Headache & Pain
Neuroimaging of headache
Dec. 02, 2023
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Given the severity of possible outcomes, as well as the effect on the unborn child, the pregnant patient can be a challenge for the neurologist. As well, the postpartum period carries with it significant and unique neurologic risks. In this article, the author reviews the common complications of the central nervous system seen in pregnancy and the postpartum period. The key presenting features of eclampsia are discussed as well as ischemic and hemorrhagic cerebrovascular events.
• Pregnancy and delivery trigger multiple physiologic changes, leading to specific complications and modifying the course of neurologic and systemic disorders.
• Intractable vomiting may result in Wernicke encephalopathy, a potentially fatal condition that requires early recognition and urgent administration of thiamine.
• Most untreated or insufficiently treated survivors of Wernicke encephalopathy develop Korsakoff syndrome, characterized by anterograde and retrograde amnesia.
• The risk of ischemic and hemorrhagic stroke is increased mostly in the peripartum and postpartum periods.
• The risk factors or stroke in young pregnant women differ from those in elderly and are mostly related to venous thrombosis, reversible cerebral vasoconstriction, and preeclampsia/eclampsia. Investigating causes of stroke in the young is equally important.
• Although the clinical trials of thrombolysis for acute stroke excluded pregnant women, tPA was used successfully.
• Endovascular thrombectomy guided by imaging has improved the treatment of stroke due to large vessel occlusion.
• Low dose aspirin may cause gastroschisis during the first trimester but may be given safely thereafter for prevention of most types of ischemic stroke.
• Preeclampsia may be prevented by careful blood pressure control and a small dose of aspirin; eclampsia should be treated with intravenous magnesium sulfate.
• Heparin is the preferred treatment in patients with thrombophilia and cardioembolism, except in those with an older mechanical mitral valve and history of thromboembolism who may benefit from warfarin.
• Subarachnoid hemorrhage should be treated according to the guidelines for nonpregnant women.
The physiologic changes that occur during pregnancy and the puerperium can adversely affect the central nervous system and complicate the management of preexisting neurologic conditions. The effect of pregnancy on chronic neurologic conditions such as epilepsy, multiple sclerosis, myasthenia gravis, and migraine will not be discussed here.
Additionally, complications of anesthesia during and after delivery may be difficult to distinguish from those of pregnancy. Headache following dural puncture and cerebrospinal fluid leak are the most frequent CNS complications of anesthesia. A retrospective cohort study consisting of 1,003,803 women who received neuraxial anesthesia for delivery revealed that headache after dural puncture is associated with cerebral venous thrombosis, subdural hematoma, meningitis, depression, and low back pain. Seventy percent of the cerebral venous thrombosis and subdural hematoma were diagnosed during readmission, which occurred after a median time of 5 days (50).
Spinal cord lesions due to trauma, compression, ischemia, or total spinal block occur rarely, but the high morbidity and mortality associated with them demand early recognition and rapid intervention. Seizures during anesthesia may also be triggered by selective inhibition of the inhibitory neurons.
Diagnosis and management of the central nervous system disorders associated with pregnancy will be specifically addressed. Eclampsia is reviewed in this article, and it is also covered as an individual article.
Wernicke encephalopathy, a potentially fatal, yet treatable complication of thiamine deficiency, was described initially by Carl Wernicke in 1881 in 2 alcoholic patients and 1 woman with intractable vomiting from gastric stenosis caused by sulfuric acid ingestion (71). Its association with hyperemesis gravidarum was later noted (115). In 1888 Sir William Gowers described eclampsia or toxemia of pregnancy characterized by convulsions in pregnant women with hypertension, proteinuria, and edema. This syndrome is uniquely associated with pregnancy-induced hypertension. In 1899 Edward Lazard described the first intracerebral hemorrhage in pregnancy, noted at autopsy, to be the result of a ruptured aneurysm. John Abercrombie made the first autopsy description of puerperal cerebral phlebothrombosis in 1828; however, the clinical syndrome of central venous thrombosis was not described until Gowers in 1893.
• Wernicke encephalopathy presents with decreased consciousness or coma.
• Stroke is characterized by focal neurologic deficits corresponding to the areas affected.
• Preeclampsia occurs when high blood pressure is associated with neurologic deficits and oftentimes proteinuria.
• Seizures in patients with preeclampsia are the hallmark of eclampsia.
• There is an overlap between the clinical manifestations of preeclampsia, posterior reversible encephalopathy and reversible cerebral vasoconstriction syndrome, and HELLP.
Wernicke encephalopathy. Wernicke encephalopathy manifests as decreased consciousness, ataxia, nystagmus, and ophthalmoparesis. The patients at risk have a history of intractable vomiting. Thiamine deficiency can develop rapidly. In a single center series of 8735 autopsies performed over 5 years in Oslo, 70 cases (0.8%) of Wernicke encephalopathy were diagnosed. Of these, 22 were acute and subacute, and the rest were chronic (Korsakoff syndrome). Stupor and coma were the dominating symptoms in active cases (113). Seizures and generalized epileptogenic activity on EEG were also noted (87). Because of various presentations, misdiagnosis of Wernicke encephalopathy as depression is possible (106).
