Headache, cerebrovascular disease, epilepsy, and neuroimmunological conditions will be discussed in relation to specific women’s issues in the childbearing age, pregnancy, peripartum, and menopausal periods.
Special considerations must often be taken when caring for female inpatients, from not only diagnostic but also therapeutic perspectives. Hormonal changes are widely recognized to have an impact on almost all neurological conditions. Pregnancy and puerperium may modify the nature or severity of a neurological condition, while predisposing women to the development of specific conditions, such as postpartum angiopathy. Menopause may carry specific management implications, such as seizure exacerbation with hormone replacement therapy. Finally, choice of therapy is heavily influenced by the potential for teratogenicity in multiple neurology subspecialties from multiple sclerosis to epilepsy.
The observation that migraine is three times more prevalent in women than in men,1 and the influence of reproductive milestones on migraine support the long-standing recognition of the impact of sex hormones on migraines. Menstrual migraine is one of many clinical examples of the links between estrogen and migraine. It is hypothesized that a fall in estradiol levels after prolonged estradiol elevations, as observed before menses, is responsible for such links.2
Pure menstrual migraine is defined as migraine without aura occurring exclusively on day 1±2 of menstruation in at least 2 of 3 menstrual cycles.3 Menstrual migraine attacks are typically more severe, longer in duration (with higher rates of status migrainosus), and less responsive to acute attack treatment, as compared to nonmenstrual migraine attacks.4 As a result, women with menstrual migraines may be more likely to require Emergency Department (ED) visits for treatment of migraine attacks.
Taking a migraine history in women should include a screen for hormonally influenced migraines including age at onset of headache in relationship to menarche, and the impact on headache frequency and severity by:
use of oral contraceptive pills (OCP) (continuous versus cyclical use, combined versus progestin-only, indication of use)
previous pregnancies and breastfeeding
previous hormonal manipulation (eg, for infertility, irregular cycles, etc.)
partial or total hysterectomy5
Multiple therapeutic strategies may be employed to reduce the frequency and severity of menstrual migraine attacks. Of note, interventions focused on menstrual migraines are more likely to be effective in pure menstrual migraine than menstrually related migraine (ie, women with migraine attacks outside of the menstrual window). Acute (abortive) therapy can be provided as in any other migraine attacks. Short-term prevention during the menstrual window of vulnerability may be initiated in women with predictable onset of menstrual headache and lack of pain freedom with acute therapy. Triptans may be given twice a day starting 2 days before and through 3 days of menstruation. Alternatively, naproxen sodium 550 mg twice daily may be given starting 7 days before expected menses with continuation through day 6 of menses.2 In women with no predictable onset (due to irregular periods), or frequent migraines outside of the menstrual window, continuous preventive therapy may be considered. If the patient is already taking preventive medication, a higher dose near time of menses may be beneficial. Finally, if the patient is already on the OCP or has other medical indications for hormonal treatment, one may consider continuous use or shortening placebo days, while staying mindful of individual patient characteristics that increase the risk of thrombotic events such as age more than 35 years, smoking, previous thrombosis, ischemic stroke, or heart disease.6
Prepregnancy planning should be discussed in women of childbearing age in whom continuous migraine prophylaxis is being considered. Nonpharmacological therapies such as biofeedback, massage, trigger avoidance, regular exercise, and good sleep hygiene should be encouraged. Magnesium 400–800 mg daily and riboflavin 400 mg per day are the safest prophylactic options. The patient may be reassured that most migraines will improve during pregnancy.5
A common neurology consult to an obstetrics unit is that of a new-onset headache in a pregnant or postpartum woman. The primary goal of the assessment is to elicit signs and symptoms suggestive of a secondary headache, then to investigate in a timely manner, with special considerations given to secondary headaches more likely to occur during pregnancy.
First, one must ascertain whether there is any previous history of primary headaches. If so, is the current headache following the usual pattern? If not, one must complete a thorough history focusing on “red flags”:
Thunderclap headache may be seen in a variety of secondary headaches, and in pregnancy should heighten a concern for cerebral venous thrombosis (CVT), reversible cerebral vasoconstriction syndrome (RCVS), and pituitary apoplexy.
Visual symptoms, including scotomas, photopsias, and blindness, may suggest pre-eclampsia and eclampsia (discussed in greater detail in Section 3.2.3), posterior reversible encephalopathy syndrome (PRES), or idiopathic intracranial hypertension (IIH).
Postural headache (worsened by sitting or standing up) may suggest intracranial hypotension syndrome (aka: CSF hypotension), which may be seen in the postpartum period in women having received epidural anesthesia. Conversely, a postural headache worsened by lying down may suggest a space-occupying lesion. Indeed, pregnancy may promote tumor progression in grade II and III glial brain tumors7 and meningiomas.8
Atypical auras. When eliciting a migraine history, special attention must be made to atypical features including prolonged nature and presence of motor or speech symptoms, as this may be suggestive of a secondary headache even in the presence of a previous migraine history.
