunosupressionwith steroid and cyclophosphamide (Cytoxan®) (32–34)

pre-Isolated angiitis of the CNS is a small-vessel

vas-culitis restricted to the brain, with few systemic symptoms

or laboratory findings It occurs in the fourth to sixthdecades, more commonly in women Strokes or sub-arachnoid hemorrhage are often the only symptom (32).Patricia Moore and colleagues set forth the followingdiagnostic criteria for the disorder: (i) patients must haveclinical features consistent with recurrent, multifocal, ordiffuse disease; (ii) a systemic inflammatory process orinfection must be excluded; (iii) neuroradiographic stud-ies, usually a cerebral angiogram, must indicate a vascu-lopathy; and (iv) brain biopsy is required to establish thepresence of vascular inflammation and exclude infection,neoplasia, or alternate causes of vasculopathy (32,35).Mortality from angiitis of the CNS either may be due tostrokes or hemorrhage over a short period of time, oroccasionally the disorder can smolder for years Therapyfor isolated angiitis of the CNS is a combination ofcyclophosphamide with a low dose of prednisone Remis-sion and cure have been reported (32)

Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) of the carotid or theintracranial arteries is a disorder of the arterial wall pre-senting with constricting bands of fibrous material alter-nating with smooth muscle (36); this results in alternat-ing constriction and dilatation of the artery A raredisorder, it is found in 0.6% of nonselective angiograms(37) It is most prevalent among middle-aged women Inone study where 70 patients were diagnosed with cere-brovascular FMD, 89% of the patients were women with

a mean age of 64; 91% of these patients presented withtransient ischemic attacks (TIAs), stroke, or pulsatile tin-nitus (36) It is not thought to be an inflammatory disor-der Patients with FMD are at a higher rate of sponta-neous carotid artery dissection The etiology of the smallstrokes and TIAs is generally unknown

NEUROLOGIC DISEASE IN WOMEN 252

Treatment of FMD depends on the symptoms

Asymptomatic FMD is often treated with aspirin only

Carotid endarterectomy alone does not effectively treat

the disease, because the vascular disorder is not isolated

to the extracranial carotid Intra-arterial angioplasty and

stenting have been performed successfully The most

important issue is that patients with intracranial FMD

need screening for aneurysms that may bleed magnetic

resonance angiography or computed tomography (CT)

angiography for aneurysms that may bleed (36)

Moya-Moya

Moya-moya is Japanese for “puff of smoke.” It is less of

a disorder per se, than the normal response to large-vessel

cerebral occlusions (Figure 17.2) The syndrome classically

presents with unilateral or bilateral intracranial carotid

stenosis or occlusions Collateral vessels form to

compen-sate for lost blood flow and form a myriad of small

col-lateral vessels that are small and tangled in appearance and

look like a “puff of smoke” on angiography (37)

Moya-moya is 50 times more likely to occur in

women than men and is found more commonly in

women who smoke and use oral contraceptives (38,39)

It can present with headaches, seizures, and

intracere-bral hemorrhage as well as stroke Angiography, which

demonstrates the small perforating collaterals, is needed

for diagnosis The presumed etiology for the

hemor-rhage is the aneurysmal thinning of blood vessels and

disease of the very small end vessels from atherosclerotic

disease (37)

Treatment is difficult because strokes are more mon in children, but hemorrhage is more likely in adults.Aspirin or warfarin are thought to worsen the risk ofhemorrhage Abnormal cerebral blood perfusion hasbeen demonstrated using SPECT or magnetic resonanceimaging (MRI) perfusion and may account for the blandinfarcts associated with the disease Pial synangiosis orencephalomyosynangiosis surgery can be performed andhas been shown to improve cerebral blood perfusion asmeasured by MRI (40) and may improve neurologic func-tion in a very small number of patients (40)

com-No improvement is gained in long-term morbidity ormortality

CEREBRAL VASOSPASTIC DISORDERS

Migraine is a prevalent disorder affecting about 6% of

men and 15 to 18% of women It occurs most oftenbetween the ages of 25 and 55 years (41) Stroke is aknown complication of migraine and has been shown to

be an independent risk factor, especially in those less than

35 years of age In one study, 160 patients were evaluatedfor migrainous strokes with other causes excluded.Migraine was found to be a significant risk factor for juve-nile stroke, with an odds ratio for individuals under 35

of 3.26 and for women of 2.68 (42)