In a retrospective analysis of 131 cases diagnosed at necropsy, only 16% presented with the classical clinical triad and 19% had no clinical signs documented (54). If untreated, patients develop Korsakoff syndrome may develop, characterized by severe anterograde and retrograde amnesia associated with confabulation in the initial stages. A disorientation to time is apparent. The emotional changes consist of apathy or mild euphoria, which respond little to various events (101). Additionally, executive function and emotion perception in others are impaired (06).
Cerebrovascular disease. All types of cerebrovascular disease, including transient ischemic attack, ischemic and hemorrhagic stroke, subarachnoid hemorrhage, dural sinus thrombosis, and cerebral venous thrombosis can be seen during pregnancy and puerperium. Clinical presentation ranges from transient focal symptoms to coma and death. The neurologic deficits reflect the location of the insult and may present with hemiparesis, hemisensory loss, visual disturbances, neglect, aphasia, or alteration of awareness/coma. Headache and seizures can also occur.
Occlusion of the deep cortical veins or the superior sagittal and lateral sinuses occurs more often during pregnancy. A higher frequency of headache (91%), seizures (39%), or increased intracranial pressure including papilledema (28%) distinguishes venous from arterial occlusion (26).
Intracerebral hemorrhage can be due to hypertension, preeclampsia, or venous thrombosis. Congenital vascular abnormalities such as aneurysms and arteriovenous malformations can also cause intracerebral hemorrhage.
Subarachnoid hemorrhage is usually caused by a ruptured aneurysm. If subarachnoid hemorrhage occurs in preeclampsia, rupture of small pial veins or superficial cortical petechiae are the likely causes (124). Subarachnoid hemorrhage with vasospasm but no aneurysm diagnosed by angiography was also reported (41; 44). A patient who became rapidly comatose after subarachnoid hemorrhage recovered after cesarean section was performed (22). Cortical vein infarction due to thrombosis is another cause of subarachnoid hemorrhage (117).
Preeclampsia is defined as systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg measured on 2 occasions, at least 4 hours apart, associated with proteinuria developing after the twentieth week of pregnancy in a woman previously normotensive. If proteinuria is absent, preeclampsia is diagnosed as hypertension associated with new onset of any of the following: thrombocytopenia (< 100x9/L), elevated liver enzymes more than twice the normal concentration, elevation of creatinine more than twice normal or greater than 1.1 mg/dL in absence of other renal disease, pulmonary edema, new onset of unexplained headache, or visual disturbances. Preeclampsia with severe features occurs when systolic or diastolic pressures are greater than 160 or 110 mmHg, respectively, and preeclampsia is associated with end organ damage as described above. In this situation, the confirmatory measurement should be performed after a few minutes to expedite treatment (05).
The visual symptoms are caused by retinal exudates, hemorrhages, edema, and/or retinal detachment. In addition, cortical blindness has been attributed to microinfarcts and petechial hemorrhages in the visual cortex. Symptoms can progress rapidly but generally resolve within 24 hours of delivery.
Eclampsia occurs when seizures or coma develop in a patient with preeclampsia. Seizures are typically generalized tonic-clonic but may have focal or multifocal features (30). Seizures or coma can develop antepartum in 50% of patients, during labor in 25%, and postpartum in 25%. Postpartum seizures generally occur within the first 24 hours; however, cases have been diagnosed as late as 26 days postpartum.
Posterior reversible encephalopathy syndrome (PRES) often accompanies preeclampsia and eclampsia (85). In 1 center study, 46 of 47 patients (97.9%) with eclampsia had posterior reversible encephalopathy syndrome on neuroimaging (18). This is characterized by headache, encephalopathy, visual disturbances, and seizures associated with reversible vasogenic edema seen on CT or MRI (57).
Postpartum angiopathy or reversible cerebral vasoconstriction syndrome may occur, sometimes associated with preexisting preeclampsia, and occasionally mimic eclampsia due to the associated seizures (45). These patients usually present with multiple thunderclap headaches, seizures, confusion, visual changes, focal neurologic deficits, and coma.
HELLP syndrome (hemolysis, elevated liver function, and low platelets) may also be associated with preeclampsia. It presents with generalized edema, right upper quadrant or epigastric pain, and nausea and vomiting, typically worse at night (10).
Approximately 80% of untreated patients who survive Wernicke encephalopathy related to alcohol abuse develop Korsakoff syndrome. The estimated mortality is 17% (116). Treatment with 100 to 250 mg of thiamine daily did not prevent mortality, and up to 84% patients developed Korsakoff syndrome. Higher dose of thiamine, more than 500 mg daily for several days, increased the rate of recovery. In a small case series, complete resolution of symptoms occurred in 7 out of 11 patients (91). A systematic review of the case studies including 177 patients with hyperemesis gravidarum found chronic cognitive impairment in 64.5%, a pregnancy loss of 50%, and maternal mortality of 5% of cases. Thiamine supplementation was inadequate in 63.6% of cases (93).
Cerebrovascular disease accounts for a significant increase in morbidity and mortality during pregnancy. Analysis of a Nationwide Inpatient Sample from the United States for the years 2000 to 2001 showed a mortality rate of stroke of 1.4 per 100,000 deliveries (60). The Maternal Mortality Collaborative reported that 8.5% of deaths during pregnancy are related to stroke (03). Another nationwide population-based study from the United Kingdom showed a case fatality rate of 20% of all strokes and 50% of hemorrhagic strokes. The mortality rate of stroke was 0.3 per 100,000 deliveries (100). However, pregnant women with hemorrhagic stroke had fewer risk factors and better prognosis compared with nonpregnant women (76).