Seizures may raise suspicion for CVT, PRES, or eclampsia.
Fever or immunocompromised status should, as in nonpregnant patients, prompt workup for secondary headaches with lumbar puncture after appropriate brain imaging.
Physical examination should focus on blood pressure measurement, funduscopy, and identification of focal neurological deficits especially of visual fields. Figure 4-1 summarizes the signs and symptoms of secondary headaches in pregnancy. Given the extensive differential diagnosis of headache, a neuroanatomical approach is suggested in Figure 4-2 to help structure the reader’s approach.9,10
Figure 4-2
Neuroanatomical approach to secondary headaches in pregnancy. This approach may structure the diagnoses that can underlie headache in pregnancy. Abbreviations: ICH, intracerebral hemorrhage; IIH, idiopathic intracranial hypertension; PRES, posterior reversible encephalopathy syndrome; RCVS, reversible cerebral vasocon-striction syndrome.
CASE 4-1
A 35-year-old woman, who was 34 weeks pregnant, presented to the ED with a headache. She described a holocephalic pulsatile 9/10 headache, which had started 2 days prior. She denied a prior history of similar headaches. She has a prior history of deep venous thrombosis at age 24, after a long flight. When screened for red flags (Figure 4-1), she endorsed a postural component and transient visual obscurations. On examination, BP was 108/70. There was mild blurring of the optic disc margins bilaterally, normal visual fields to confrontation, and 20/20 visual acuity bilaterally. Remainder of the neurological examination was intact.
The red flags on history (new postural headache, transient visual obscurations, previous history of thrombosis) and physical examination (papilledema) raise the suspicion of a secondary headache, possibly symptomatic of a raised intracranial pressure (ICP).
If signs and symptoms suggestive of secondary headaches are present, then neuroimaging should be obtained. Given the high risk of vascular abnormalities accounting for headache in pregnancy, from both the arterial and the venous side, an urgent MRI of the brain with time-of-flight (TOF) (ie, without gadolinium) MR angiography (MRA) and MR venography (MRV) is preferable. Practice guidelines regarding the safety of imaging protocols in pregnancy are summarized in Table 4-1. In addition, one should have a low threshold for urinalysis for protein in women above 20 weeks of pregnancy and hypertension, given the significant implications of a positive result in the management of the patient. Finally, a lumbar puncture (LP) with opening pressure should be performed if the aforementioned investigations do not yield a diagnosis and entities such as idiopathic intracranial hypertension (IIH) or meningitis are being considered.
CASE 4-1 (continued)
Given the concerning red flags, urgent neuroimaging was obtained, with an MRI with TOF MRA/MRV, which revealed a superior sagittal sinus (SSS) and right transverse and sigmoid sinus thrombosis (Figure 4-3). Anticoagulation with heparin was initiated (see Section 3.2.6), and the patient’s headache improved. Formal visual field testing was arranged.
Had the TOF MRA/MRV been equivocal, a CTA/CTV may have been performed to definitely rule out venous thrombosis (Table 4-1). Had the MRV been normal, LP with opening pressure would have been indicated to rule out IIH, which may present during pregnancy.
Figure 4-3
MRV demonstrates thrombosis of the majority of the superior sagittal sinus (indicated by green arrows), as well as the right transverse sinus and the right sigmoid sinus (less well visualized on this sagittal view). Of note, this was an MRV obtained with gadolinium, whereas typically TOF MRV would be obtained in pregnant patients (Table 4-1). Used with permission from Dr. Rick Swartz, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Summary of Practice Guidelines and Recommendations for Safety of Imaging Protocols in Pregnancy11,12
| Imaging Modality | Potential Harm to Fetus | Recommendations |
|---|---|---|
| Computed tomography |
|
|
| Iodine contrast |
|
|
| Magnetic resonance imaging |
| |
| Gadolinium |
|
|
De novo migraine during pregnancy is rare; therefore, new-onset headache with migraine characteristics during pregnancy should typically prompt a workup. Improvement of migraine is common but not the rule, and may be more noticeable in the second and third trimesters, especially in women with menstrual migraines.
Nonsteroidal anti-inflammatory drugs may be used before 32 weeks gestational age. Acetaminophen 650–1000 mg is safe in pregnancy and effective for symptomatic relief.13 It may be taken with caffeine 40–50 mg. Opioids should be used with caution, as codeine has recently been implicated in midline defects. Triptans should be avoided (FDA category C – see Table 4-2 for definitions), along with ergotamines. (FDA category X). The anti-emetics ondansetron 4–8 mg and metoclopramide 10 mg may be used (FDA category B). Steroids (dexamethasone FDA category C due to increased incidence of cleft palate) may be used in the second or third trimester if the acute attack is refractory to the aforementioned interventions. One should also monitor for potential medication overuse headache.