Not only are patients who have migraine at risk forstroke but also women of childbearing age who havemigraine with aura are at greater risk Another study fol-lowed 86 women with migrainous strokes and found thatwomen were more likely to have strokes if they hadmigraine with aura instead of migraine without aura, and

if they had 12 or more migraines with aura per year Nocorrelation was found among oral contraceptive use,migraine, and stroke (43)

Treatment for migrainous strokes has typicallyincluded prophylaxis, because the fewer migraines withaura, the lesser the chance of a stroke Because of thevasospastic quality to the stroke etiology, a calcium chan-nel blocker (verapamil) is used in combination withaspirin Smoking should be discontinued A careful work-

up for stroke etiology should always be done, includingscreening for antiphospholipid antibody; migrainousstrokes are often thought of as a diagnosis of exclusion

Reversible segmental vasoconstriction or Call’s

syn-drome is a poorly understood disorder It presents withheadaches, seizures, lethargy, and strokes, typically inyoung women with a history of migraine The strokeworkup shows multifocal areas of vasodilation and vaso-constriction in multiple vascular territories in the Circle

of Willis Diffuse brain edema, hemorrhages, and deathcan also occur Repeat angiography may show sponta-neous resolution of vasoconstriction It is treated usingcalcium blocking agents, corticosteroids, and increased

FIGURE 17.2

Cerebral angiograms Lateral intracranial view of the left

com-mon carotid injection (A) shows occlusion of the distal

inter-cranial carotid artery with a tuft of enlarged collaterals distal

to the occulation Lateral intercranial view after vertebral

artery injection (B) shows extensive collateral vessels

resem-bling ‘puff of smoke’ arising from the basilar artery and the

posterior cerebral arteries (Reproduced with permission from

Wityk RJ, Hillis A, Beauchamp N, Barker PB, Rigamonti D.

Perfusion-weighted magnetic resonance imaging in adult

moya-moya syndrome: characteristic patterns and change

after surgical intervention: case report Neurosurgery

2002;51:1499–1506.)

CEREBROVASCULAR DISEASE IN WOMEN 253

intracranial pressure management; a functional outcome

is variable (44,45)

Angiitis of pregnancy is a similar disorder that tends

to present with hemorrhages and strokes in the postpartum

period It tends to present more often with hemorrhages It

occurs in the absence of typical clinical findings suggestive

of eclampsia or preeclampsia It also presents initially with

diffuse and severe vasoconstriction on conventional

angiog-raphy How this disorder relates in etiology to reversible

seg-mental vasoconstriction, migraine, and eclampsia or

preeclampsia is not clear Whether these are distinct

vasospastic disorders or ends of the same spectrum is

unclear Angiitis of pregnancy is treated with corticosteroids,

blood pressure control, and intensive care management; it

generally has a good functional outcome (45,46)

CNS HEMORRHAGE Cerebral Venous Thrombosis

Cerebral venous thrombosis (CVT) occurs more

fre-quently in women than in men; pregnancy and oral

con-traceptive use are significant risk factors for the disease

CVT is often described as the deep venous thrombosis

(DVT) of the brain An occlusion of the cerebral veins

causes a back-up of pressure and bland ischemic infarcts

with hemorrhagic transformation The infarcts from

venous occlusions are often in nonclassic arterial

vascu-lar distributions and provide the clue to the diagnosis It

presents typically with a constellation of symptoms:

headache, papilledema, seizures, and focal neurologic

deficits In the largest published series of 160 patients,

headache occurred in 82%, papilledema occurred in

55.5%, focal deficits occurred in 42%, seizures occurred

in 39%, and alteration of coma occurred in 30.5% (47)