Complications of pregnancy that were significant risk factors for stroke were postpartum hemorrhage, OR 1.8; preeclampsia and gestational hypertension, OR 4.4; transfusion OR 10.3; and postpartum infection, OR 25.0 (60).
The mortality rate from subarachnoid hemorrhage was estimated at 27% to 40%, whereas the mortality rate from arteriovenous malformations was 28% (28). Prognosis was directly related to severity of neurologic grade at presentation of bleed (121).
Early surgery for aneurysm rupture was associated with decreased mortality rates to surgical or endovascular treatment of aneurysms should be done based on neurosurgical principles; no mortality benefit was noted with interventional treatment of ruptured arteriovenous malformations (28). Labor and delivery do not appear to increase the risk of hemorrhage from arteriovenous malformations or aneurysms, and the decision to perform caesarean section should be based on obstetric indications (58).
Historically, cerebral venous thrombosis has been associated with a high mortality rate; however, of the patients presenting with cerebral venous sinus thrombosis, 59% had modified Rankin scale (mRS) of 0 and 94% and had mRS of 0 to 2 at follow-up. Patients with headache alone had an excellent outcome. Obtundation and coma predicted against excellent outcome (65). A multicenter observational study showed that patients with gender-specific risk factors (ie, pregnancy) had a rate of death/dependency of 12% compared with 20% in men and women without such risk factors (26).
Eclampsia causes approximately 60,000 maternal deaths per year worldwide (123). In the United States, the overall preeclampsia-eclampsia case-fatality rate was 6.4 per 10,000 cases at delivery, and it was twice as high for black women as for white women (83). Neonatal and maternal complications markedly increase when preeclampsia develops before 32 weeks’ gestation (102). Although believed to be transient, white matter lesions persisted on brain MRI performed after 7 years in 40% of eclamptic women compared with 17% of controls. Additionally, neurocognitive testing revealed memory impairment in women who had preeclampsia or eclampsia (124). Furthermore, data from the Stroke Prevention in Young Women Study found a 60% increased risk of nonpregnancy-related ischemic stroke in women with a history of preeclampsia (20).
In a retrospective cohort of 70 patients with PRES, 94% had altered consciousness, 81% had seizures, and 14% had ischemic stroke or intracerebral hemorrhage. Most patients (56%) recovered at 90 days but 16% died and 37% had marked functional impairment (78).
Few patients with reversible cerebral vasoconstriction syndrome continue to have neurologic sequelae after stroke; 9% have severe deficits. Mortality from reversible cerebral vasoconstriction syndrome is approximately 2% (104).
The prognosis of HELLP is similar to severe preeclampsia except for the hematologic variables (52).
A 30-year-old primigravida presented at 39 weeks’ gestation with symptoms of early labor. She had no complications with pregnancy. Her only medication was low-dose aspirin for a remote history of a patent foramen ovale and transient visual symptoms. She delivered a healthy male infant with a forceps-assisted vaginal delivery. No symptoms of hypertension, edema, or proteinuria were noted. Approximately 6 hours postpartum, her blood pressure was 180/110 mm Hg and new proteinuria developed. She complained of chest pain and severe headaches. Within a few hours, she developed blurry vision in her right eye, ptosis, and lower extremity numbness. Subsequently, she had a generalized tonic-clonic seizure lasting 30 seconds. She was treated with intravenous diazepam and magnesium sulfate. Blood pressure responded to nitroglycerin.
Laboratory abnormalities were platelet count of 34,000, liver transaminases greater than 1600 mg/dl, prolonged prothrombin time, elevated creatinine, and hemolysis on peripheral blood smear. CT, MRI, and MR angiography showed a right frontal subarachnoid hemorrhage and diffuse cerebral edema. There was no venous thrombosis or arterial occlusion.
The headache and mental status worsened, requiring transfer to the neurointensive care unit. She received mannitol and dexamethasone. The seizures stopped and her neurologic deficits resolved. Over the next 5 days, her laboratory abnormalities normalized.
This patient illustrates many aspects of severe eclampsia associated with HELLP syndrome. She had a rapid progression of neurologic symptoms in the early postpartum period. Symptoms resolved rapidly with aggressive treatment of hypertension, seizures, and cerebral edema.
• Hyperemesis gravidarum causes thiamine deficiency, Wernicke encephalopathy, and Korsakoff syndrome if left untreated.
• Most strokes occurred in the peripartum period and the risk factors differed from the general population.
• Congenital and acquired coagulopathies play an important role in the genesis of both arterial and venous stroke.
• There is an overlap between the hormonal changes and interaction with vasoactive agents in the development of preeclampsia, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome.
The central nervous system complications in pregnancy have multiple causes. Physiologic changes occurring during pregnancy include a relative hypercoagulable state, hormonal changes, and shifts in vascular volume.
