Neurovascular disorders in pregnancy: A review

Short abstract

While rare, neurovascular disorders that occur in pregnant or postpartum women are associated with high morbidity and mortality, thus necessitating prompt identification and treatment. The most common symptoms include headache, focal neurological features, and seizures. Factors such as pregnancy-related hypercoagulability and hemodynamic changes put women at risk for neurovascular disorders in the third trimester and early postpartum period. The biggest risk factors for stroke in pregnancy are hypertension and the preeclampsia/eclampsia spectrum. This review outlines the diagnosis and treatment of pregnant and postpartum women with ischemic and hemorrhagic stroke, cerebral venous sinus thrombosis, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome.

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Introduction

Neurovascular disorders refer to a collection of diseases that result from thrombosed, ruptured, leaky, or constricted cerebral blood vessels. When they occur in pregnancy and postpartum, these diseases can be life-threatening and disabling. In this review, we will discuss pregnancy and postpartum-related ischemic and hemorrhagic stroke, cerebral venous sinus thrombosis (CVST), posterior reversible encephalopathy syndrome (PRES), and reversible cerebral vasoconstriction syndrome (RCVS). Pregnant and postpartum women are at risk for these disorders due to several shared physiologic and pathologic factors. First, hypercoagulability of pregnancy increases the risk for ischemic stroke and thrombus formation. Second, while the normal maternal brain is protected against the vasoactive effects of circulating placental factors by a robust endothelium¹ and fluctuations in perfusion by cerebral autoregulation,¹ the hypertensive disorders of pregnancy upset that careful balance. Preeclampsia and eclampsia cause endothelial dysfunction and failure of autoregulation, leading to cerebral vasoconstriction, forced vasodilation, vasogenic edema, and hypertension itself can lead to ischemia and/or vascular rupture. In pregnancy, neurovascular disorders can occur in isolation or overlap with one another; it is possible, for example, to have CVST with features of both ischemia and hemorrhage, and it is possible to have RCVS, PRES, ischemic, and hemorrhagic stroke all at once.

Clinical features and diagnosis

The clinical features of neurovascular disorders also overlap substantially, with common symptoms like seizure or confusion, and focal neurological features, like aphasia, visual loss, sensory loss, dysarthria, hemiparesis, or abnormal gait. Headache is a major feature present in most neurovascular disorders. A retrospective study of 140 pregnant inpatients with headache at Montefiore Hospital, seen by a neurologist, found that over one-third had secondary causes of headache, and the majority of these secondary headaches were due to neurovascular causes.² Therefore, clinicians caring for pregnant women should be alert to the presence of headache “red flags”: systemic and neurological signs and symptoms, sudden onset of headache pain, positional headaches, and no prior headache history.

When symptoms are acute (hours to days), and the index of suspicion is high and would warrant urgent intervention, then brain computerized tomography (CT) and CT angiogram (CTA) are recommended should MRI not be immediately available. CT and CTA can rapidly detect acute hemorrhage and detect a ruptured vascular malformation (aneurysm or arteriovenous malformation) or large vessel occlusion that would require urgent intervention. Head CT is associated with less than 0.1mGy exposure to the fetus and a single dose of CT contrast in pregnancy is felt to be safe.^3,4 For gradual symptoms over days to weeks, or as a follow-up to CT, MRI is the preferred test, along with non-contrast MR angiogram (MRA) and MR venogram (MRV) to evaluate the cerebral vasculature; these tests do not require gadolinium, which is avoided in pregnancy. MRI is more sensitive than CT for visualizing the brain parenchyma. Neurovascular disorders warrant an early neurology consultation, as early intervention can vastly improve the chance of a favorable neurological outcome.

Acute ischemic arterial stroke

Stroke of any cause is responsible for around 12% of maternal deaths, as well as significant adverse effects on the fetus.⁵ The incidence of stroke in pregnancy is around 30 cases per 100,000 deliveries.⁶ Pregnant women are at two to three times higher risk for stroke compared to the general population, with the highest risk in the third trimester and first 6–12 weeks after delivery.^6,7 Women with hypertensive disorders in pregnancy, which occur in 5–10% of all pregnancies worldwide, are at even higher risk for stroke, 4–5 times higher than healthy controls.^5,8–10