CVT can also present with isolated intracranial

hyper-tension only Pulsatile tinnitus and multiple cranial

neu-ropathies have also been described

CVT is caused by trauma, tumors compressing on

the sagittal sinus, dehydration, and prothrombotic states

In general, those prothrombotic states that predispose to

DVT can also predisposed to CVT and include sickle cell

disease, factor V Leiden, prothrombin G20210A

muta-tion, resistance to activated protein C, APLA syndrome,

oral contraceptive use, and antithrombin III deficiency

(47,48) These hypercoagulable factors predispose more

to venous clots than arterial clots or stenosis Hemorrhage

in CVT may be cortically based and appear as a primary

CNS hemorrhage; only with workup is a sagittal or

cor-tical vein thrombosis noted Workup includes brain

imag-ing with CT and MRI Findimag-ing of the “delta sign,” in

which a clot within the confluence of the sinuses is seen

as a bright triangle, can be difficult to see on brain CT

(Figure 17.3) New techniques of venograms using CT

and MRI have made this easier to diagnose The “goldstandard” remains conventional angiography

Treatment is with anticoagulation; therefore, nosis must be clear, because hemorrhage is often associ-ated with the venous infarct The studies showing bene-fit have few patients but the results are fairly robust.Heparin showed benefit in a randomized prospective trial

diag-in which 20 patients with CVT were studied Eightpatients in the heparin group recovered completely,whereas only one in the placebo group did; there were

no deaths in the heparin group and three in the placebo

FIGURE 17.3

A MRI with clot within the superior sagittal sinus see arrows Blood will be bright in subaxute setting B CT scan with nonarterial distribution stroke Arrow points to ‘delta sign.’ (Special thanks to Robert Wityk, Johns Hopkins Hospital, for providing these images.)

A

B

NEUROLOGIC DISEASE IN WOMEN 254

group (49) Studies looking at low molecular weight

heparin showed less robust findings Heparin has been

shown to provide an absolute risk reduction of 70% for

mortality from CVT (50)

Newer techniques include rt-PA administered

endovascularly and the use of vacuum catheters Patients

seem to suffer more often from new or progressive

hem-orrhages with endovascular thrombolytics but the

occlu-sions resolve more quickly with endovascular techniques

than with systemic anticoagulation It is unclear at present

whether patients do better with heparin alone or with

endovascular treatment (47,51) Mortality is reduced with

treatment, and 80% of patients were living independently

after 3 years, although three out of four patients had

resid-ual symptoms including seizures, weakness, headaches,

and visual field defects (52) Outcome is often poor

with-out intervention

Cerebral Aneurysms

Cerebral aneurysms are lesions consisting of weakening

of the wall of a cerebral artery and thinning of the vessel

wall The aneurysm itself can compress local structures,

but the most dangerous consequence is subarachnoid

hemorrhage (SAH) The most common presentation is

severe acute-onset headache, vomiting, focal neurologic

findings, and meningeal signs Cerebral aneurysms with

subarachnoid hemorrhage are more common in women

over 55 years of age than in age-matched men (53,54)

Women are more likely to have multiple aneurysms, as

shown in one study (281 women; 80 men) The

propor-tion of patients with multiple aneurysms and

subarach-noid hemorrhage was higher in women for all age

cate-gories (5.2%:15.2%) Women tended to have worse

outcomes than men (54) There is no gender difference

in outcome in SAH with a single aneurysm (55)

Diag-nosis is made based on head CT and lumbar puncture

findings and confirmed with conventional angiography

Recently, MR angiography and CT angiography have

become less invasive screening tests for both symptomatic

and asymptomatic cerebral aneurysms Treatment

involves surgical clipping or endovascular coiling of the

aneurysmal dilatation

HORMONES AND STROKE

Oral Contraceptive Pills and Stroke

Oral contraceptive pills (OCPs) and hormonal

contra-ception have been linked to an increased stroke risk in

multiple studies (56–60) Much of this perceived

increased stroke risk is based on early studies of higher

dose preparations containing >50 mcg of estradiol

(57,61,62) In normotensive, nonsmoking women, OCPs

containing 35 mcg of estradiol or less do not increase therisk of stroke (63,66) The majority of studies of second-and third-generation OCPs containing these lower doses

of estrogens did not find an increased risk of stroke(61,62,67–70) A pooled analysis of two large populationcase-control studies showed no increased risk of hemor-rhagic or ischemic stroke in current users of OCPs con-taining less than 50 mcg of estradiol, compared with pastusers or “never-users” (71) One case-control study didreport an increased risk of stroke using first-, second-, orthird-generation OCPs, however, but the reasons for thisdiscrepancy are unclear (72)