Nausea and vomiting occur in approximately 70% of pregnant women. The more severe form hyperemesis gravidarum may affect 0.3% to 10.8% of pregnancies and lead to depletion of thiamine, a coenzyme essential for glucose metabolism. Etiology has a placental component by implicating common variants in genes encoding placental proteins and hormone receptors (40).
Thiamine deficiency triggers, particularly in Europeans, Wernicke encephalopathy and polyneuropathy or dry beriberi (16). This results in lactic acidosis and necrosis in the medial thalami, mammillary bodies, periaqueductal and paraventricular areas, locus ceruleus, cranial nerve nuclei, and superior cerebellar vermis (108).
The human body stores approximately 30 mg thiamine and requires 1 to 2 mg of thiamine daily for the oxidative metabolism. The daily needs are increased by alcohol consumption (110). Moreover, the blood level of thiamine may be decreased in pregnant women despite taking multivitamins (08). Wernicke syndrome may be accelerated by prolonged administration of glucose infusion without thiamine (118).
Certain individuals have a genetic susceptibility to develop thiamine deficiency on a diet limited in thiamine (101). Multiple humoral factors, from growth differentiation factor 15, insulin-like growth factor binding protein 7, glial cell line-derived neurogenic factor family receptor alpha-like receptor, to the progesterone receptor play a role in etiology of hyperemesis gravidarum (37).
Etiology of stroke may or may not be related to pregnancy. Arterial occlusion caused by cardioembolism, arterial disease, and hematologic abnormalities is the major cause of ischemic stroke in pregnancy (31). Additional risk factors include conditions unique to pregnancy such as peripartum cardiomyopathy, cerebral angiopathy, trophoblastic disease, preeclampsia, and eclampsia. A single-center retrospective study among women with pregnancy-associated stroke had fewer vascular risk factors. Most strokes occurred postpartum and were caused by cerebral venous thrombosis and reversible vasoconstriction syndrome (90).
The risk factors for stroke were age of 35 years and older; African-American race odds ratio (OR) of 1.5; migraine headache OR 16.9; thrombophilia OR 16.0; systemic lupus erythematosus OR 15.2; heart disease OR 13.2; sickle cell disease OR 9.1; hypertension OR 6.1; and thrombocytopenia OR 6.0 (60).
Atherosclerosis accounts for 25% of cases during pregnancy. Pregnancy may aggravate preexisting cardiac abnormalities (eg, valvular disease) or may cause new abnormalities (eg, peripartum cardiomyopathy). Arterial abnormalities like dissection, moyamoya, and Takayasu arteritis may be exacerbated by pregnancy. Other rare causes include air, fat, and amniotic fluid emboli (69). Retrospective analysis of 12 papers including 270 pregnant women with moyamoya disease has not detected an increased risk of stroke during pregnancy (42).
Inherited thrombophilias are associated with venous thromboses during pregnancy (46). Pregnancy is associated with a relative hypercoagulable state. Increased levels of fibrinogen and factors I, II, VII, VIII, IX, and XII, and decreased levels of protein S and C have been documented. Moreover, the thrombolytic pathway is inhibited (17). Acquired hematologic abnormalities that increase the risk of arterial occlusion include disseminated intravascular coagulation, sickle cell disease, thrombotic thrombocytopenic purpura, and antiphospholipid antibodies (112; 49). Clinical risk factors for peripartum and postpartum strokes include hypertension, cesarean delivery, and electrolyte and acid-base disorders (75).
Venous occlusion is associated with dehydration, infection, and hyperviscosity, which commonly occur during pregnancy. Antithrombin III deficiency, protein S and C deficiencies, and paroxysmal nocturnal hemoglobinuria are some of the acquired disorders associated with increased venous infarcts (31). Additionally, genetic mutations in the prothrombin, factor V Leiden, and methylenetetrahydrofolate reductase genes have been associated with an increased risk of venous thromboembolism (46).
In patients with preeclampsia and eclampsia, loss of cerebral blood flow autoregulation, hyperperfusion, and edema was observed (23). The increase in progesterone, human chorionic gonadotropin, and relaxin may affect the cerebral vasculature (28). Additionally, excessive release of antiangiogenic factors by placenta like the soluble fms-like tyrosine kinase 1 and soluble endoglin was noted. This, coupled with reduced levels of proangiogenic factors like placental growth factor and vascular endothelial growth factor A, may explain the cerebrovascular manifestations (36). Other vasoactive agents involved in preeclampsia are nitric oxide, prostacyclin, thromboxane A2, endothelin-1, and angiotensin II (47).
The blood-brain-barrier (BBB) permeability is also affected. The plasma concentrations of neuronal injury like neurofilament light (NfL), tau protein, neuron-specific enolase (NSE), and S100B were higher in women with preeclampsia than in women with normal pregnancies. Moreover, NfL level was increased in preeclampsia than in nonpregnant women and was associated with decreased transendothelial electric resistance of in-vitro model of blood-brain-barrier (43). In women with preeclampsia, neuron-specific enolase and S100B elevation persists at 1 year following delivery (13).
Neuroinflammation plays an important role too. Women with preeclampsia had increased CSF levels of interleukin 6 and 8. Women with eclampsia had, in addition, increased level of tumor necrosis factor alpha (14).