Patients with acute ischemic arterial stroke most often present with the sudden onset of focal neurological signs and symptoms, often without headache or with a mild headache—a feature more common among younger women with strokes.^11,12 An acute ischemic stroke is not typically detected on head CT, but the CT is performed to exclude hemorrhage and assess the cerebral blood vessels (CTA). Outside of pregnancy, patients who present within 4.5 h of ischemic stroke onset, and with no evidence of hemorrhage on CT or recent surgeries, bleeding, or taking anticoagulants are candidates for lytic therapy with intravenous alteplase. Since 2015, five major studies have determined mechanical thrombectomy (clot retrieval via cerebral angiography) plus intravenous alteplase to be superior to intravenous alteplase alone in the treatment of acute arterial ischemic stroke.¹³ The use of alteplase in pregnant women is controversial and no guidelines exist. Although alteplase does not cross the placenta, there have been rare cases of uterine hemorrhage.¹⁴ Therefore, the use of intravenous alteplase and mechanical thrombectomy to treat pregnancy-related stroke is determined on a case-by-case basis, weighing the severity of stroke deficits against the potential risk of hemorrhage.

Among the nonpregnant population with ischemic arterial stroke, antiplatelet therapy is used for secondary stroke prevention; anticoagulation is reserved for those patients in whom a definite cardioembolic source is found. In pregnancy, low-dose aspirin is recommended secondary prevention, as there is insufficient data to support anticoagulation without an obvious stroke source.¹⁵ Investigation of stroke etiology in pregnancy includes MRI without contrast, electrocardiogram, cardiac telemetry, transthoracic echocardiogram with bubble study to evaluate for shunt, carotid ultrasound, transcranial dopplers, medical risk factor stratification (including HbA1c, lipid panel, smoking history), and thrombophilia workup.⁶

CVST and venous stroke

CVST refers to thrombus formation in the veins or venous sinuses of the head. CVST is an uncommon cause of stroke in the general population (0.5–1% of all strokes) but has a higher incidence in pregnancy (2% of pregnancy strokes), with a prevalence of about 12 cases per 100,000 pregnancies.^5,16 Patients with CVST typically present with gradual onset, worsening headaches, often with a high-pressure phenotype and with a postural relationship (typically worse lying than sitting or standing) and worse with Valsalva, due to further elevation of intracranial pressure. These headaches sometimes with additional mental status changes, seizures, and focal neurological deficits. Ischemic or hemorrhagic strokes can occur because of venous congestion with secondary ischemia, with or without vessel rupture. The clinical presentation may mimic that of preeclampsia or eclampsia, and the distinction is made with MRI and MRV, performed without contrast. MRV can be difficult to interpret due to the natural asymmetry of the venous sinuses; therefore, interpretation by a trained neuroradiologist is preferred, to prevent spurious diagnosis. Pregnancy-related hypercoagulability is the major risk factor, but other factors include dehydration, trauma, infection, and a genetic or acquired thrombophilia. Treatment for CVST identified in pregnancy is low-molecular-weight heparin (LMWH) at therapeutic doses. LMWH is typically continued for at least six weeks postpartum¹⁶ or until vessel recanalization. In pregnant patients with history of CVST in prior pregnancies, LMWH prophylaxis is recommended. In severe and acute cases, thrombolytic therapy or mechanical thrombectomy may be considered, but only case reports of thrombolytic therapy exist among pregnant women with stroke.¹⁷

Hemorrhagic stroke (intracranial hemorrhage)

Hemorrhagic stroke, synonymous with intracranial hemorrhage, occurs in the postpartum state more frequently than in pregnancy and is associated with an in-hospital maternal mortality rate of around 20%.¹⁷ Hemorrhage can result from perfusion of infarcted tissue, rupture of a vascular abnormality, or vascular rupture due to hypertension, RCVS or PRES, which are discussed below. Hemorrhagic stroke often presents with sudden onset, severe headache—termed a “thunderclap headache,” or described as the “worst headache of life,” with or without other neurological symptoms. An urgent CT and CTA can identify a ruptured aneurysm or arteriovenous malformation, vascular abnormalities that must be promptly identified and secured surgically or endovascularly to prevent maternal or fetal death.^18,19

Medical management of patients with hemorrhagic stroke involves supportive care—management of blood pressure, avoidance of and/or reversal of anticoagulant medications, and treatment in an intensive care unit. There is conflicting and inconclusive evidence regarding the risk of rupture of a known aneurysm and arteriovenous malformation in pregnancy compared to the nonpregnant state.^18,20

Posterior reversible encephalopathy syndrome (PRES)