Among OCP users, cigarette smoking, hypertension,diabetes, migraine headache, and prior noncerebralthromboembolic events also increase the risk of stroke(64,65,67,71,73) Some data (71) suggest, however, thatwomen with chronic hypertension can use combinationOCPs containing 35 mcg of estradiol or less, providedthat they are otherwise healthy nonsmokers under the age

of 35, and that their blood pressure is well-controlled andmonitored before beginning OCPs and for several monthsafter starting use (74) The pooled analysis of two case-control studies found no elevation in stroke risk in OCPusers who were over the age of 35, smokers, obese, orthose with uncontrolled hypertension (71) The Ameri-can College of Obstetricians and Gynecologists (ACOG)recommends that OCPs should be prescribed with cau-tion, if ever, to women who are older than 35 and aresmokers (74)

Migraine headaches are common in women ofreproductive age Some women with migraines experi-ence an improvement in their headaches on OCPs but,

in women on OCPs, most migraines occur during the mone-free interval A large case-control study found thatwomen with a history of migraines and who were usingOCPs did not have a significantly increased risk ofischemic stroke compared with women who were notusing OCPs and were without migraines (75) Comparedwith women who did not smoke, did not use OCPs, andwere without migraines, women who smoked, were usingOCPs, and had a history of migraines had a 34-foldincreased risk of stroke in this study The pooled analy-sis of two large, U.S population-based case-control stud-ies also observed a statistically significant twofoldincreased risk of ischemic stroke among women on OCPswith migraine headaches (71) In a large Danish popula-tion-based case-control study, the risk of stroke was ele-vated approximately threefold among women with a his-tory of migraines (73) Neither study categorizedmigraines by type, however The additional risk of strokeattributable to OCPs for women with migraines has beenestimated as 8 per 100,000 women at age 20 years, and

hor-80 per 100,000 women at age 40 years (76) Because theabsolute risk of a cerebrovascular event remains lowamong women of reproductive age, the use of OCPs may

CEREBROVASCULAR DISEASE IN WOMEN 255

be considered for women with migraine headaches who

do not have focal neurologic signs, do not smoke, are

younger than age 35, and are otherwise healthy OCPs

should be discontinued in these women if the frequency

or severity of headaches increases or focal neurologic

signs or symptoms arise

A strong association between CVT and use of oral

contraceptives has been established in several

case-con-trol studies (77–79) Mutations in the prothrombin gene

and the factor V Leiden gene are associated with CVT

The presence of both the prothrombin gene mutation and

oral contraceptive use further increases the risk of CVT

(77,78) Routine screening for the prothrombin gene

mutation in young women is not currently recommended

before prescribing them OCPs

A recent meta-analysis concluded that the risk of

ischemic stroke is increased in OCP users, but that the

absolute increase in risk would be small due to the low

stroke incidence in this young and healthy population (80)

An individual’s risk of stroke must be weighed against the

benefits of effective contraception and the risks of

unin-tended pregnancy The impact of stroke in a woman of

reproductive age is so devastating, though, that clinicians

should consider alternative forms of contraception such as

progestin-only (oral or injectable), barrier, or intrauterine

contraceptives in the setting of the additional risk factors

mentioned above (81) Stroke risk is not increased with the

use of progestin-only OCPs or injectables, except among

women with hypertension (82,83)

HORMONE REPLACEMENT THERAPY

Hormone replacement therapy (HRT) is commonly used

for the treatment of vasomotor symptoms and

urogeni-tal atrophy, as well as for the prevention of osteoporosis

and cardiovascular disease in women Data on the

asso-ciation of postmenopausal HRT and stroke have been

inconsistent The impact of HRT on stroke risk is

ill-defined due to a lack of well-designed, controlled studies;

as a result, definitive conclusions cannot be reached Since

1980, at least 18 studies have been published on this

sub-ject (84) The Framingham Heart Study found a 2.6-fold

increase in the relative risk of atherothrombotic stroke

among women receiving HRT versus nonusers (85) None

of the other studies detected a large increase in stroke risk,

and several reported a slight (but often insignificant)

decrease in risk (86–92)