The clinical characteristics of preeclampsia, eclampsia, and posterior reversible encephalopathy syndrome are similar. However, in preeclampsia, the symptoms can occur at blood pressures significantly lower than in posterior reversible encephalopathy syndrome. Reversible vasogenic edema resembles that seen in posterior reversible encephalopathy syndrome was demonstrated on CT or MRI (57). In a retrospective study of 49 women with preeclampsia and eclampsia with neurologic symptoms, 90% of patients with eclampsia and 20% of those with preeclampsia had MRI changes suggestive of posterior reversible encephalopathy syndrome (85).
The focal neurologic deficits of preeclampsia are related to intracerebral hemorrhage (117), severe cerebral edema (56), ischemic stroke from vasospasm (55), or even carotid artery occlusion during rebound thrombocytosis as was seen in 1 patient with HELLP (66).
Mortality typically results from large hematomas and severe cerebral edema (64).
• Of nonalcoholic cases of Wernicke encephalopathy, hyperemesis gravidarum is the most common cause.
• Insufficient treatment of Wernicke encephalopathy leads to Korsakoff syndrome.
• The risk of both ischemic and hemorrhagic stroke is lower in prepartum women but increases up to the 12 weeks.
Out of 585 cases on nonalcoholic cases of Wernicke encephalopathy, the most common cases were due to hyperemesis gravidarum (177), cancer (129), and hunger strike (119) (94). Wernicke encephalopathy is diagnosed postmortem in up to 80% of cases (54). Approximately 80% of untreated or incompletely treated survivors with a history of alcohol related Wernicke encephalopathy develop Korsakoff syndrome characterized by severe memory impairment (116).
Between 1955 and 1979, the likelihood of pregnancy-related stroke was 13 times the expected rate in nonpregnant women of similar age distribution (122). However, the stroke risk varies with the pregnancy stage. The relative risk of ischemic stroke adjusted for age and race was 0.7 during pregnancy but increased to 8.7 postpartum (up to 6 weeks) (68).
A U.S. nationwide sample showed an incidence of stroke of 34.2 per 100,000 deliveries. There were 1.4 deaths per 100,000 deliveries (60). A systematic review and metanalysis that included 11 studies found that stroke affects 30 out of 100,000 pregnancies (107). Although rare, peripartum stroke is 3 times more frequent than in the young population of European descent (53). Discharge data from nonfederal emergency departments and acute care hospitals in California show a modestly increased risk of thrombotic events (stroke, myocardial infarction, or venous thromboembolism) after the seventh week until the twelfth week, but not beyond (63).
In England, data from an open cohort study revealed an increased incidence rate of first ischemic and hemorrhagic stroke both in peripartum and early postpartum. The incidence rate of stroke was 25.0 per 100,000 person-years outside pregnancy. The rate was lower antepartum, 10.7 per 100,000 person-years, but increased 3-fold within 6 weeks to 47.1 per 100,000 person-years, and up to 9-fold to 161.1 per 100,000 person-years within 12 weeks (09).
In New York State, the risk of stroke associated with pregnancy was increased in women younger than 35 years of age, but not in older women (88).
The risk of recurrent strokes in subsequent pregnancies was less than 1% at 1 year and 2.3% at 5 years (74).
The incidence rate of intracerebral hemorrhage is 3.5 to 4.6 per 100,000 deliveries. The adjusted relative risk was 2.5 during pregnancy, but it increased to 28.3 for the postpartum period. Overall, for both ischemic and hemorrhagic stroke during pregnancy and peripartum period, the adjusted relative risk was 2.4. The attributable, or excess, risk was 8.1 strokes per 100,000 pregnancies (68).
A pooled analysis of 13 studies showed that the risk of pregnancy-related venous thrombosis and venous thromboembolism were low, 0.9% and 0.27%, respectively. However, the relative risk of noncerebral venous thromboembolism is 16-fold higher (2.7%), and the recurrence of cerebral venous thrombosis is 80-fold higher (0.9%) than the risk in general population. The rate of miscarriage is not different from the general population (04). Cerebral venous sinus thrombosis occurred in 10 to 20 per 100,000 births in North America and Europe but in up to 200 to 500 per 100,000 births in India. Most cases occurred during the second or third week postpartum (31; 75).
Subarachnoid hemorrhage occurs in 1 of 10,000 pregnancies but is 5 times more common in pregnant versus nonpregnant women (121).
The incidence of gestational hypertension/preeclampsia is approximately 6% to 8% in the United States. The rate of preeclampsia is 2% to 7% in healthy nulliparous women; 14% in women with twin gestation; and 18% in women with prior preeclampsia (102). There appears to be a racial predisposition; 5% to 10% of whites and 15% to 20% of blacks are at risk. Other high-risk groups include new paternity, multiparous women older than 35 years of age with extrauterine pregnancy, hydatidiform mole, or multiple pregnancies (103; 64; 119). The incidence of eclampsia was 2.7 cases per 10,000 births in a population-based epidemiologic study in the United Kingdom in 2005, a nearly 50% reduction compared to data from 1992 (70).
• Thiamine should be given to any patient at risk of Wernicke encephalopathy.
• Hypoglycemia may be corrected urgently before thiamine is given but must be followed by thiamine.
• Korsakoff syndrome responds little to thiamine once it has developed.
• Aspirin in small dose helps prevent ischemic stroke.