The typical presentation of PRES involves the gradual onset of headache, with visual and mental status changes, seizures, and neurological deficits. On MRI, widespread T2/FLAIR hyperintensities (which appear as confluent white patches) representing vasogenic edema can be seen in the white matter of the posterior brain regions: the occipital, parietal and temporal lobes, the cerebellum, and the brainstem. The word “reversible” describes the radiographic and clinical course of PRES—as the causative factor is treated or withdrawn if known, both the symptoms and MRI normalize. One exception to the “reversible” nature of this disorder is that cerebral ischemia and hemorrhage may occur in the context of PRES, and while neurological sequelae may improve, they may not completely resolve following resolution of the episode. PRES may occur either during pregnancy or postpartum. Outside of pregnancy, risk factors include hypertension, the use of transplant and immunosuppressant drugs, chemotherapy, autoimmune disease like systemic lupus erythematosus, sepsis, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.²¹ Treatment of PRES involves supportive care, treatment of seizures with anticonvulsant medications, and treatment of ischemic and hemorrhagic strokes should they occur.

PRES is considered to be the “typical” MRI finding in eclampsia, although not all patients with eclampsia have evidence of PRES on MRI, and not all pregnant or postpartum patients with PRES are hypertensive. When PRES is seen with preeclampsia/eclampsia, it may indicate a more severe disease process—evidenced by higher hematocrit, serum creatinine, transaminases, lactate dehydrogenase, mean platelet volume, and infants with worse 1-min APGAR scores.^22,23

Reversible cerebral vasoconstriction syndrome (RCVS)

RCVS presents with a “thunderclap headache,” or the sudden onset of the worst headache of one's life. Cerebral aneurysm rupture should be excluded in all individuals with this clinical presentation, with urgent CT and CTA of the head. The characteristic finding of RCVS on CTA (or MRA) is segmental constriction of medium-sized cerebral arteries. After the initial “thunderclap”, the headaches of RCVS can recur over one to three weeks, giving way to dull and sometimes intractable headache pain. Like PRES, RCVS can also be associated with mental status changes, visual complaints, and seizures. RCVS occurs more commonly in postpartum than pregnant women, and it was previously known as postpartum angiopathy. Subarachnoid hemorrhage occurs in up to 22% of cases (classically located over the high cerebral convexity) and ischemic stroke occurs in 7% of cases.²⁴ Outside of pregnancy, RCVS can occur due to the use of vasoactive drugs (triptans, nasal decongestants, selective serotonin reuptake inhibitors, cocaine, and marijuana), following cervical artery dissection, and in individuals with history of migraine. RCVS affects women more than men and peak incidence outside of pregnancy is around age 40. Like PRES, RCVS resolves completely within three months unless there is associated ischemia or hemorrhage.²⁵ Calcium channel blockers like nimodipine and verapamil are typically prescribed for patients with RCVS, although based on little evidence. Prophylactic calcium channel blockers and oral magnesium can also be used to prevent headaches following RCVS.²⁶

Like PRES, RCVS is not always associated with elevated blood pressure. Nonetheless, identifying PRES or RCVS in a pregnant or postpartum woman, even in the absence of elevated blood pressure, should prompt consideration for preeclampsia, given the shared mechanisms of vasoconstriction and leaky vessels. As one might predict, PRES and RCVS have substantial overlap, with between 8% and 38% of patients with RCVS demonstrating PRES on MRI.^23,24 In small MRI studies of patients with eclampsia, the majority had radiographic evidence of PRES,²² with a quarter of preeclamptic patients also demonstrating PRES on MRI, sometimes with additional evidence of cerebral vasoconstriction.²² The prevalence of PRES and RCVS in pregnancy and postpartum is unknown.

Discussion

Neurovascular disorders in pregnancy are emergencies and carry potential for many short- and long-term sequelae. Clinicians can identify a neurovascular syndrome immediately by the presence of secondary headache, focal neurological symptoms, and seizures; however, symptoms and syndromes intersect. The acuity of presentation and consultation with neurology consultation should guide the neuroimaging choice. Slowly progressive symptoms warrant MRI, MRA, and MRV, while the acute onset of symptoms warrants urgent CT and often CTA, often followed by MRI, MRA, and MRV. Long term, women with a history of preeclampsia/eclampsia are twice as likely to experience a stroke in their lifetime compared to women with no history of the disease,²⁷ and more likely to have microvascular disease (white matter lesions) on MRI years later.^27,28 It is unknown if preeclampsia itself confers increased stroke risk or simply acts as a marker of future cerebrovascular disease in women. Although few guidelines exist for the treatment of pregnant and postpartum women with neurovascular syndromes, vascular neurology is a rapidly changing field with many new treatment options. With a prompt diagnosis, prognosis can be excellent.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Informed consent

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Guarantor

JR

Contributorship

JR and GD wrote and edited this manuscript.