In the 20-year report from the Nurses’ Health Study,

the investigators noted for the first time an increased risk

of stroke in women taking estrogen alone (35%) and in

women taking combined therapy of estrogen and a

prog-estin (93) However, the overall risk in current users for

all HRT regimens was increased by only 13% The risk

of fatal stroke was decreased by 19% in women on

estro-gen alone, compared with an increase of 22% in those oncombined HRT

These findings conflict with those of previous vational reports Neither estrogen alone nor combinedtherapy increased the risk of nonfatal stroke in a largeDanish case-control study (94) In another prospectivecohort, estrogen therapy was associated with a 46% over-all reduction in stroke mortality, with a 79% reduction

obser-in current users (95) Fobser-inucane et al showed a similarreduced risk for women who had used HRT comparedwith those who had never used HRT, with stroke inci-dence lower by 31% and stroke mortality by 63% (90).The Copenhagen City Heart Study, a case-control study

of women aged 45 to 69 years in the United Kingdom,showed no effect of HRT on stroke incidence (86) Themuch-publicized Women’s Health Initiative (WHI) trialrevealed an excess of eight nonfatal strokes per 10,000women per year in the combined therapy group, but, as

in the Nurses’ Health Study, the rate of fatal strokes wasnot increased (96) The limitations of this study includethe older average age of enrolled patients, use of only oneHRT regimen, and increased unblinding of the studypatients on HRT

The most compelling evidence for the benefit ofHRT in stroke prevention are the data on mortality fromstroke As discussed above, the larger cohort studies thathave assessed the impact of hormone use on stroke mor-tality have demonstrated a beneficial impact, with theexception of the Nurses’ Health Study (89,90,95,97).These data are consistent with the possibility that hor-mone therapy decreases the severity of strokes and there-fore the incidence of stroke-related mortality, if notstroke events Hormone replacement therapy appears toinfluence stroke risk factors positively The CopenhagenCity Heart Study showed a reduced stroke risk for smok-ers taking HRT compared with smokers not taking HRT(86) The Lipid Research Clinics of North Americarevealed that HRT decreases cholesterol, decreases low-density lipoprotein, and raises high-density lipoproteincompared with women not receiving HRT after con-trolling for compounding risk factors (97) Therefore,HRT may be especially protective for women whosmoke and/or have elevated cholesterol Multiple case-control and cohort studies offer overwhelming evidencefor at least a 40 to 50% reduction in the risk of primarycoronary heart disease and myocardial infarction inestrogen users (98) The recently reported results of therandomized WHI trial would indicate the situation isotherwise, but this was not a primary prevention trial—the findings also may have been biased by the new andunreported statin and aspirin use in the placebo groupafter the trial started (96) The WHI data not with-standing, HRT may be particularly beneficial for reduc-ing stroke risk in patients with preexisting occlusive ves-sel disease, even after adjusting for any “healthy-user”