• Low molecular weight heparin prevents venous thromboembolism.
• Warfarin is used for metallic valves after the thirteenth week.
• Pregnancy does not need to be terminated after discovery of unruptured aneurysms or arteriovenous malformations.
Wernicke encephalopathy is prevented by administering intravenous thiamine to patients at risk. However, if glucose administration is urgent, it should be given before thiamine infusion is started (51). In absence of clinical trial data, rapid thiamine supplementation after or during the glucose administration is recommended (99). Prompt administration of intravenous thiamine may also prevent Korsakoff syndrome, which responds little once developed. Intramuscular thiamine 250 mg should be administered daily to patients with poor nutritional status (109).
Prevention of stroke during pregnancy should address the usual risk factors, in particular smoking.
If the risk of stroke is low, low dose aspirin is recommended. Aspirin crosses the placenta and may cause gastroschisis during the first trimester (73). Aspirin teratogenicity seen in retrospective studies was not confirmed by the prospective studies (11). However, of concern is premature closure of the fetal ductus arteriosus, maternal and/or fetal hemorrhage. During the second and third trimesters, aspirin dose less than 150 mg daily is safe (59).
Subcutaneous unfractionated heparin (UFH) or low molecular weight heparin (LMWH) is recommended for prevention and treatment of venous thromboembolism and of stroke in pregnant women with thrombophilia. Heparins do not cross the placenta and are not associated with teratogenicity or increased risk of fetal hemorrhage.
Low molecular weight heparin has a lower risk of osteoporosis and thrombocytopenia compared to unfractionated heparin (27). Low molecular weight heparin can be administered throughout pregnancy except for a minimum of 24 hours before the expected neuraxial anesthesia, induction of delivery, or C-section.
Patients with mechanical valves may benefit from 1 of the following regimens:
(a) Unfractionated heparin given subcutaneously every 12 hours and adjusted to keep mid-interval PTT at least twice the control level.
(b) Low molecular weight heparin adjusted to maintain the manufacturer’s peak anti-Xa heparin level 4 hours after the injection.
(c) For older metallic mitral valve prosthesis with higher risk for thrombosis, or additional history of thromboembolism, unfractionated heparin or low molecular weight heparin may be used as above until the thirteenth week, after which they are replaced by warfarin. Shortly before delivery, heparin is resumed. Women who are more concerned about the fetal risk more than the risk of valve thrombosis may choose heparin over warfarin. Addition of 75 to 100 mg of aspirin to the regimen of patients at very high risk is also suggested.
Women requiring long-term anticoagulation for other indications should be switched as soon as pregnancy is determined to dose adjusted or 75% of therapeutic low molecular weight heparin for the duration of pregnancy.
Warfarin crosses the placenta, is teratogenic during the first trimester, and increases the risk of fetal hemorrhage. Its use is limited to very high-risk cases such as mechanical heart valve, or when there are concerns about the safety or efficacy of heparin or low molecular weight heparin. A discussion about the risks, benefits, and patient’s concerns is very important.
The new oral anticoagulants, such as direct thrombin inhibitors (eg, dabigatran) or anti-Xa (eg, rivaroxaban, apixaban) should be avoided (11).
Pregnancy and puerperium do not increase the risk of hemorrhage in women with cavernous hemangioma (62) or aneurysm (111; 67). This suggests that pregnancy is not contraindicated or needs to be terminated when an incidental lesion is found. Unruptured arteriovenous malformations did not tend to bleed in 1 study (80) but bled more often in another (96). This conflicting data may reflect outcomes in different populations.
Prevention of subarachnoid hemorrhage includes treatment of hypertension, avoidance of alcohol and tobacco, and a diet rich in fiber. In patients with first degree relatives with a history of subarachnoid hemorrhage or history of subarachnoid hemorrhage it is reasonable to offer noninvasive screening for undiagnosed or late regrowth of an aneurysm. Immediately after an aneurysm is secured by clipping or coiling, follow-up imaging is useful in detecting remnants or recurrence of an aneurysm that may require further management (25).
Screening for preeclampsia is recommended through pregnancy by measuring blood pressure (114).
Low dose aspirin is recommended throughout pregnancy starting from the second trimester (11). The number needed to treat (NNT) to prevent 1 case of eclampsia was 68 overall, though by separating out just high-risk women, the NNT dropped to 18 (34). Magnesium sulfate is superior to placebo or phenytoin at preventing seizures in women with preeclampsia (82; 24; 84). In a comparison study of women with severe preeclampsia, magnesium sulfate was more effective for seizure prophylaxis than nimodipine (12). The role of prophylactic magnesium sulfate in mild preeclampsia remains unclear (81; 102).
• Focal neurologic symptoms suggest ischemic or hemorrhagic stroke, tumor, abscess, or encephalitis.
• Malnutrition or prolonged vomiting suggest Wernicke encephalopathy.
• Altered mental status should prompt exclusion of top of the basilar syndrome, encephalitis, Behcet disease, Miller-Fischer syndrome, Creutzfeldt-Jakob disease, and toxic-metabolic states.
• Preeclampsia should be differentiated from thrombocytopenic thrombotic purpura, hemolytic uremic syndrome, and pheochromocytoma.