US Food and Drug Administration (FDA) Pregnancy Categories
| Category | Definition |
|---|---|
| A | Adequate and well-controlled studies show no risk to the fetus. |
| B | Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no studies in pregnant women. |
| C | Animal reproduction studies have shown an adverse effect on the fetus, and there are no studies in humans. |
| D | There is positive evidence of human fetal risk based on adverse reaction data in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks. |
| X | Studies in animals or humans have demonstrated fetal risk, and the risks involved in the use of the drug in pregnant women clearly outweigh potential benefits. |
Perimenopause is characterized by an increased variability in length and frequency of menstrual cycles, leading to fluctuations in estrogen levels. Migraines typically worsen during the perimenopausal transition and then significantly improve after menopause.6 Hormone replacement therapy (HRT) is an important exogenous hormonal factor to take into consideration. All forms of HRT may worsen migraines, but it has been suggested that continuous instead of cyclical and transdermal instead of oral preparations are less likely to aggravate migraines.6
Multiple meta-analyses regarding the cumulative risk of stroke in women using OCPs have been completed due to the widely recognized thrombotic risk associated with OCP use. Overall, the relative risk of stroke with low-dose OCPs is small, ranging from 1.4 to 2.0 times that of women not taking OCPs. In one recent large study, the incidence of stroke in women taking OCPs was 21.4 per 100 000 person-years, with a relative risk of thrombotic stroke and myocardial infarction of 1.4–2.2 in ethinyl estradiol concentrations of 30–40 ug, and 0.9–1.5 in concentrations of 20 ug. Of note, progestin-only formulations were not associated with an increased risk of stroke and transdermal patch was associated with a nonsignificant increased risk. Newer formulations including vaginal ring carry similar risk as pills.14
Noting the relatively low increase in incidence of thrombotic events, additional risk factors are the deciding factor in the evaluation of potential harm in prescription of OCPs. Cigarette smoking, older age, hypertension, obesity, hypercholesterolemia, and prior thromboembolic events compound the increased risk of stroke further in women taking OCPs. Of note, women with migraine with visual aura who take OCP but do not smoke do not have a higher risk of stroke, while smokers with visual aura who take OCP have a 7.0-fold higher risk of stroke. Finally, OCPs may lead to systemic hypertension; therefore, baseline measurement of blood pressure is indicated.15
The highest stroke risk in pregnancy occurs in the third trimester and in the 6-week postpartum period. Several physiological changes may account for this increased risk. High metabolic demand is met by cardiovascular changes including an increase in plasma volume and a decrease in systemic vascular resistance, which leads to an increase in cardiac output and heart rate. Women with an underlying structural cardiac abnormality such as myopathic, valvular, or septal defects may be vulnerable to cardioembolic stroke. Meanwhile, blood vessels develop loss of distensibility, which, combined with hemodynamic changes, may increase the risk of hemorrhagic stroke. In addition, venous stasis and coagulation factor changes as seen in hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome lead to an overall increase in hypercoagulability, mostly seen in the third trimester and the postpartum period, leading to an increased risk of ischemic strokes.16
Risk factors for stroke in pregnancy include history of migraine, gestational diabetes, and pre-eclampsia or eclampsia.17 Some variations are seen in risk factors for ischemic versus hemorrhagic strokes, with hypertensive disorders being more strongly associated with hemorrhagic and migraine with ischemic strokes.
Cardioembolism, pre-eclampsia, eclampsia (discussed in further detail in Section 3.2.3), and venous thrombosis are major contributors to stroke in pregnancy. One must also include the causes of stroke in the young in the differential diagnosis, such as arterial dissection and moyamoya syndrome. Pregnancy-specific cardioembolic etiologies include peripartum cardiomyopathy, a poorly understood cause of dilated cardiomyopathy in the peripartum period and paradoxical cerebral amniotic fluid embolism, especially if seen in conjunction with sudden cardiovascular collapse.18 Hematological conditions such as antiphospholipid antibody syndrome (APAS) and thrombotic thrombocytopenic purpura (TTP) may be triggered by pregnancy and lead to stroke. Finally, metastatic gestational choriocarcinoma can present with subdural, subarachnoid, and intracerebral hemorrhage due to metastases with invasion and erosion of blood vessels and oncotic aneurysmal formation.19 Figure 4-4 summarizes stroke mechanisms to which one should give special considerations.
Figure 4-4
Special considerations in etiology of ischemic strokes during pregnancy. The particular etiologies outlined in Section 2.2.b are illustrated here to highlight specific, cardiac, intraluminal (ie, hematological), and arterial conditions that can be specifically seen in pregnancy. Of note, venous thrombosis is not illustrated here but is a common and important consideration when investigating stroke in pregnancy. Abbreviations: APAS, antiphospholipid antibody syndrome; RCVS, reversible cerebral vasoconstriction syndrome; TTP, thrombotic thrombocytopenic purpura.
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