NEUROLOGIC DISEASE IN WOMEN 256

effect, although additional studies are necessary and

ongoing

For women who have already suffered a stroke, the

Women’s Estrogen for Stroke Trial (WEST) study was

designed to evaluate estrogen and the secondary prevention

of stroke In this trial, no significant differences were found

between treated and placebo groups in outcomes for fatal

and nonfatal stroke, nonfatal myocardial infarctions, or

coronary death (99) The risk was actually greater in the

first year of estrogen exposure The WEST group concluded

that estrogen therapy was not effective for preventing a new

or recurrent cerebrovascular event in stroke patients

In 2003, the results of the Women’s Health Initiative

Study was published in JAMA Specifically it looked at

dementia and possible protective effects of estrogen plus

progestin in postmenopausal women A paper describing

stroke risk in treatment and placebo groups was reviewed

The study found that of the there were significantly more

strokes in the treatment group versus the placebo group

Looking at the article one finds that of 16,608 women there

were 258 strokes of which almost 80% were ischemic

strokes There were 151 strokes in the treatment group and

107 strokes in the placebo group which constituted a

haz-ard ratio for ischemic stroke (greater than 1 suggesting

harm, less than one suggesting protection) of 1.44 (95%

CI, 1.09–1.90) and for hemorrhagic stroke, 0.82 (95% CI,

0.43–1.56) This, despite similar background stroke risks

in the women aged 50–79, there was greater risk of

ischemic stroke Admittedly the number needed to harm

(the number of patients needed to put on therapy to cause

one stroke) is approximately 226, still there is statistically

significantly greater risk of stroke with HRT in this trial

care should be taken when HRT is considered as there is a

small but significant risk of stroke (99a)

In summary, the risk of stroke associated with HRT

appears low but requires further study The existing data

have methodologic limitations, including nonspecific

end-points, lack of control for prior HRT use or specific

reg-imens, a lack of sufficient numbers of women from

minor-ity racial or ethnic groups, and possible confounding by

a healthy-user effect No healthy postmenopausal women

should be denied the benefits of hormone therapy for fear

of stroke alone; the other potential benefits, risks, and side

effects of therapy must be considered and tailored to the

individual patient

Hormone Replacement Therapy and

Subarachnoid Hemorrhage

The etiology of SAH is poorly understood Because the

incidence of SAH is highest in women after menopause

(100), it has been hypothesized that estrogen might be

protective for this condition (101,102) Unlike ischemic

stroke, most of the epidemiologic data have shown that

the risk of hemorrhagic stroke, including SAH, is not

affected by either hormone replacement therapy or OCPs

A large population-based, case-control study of womenwith SAH showed significant independent associationsbetween use of either HRT or OCPs and reduced risk ofSAH (102) In this study, premenopausal women had amarkedly reduced risk of SAH compared with post-menopausal women The protective effect of HRT inpostmenopausal women was highest in postmenopausalsmokers receiving HRT compared with those not receiv-ing HRT The Nurses’ Health Study (103) compared SAHrisk in current versus former users of HRT; current usershad a reduced risk compared with nonusers after adjust-ing for other variables No protective effect was observed

in women who had used HRT in the past

The studies of HRT and risk of SAH have been ficult to interpret due to methodologic problems of smallstudies, incomplete data, differences in therapy, andpotential confounding variables A study of women inSweden showed that SAH risk was reduced for users ofcombined estrogen and progestin therapy compared withthose using estrogen alone (104) Additionally, there was

dif-no protective effect of former estrogen use, whereas mer estrogen-progestin use may be beneficial A recentprospective, multicenter, population-based, case-controlstudy demonstrated that estrogen, either alone or in com-bination with a progestogen, reduces the risk of SAH(105) The inverse association was moderately strong forany use of HRT and risk of SAH, but only borderlinewhen current or past use of HRT was considered sepa-rately Data pertaining to the risk in relation to endoge-nous hormonal factors, such as menstrual patterns, arelimited One study (102) demonstrated that among pre-menopausal women with SAH, 74% were menstruating

for-at the time of the event, suggesting thfor-at stfor-ates of relfor-ativeestrogen deficiency, such as menopause and the premen-strual period, may increase the risk of SAH in women.HRT has been shown consistently to decrease the risk

of fatal stroke (106,107) Stratification by fatal and fatal strokes may be important in clarifying the linkbetween HRT and both ischemic and hemorrhagic stroke,because the majority of nonfatal strokes are ischemic,whereas approximately one- and two-thirds of fatal strokesare hemorrhagic, including SAH (108) The currently avail-able data support a key role for hormonal therapy in theprevention of SAH among postmenopausal women

non-STROKE AND PREGNANCY Ischemic Stroke

Risk factors for stroke in pregnancy and the postpartumperiod (or puerperium) include all the established causesfor any young nonpregnant stroke patient, such as vas-culopathy, cardiogenic embolism, drug use, migraine, andhematologic disorders Pregnancy and the puerperium