• Eclampsia differential diagnosis includes epilepsy, metabolic disorders, and pheochromocytoma.
Considerable overlap exists between the clinical presentations of the various central nervous system complications described. Focal neurologic symptoms should prompt investigation for cerebrovascular disease (particularly venous thrombosis, arterial occlusion, or embolism) and intracerebral or subarachnoid hemorrhage. Space-occupying lesions such as tumors and infection from brain abscess, meningitis, and encephalitis can also cause symptoms.
The association of ataxia, ophthalmoparesis, and altered mental status in the context of malnutrition or prolonged vomiting suggest Wernicke encephalopathy. However, not all symptoms are present and often alcohol abuse is suspected.
Other causes for acute encephalopathy should be excluded. Among these are stroke (top of the basilar syndrome), paraneoplastic encephalitis, Bickerstaff encephalitis, Bechet disease, ventriculoencephalitis, Miller-Fischer syndrome, Leigh disease, variant Creutzfeldt-Jakob disease, as well as various toxic metabolic states (101).
Transient focal neurologic symptoms during pregnancy present a diagnostic challenge. In a case control series of patients with transient focal dysphasia, hemisensory or hemimotor phenomenon in the absence of migraine, recurrent thromboembolism, or known cerebral vascular disease, only 1 of the 14 patients had infarction on MRI DWI (79). Nine of the 14 patients had headache of variable severity. None had abnormal MRV, echocardiogram, or carotid duplex ultrasonography, and none had a hypercoagulable state. No patients had recurrence of focal neurologic symptoms over a mean period of 12 months, although 4 patients developed recurrent migraine headaches.
Diagnosis of eclampsia can be difficult when seizures and coma herald the onset of neurologic involvement when preeclamptic symptoms are minimal. Epilepsy must always be considered in the diagnosis of convulsions during pregnancy. Metabolic disorders like hypoglycemia, hypocalcemia, and water intoxication can also induce seizures and coma. Pheochromocytoma associated with fluctuating hypertension and hypertensive encephalopathy should also be excluded (64).
Preeclampsia with hematologic abnormalities should be differentiated from thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Thrombotic thrombocytopenic purpura is an idiopathic severe multisystem disorder, often precipitated by pregnancy. Clinical features include fever, hemolytic anemia, thrombocytopenic purpura, renal disease, and neurologic symptoms of stupor, coma, and convulsions (39). Hemolytic uremic syndrome is considered part of the same spectrum of disease, with similar clinical features. Both disorders are managed with plasma therapy and corticosteroids (120).
• Wernicke encephalopathy should be suspected in any patient with insufficient food intake or excessive vomiting.
• Stroke evaluation should include the etiologies in young patients.
• Shielded CT scans are required in pregnant patients.
• CT is sensitive enough to detect subarachnoid hemorrhage in almost all cases.
• The blood tests for preeclampsia, eclampsia, and HELLP should include electrolytes, hemogram, hemolysis, and liver function.
The diagnosis of Wernicke encephalopathy is mainly based on the clinical features, as there are no specific routine laboratory tests. Thiamine level or red blood cell transketolase activity may confirm the initial suspicion. High-performance liquid chromatography has improved thiamine assessment (101). Lesions suggesting necrosis are visible on cerebral MRI in the regions associated with Wernicke encephalopathy: medial thalami, mammillary bodies, periaqueductal and paraventricular areas, locus ceruleus, cranial nerve nuclei, and superior cerebellar vermis (72; 07).
Acute ischemic strokes requires evaluation for causes of stroke in the young person (95). Complete blood count, sedimentation rate, syphilis screen, and coagulation studies should be performed. Testing for hypercoagulable states includes protein C and protein S levels, antithrombin III levels, and Russell viper venom test for antiphospholipid antibodies. Genetic screening includes Factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase mutations. Measurement of human chorionic gonadotropin can be useful if choriocarcinoma is a suspected cause of hemorrhagic stroke (31).
CT scan with proper shielding can rapidly exclude intracerebral hemorrhage or evaluate for edema. MRI can assess focal brain pathology, acute ischemia, and cerebral edema. CT or MR angiography may demonstrate arterial stenosis, vasospasm, or occlusion. MR venography can detect cerebral venous thrombosis. If contrast agents are used, adequate hydration is recommended. CT perfusion is useful for determining the existence of penumbra and mismatch between core and penumbra. Cardioembolism can be detected with EKG, loop recorder, and echocardiogram.
Lumbar puncture is essential for excluding subarachnoid hemorrhage but should be avoided if venous thrombosis with increased intracranial pressure is suspected (29). Advances in CT technology have improved the sensitivity for subarachnoid hemorrhage to 0.987 and specificity to 0.999 and may rule out hemorrhage within 6 hours from onset, without the need for lumbar puncture (32). Conventional cerebral angiography is useful for diagnosis of aneurysms and vasculitides.
If preeclampsia or eclampsia is suspected clinically, laboratory evaluation should include peripheral smear, hemolysis studies, and kidney and liver function tests. In less than one third of patients, the diagnosis of HELLP syndrome is made based on specific laboratory abnormalities (64).
• Thiamine is best administered intravenously in hyperemesis gravidarum.
• Antiemetics help reduce vomiting in hyperemesis gravidarum.
• Alteplase was used off-label in pregnant women and is reasonable to use if benefits outweigh the risks.
• Large arterial occlusion is more likely to be treated successfully with endovascular therapy.
• The benefits and risks of treatments in pregnant women should be thoroughly discussed with the patients.
• Vaginal delivery is safe after aneurysm repair.
• If the aneurysm is unsecured, cesarean section is recommended.
• Preeclampsia and eclampsia are best treated by delivery.
• Seizures respond better to magnesium sulfate intravenously.
Wernicke encephalopathy responds best to intravenous thiamine (54). Although no randomized trials are available, different regimens have been used: 500 mg intravenous over 30 minutes 2 to 3 times a day for 2 to 3 days or up to 6 days if no response is seen initially. If this regimen is effective, 250 mg intravenous or intramuscular is given daily for 5 days or until clinical improvement ceases.
Moderate to severe nausea respond to pyridoxine-doxylamine, promethazine, metoclopramide, and ondansetron (86).
Pregnant women were excluded from the randomized trials of stroke treatment. Alteplase or tPA is category C, does not cross placenta, and is not associated with animal teratogenicity. Off-label use of thrombolytics in 11 pregnancies (5 intravenous and 6 intraarterial) resulted in 1 fatal intracerebral hemorrhage and 3 extracranial hematomas. Six fetuses were lost to abortion, 3 of which were elective (02). Analysis of Get With The Guidelines-Stroke registry data shows that nonpregnant women who received rt-PA had similar outcomes (77). It is reasonable to treat moderate or severe stroke with tPA if the benefit seems to outweigh the increased risk of uterine hemorrhage (97).
In the clinical trials that enrolled nonpregnant patients, large vessel occlusion is treated more effectively by endovascular treatment than intravenous rtPA alone (15; 21; 48; 61; 98). Perfusion imaging helps selection for endovascular intervention of patients presenting between 6 to 16 hours from the last time they were known to be normal (01). Even patients with stroke onset between 6 to 24 hours who exhibit a mismatch between the core delineated by MRI-DWI or CT perfusion and clinical severity may benefit from endovascular intervention (92). As endovascular treatment was not tested specifically in pregnant women, a thorough discussion of the risks and benefits as well as careful shielding are needed (19).
The definitive treatment of aneurysmal subarachnoid hemorrhage is urgent coiling or clipping of the aneurysm. Until the aneurysm is secured, the target systolic blood pressure is less than 160 mmHg, to prevent rebleeding while maintaining cerebral perfusion. During anesthesia, it is important to avoid hypotension.
Vasospasm and delayed cerebral ischemia may be prevented by administration of oral nimodipine and intravenous fluids. Vasospasm may be detected with serial transcranial ultrasound. CT or MR perfusion may delineate the areas vulnerable to ischemia. If vasospasm and cerebral ischemia does not respond rapidly to hydration, intra-arterial balloon angioplasty combined with a vasodilator may be needed to prevent stroke (25).
After the ruptured aneurysm is secured, vaginal deliveries are safe. In untreated cases, cesarean section is recommended. Surgical repair of the aneurysm immediately after delivery has been successfully performed (121; 30). Management of aneurysmal subarachnoid hemorrhage and arteriovenous malformations may require transfer to a specialized medical center (105). Treatment of vascular malformations during pregnancy should be based on the same neurosurgical principles as in the nonpregnant state (28).
The definitive treatment of preeclampsia and eclampsia is delivery (119). Control of hypertension, seizures, and management of cerebral edema may be needed. In severe cases, transfer to a neurointensive care unit, intubation, and hyperventilation may be necessary to manage cerebral edema. Mannitol may be used cautiously to avoid placental dehydration and pulmonary edema (64).
The management goal is prevention of cerebral and cardiovascular complications by lowering mean arterial pressure by 20% to 25%. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during pregnancy. In a meta-analysis of antihypertensive therapy, early treatment decreased the frequency of the maternal hypertensive crisis and of neonatal complications. Treatment should be guided by physician’s familiarity with the specific agents. Labetalol and nifedipine were more effective and safer than hydralazine. Nimodipine, diazoxide, ketanserin, and magnesium sulphate are best avoided for hypertension treatment (35).
Seizures, one of the most common neurologic complications in preeclampsia, respond best to magnesium sulfate (24; 33; 84). Potential mechanisms include magnesium-induced vasodilation, protection of the blood-brain barrier resulting in decreased cerebral edema, or anticonvulsant activity mediated through NMDA receptor antagonism (38). Toxicity of magnesium includes profound weakness, hypoventilation, tocolysis, anesthetic complications, and neonatal weakness (30). Magnesium sulfate should be administered for prevention of seizures, with close monitoring of toxicity and serum levels of 4.2 to 8.4 mg/dL (38).
In patients with ischemic or hemorrhagic stroke, neuraxial analgesia and anesthesia are generally safer than general anesthesia. Unless cesarean is required for obstetrical reasons, vaginal delivery is preferred. Therapeutic anticoagulation or increased intracranial pressure are indications for cesarean delivery, in which case, general anesthesia is preferred (89).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Adrian Marchidann MD
Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.See Profile
Peter J Koehler MD PhD
Dr. Koehler of Maastricht University has no relevant financial relationships to disclose.See Profile
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