The appropriate neurologic evaluation for a pregnant woman with a first seizure does not substantially differ from the evaluation indicated for any patient with a first-time seizure. A careful neurologic history is taken and an examination performed to detect any neurologic symptoms or signs that would indicate increased intracranial pressure, a CNS infection or hemorrhage, or a focal CNS lesion. The history is explored for risk factors for seizures and for epilepsy. The basic evaluation should include a complete blood cell count, measurement of electrolytes, liver and renal function tests, and a toxicology screen—particularly to detect cocaine or alcohol, which are the most common substances of abuse associated with seizures.⁴² The obstetric history includes determination of dates and an evaluation for hypertension, proteinuria, and edema to exclude pre-eclampsia and eclampsia.

Electroencephalogram (EEG) and neuroimaging are indicated in any woman seen with a seizure in the absence of eclampsia. If it has been determined that the seizure arose from pre-eclampsia/eclampsia and the presentation is otherwise not complicated, then EEG and neuroimaging are not usually required. However, if the patient with pre-eclampsia/eclampsia has focal neurologic symptoms or signs and partial seizures, EEG and neuroimaging should be obtained. Magnetic resonance imaging (MRI) is generally preferred to computed tomography (CT). Magnetic resonance imaging is the most sensitive technology for detecting CNS pathology and is safer for the pregnant woman. There is no known risk to humans from MRI scans using <2.0tesla.⁵⁶ The remainder of the evaluation is guided by the differential diagnosis.

When an antiepileptic drug is used in pregnant women, a dosage adjustment may be required from what is customary in the nonpregnant woman. Because of a reduction in protein binding during pregnancy, highly protein-bound antiepileptic drugs may have higher free, or non–protein-bound, fractions than would usually be anticipated. This translates into a higher CNS concentration. For example, during pregnancy the non–protein-bound fraction of phenytoin may represent 15% of the total fraction, in contrast to 10% in the nongravid state. The standard load of phenytoin (20 mg/kg) may prove excessive for the pregnant woman. A suggested regimen for pregnant women is to give 10 mg/kg and repeat with 5 mg/kg in 2 to 6 hours.⁵⁴

Seizures may be a sign of cerebral ischemia. The risk that a pregnant woman will experience a cerebral infarction varies from 1/481 in India to 1/26,099 in Rochester, Minnesota.⁶⁸ In one retrospective and prospective study of strokes associated with pregnancy and the puerperium in women delivering in public hospitals in Ile de France, 31 cases of stroke were identified among 348,295deliveries.⁵⁷ Arterial occlusion represents 50% to 80% of all cerebral infarctions occurring during pregnancy, with central venous thrombosis next most common. Arterial infarctions tend to occur in the second and third trimesters,
whereas venous infarctions are more likely to occur in the first trimester. In the Ile de France study, nonhemorrhagic strokes (47%) and intracranial hemorrhage (44%) were most likely to occur in association with eclampsia.⁵⁷

Stroke during pregnancy resulting from an arterial thrombosis usually arises in individuals with an identifiable risk factor for stroke. Most arterial infarctions are a consequence of arteropathy associated with premature atherosclerosis, moyamoya disease, Takayasu arteritis, fibromuscular dysplasia, and, rarely, isolated CNS vasculitis. Stroke and seizures may also be the initial manifestation of hematologic disorders, such as hemoglobinopathy (sickle cell disease), antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, and deficiencies in antithrombin III and proteins C and S. The factor V Leiden mutation is a hereditary abnormality of the coagulation system that appears to enhance resistance to activated protein C, which inhibits coagulation. Up to 5% of the population exhibits resistance to activated protein C, and about 20% of patients with venous thromboembolism carry the factor V Leiden mutation.^30,71 Evaluation of a patient with stroke and seizures would also consider cardioembolism and paradoxic embolism from a patent foramen ovale, deep venous thrombosis, thrombosis of the pelvic or ovarian vein, or fat embolism. During labor and delivery, amniotic fluid and air embolism are considered in the differential diagnosis.

The clinical syndrome of cerebral venous thrombosis is characterized by headache, nausea and vomiting, visual symptoms, encephalopathy, lateralized neurologic deficits, and focal or generalized seizures.²¹ Unlike arterial thrombosis, cerebral venous thrombosis develops in pregnant women who have no other specific risk for stroke. Cerebral venous thrombosis appears to be caused by the combination of the hypercoagulable state of pregnancy and the decrease in cerebral blood flow consequent to blood loss during labor and delivery. Other conditions associated with cerebral venous thrombosis include infection; hyperviscosity syndromes; sickle cell anemia; leukemia; antiphospholipid antibody syndrome; protein C, S, and antithrombin III deficiency; and factor V Leiden mutation. Malignancies and arteriovenous malformations should also be considered.⁶⁸ Although cerebral venous thrombosis may require acute treatment for seizures, the long-term prognosis is good. In one series of 77 patients with cerebral venous thrombosis, of 28 patients who experienced seizures acutely, seizures recurred in only four.⁴⁵

Cerebral hemorrhage occurs in between 1 and 5 pregnancies per 10,000. Associated mortality is 30% to 40%.⁶⁹ The risk for intracranial hemorrhage appears to be increased in pregnant women,^57,70 although data from Rochester, Minnesota, found no evidence of a gestational increase.⁶⁷ Pregnant women are likely to experience conditions that increase the risk for hemorrhage, however, such as eclampsia, metastatic choriocarcinoma, cerebral emboli, and coagulopathies. In addition, physiologic changes occur in pregnancy that predispose to intracranial hemorrhage, such as hypertension and increases in cardiac output, blood volume, and venous pressure. High concentrations of circulating estrogens may cause arterial dilation and be an additional risk factor for cerebral hemorrhage.⁶⁹

Subarachnoid hemorrhage in the pregnant woman is most likely to be caused by cerebral aneurysms and arteriovenous malformations. Other causes of subarachnoid hemorrhage are eclampsia, cocaine abuse, coagulopathy, subacute bacterial endocarditis, and choriocarcinoma.⁶⁹ Aneurysmal bleeding is most likely to occur in older patients (25–35 years of age) and in the second and third trimesters of gestation. Bleeding is unlikely to occur in the postpartum period. In contrast, hemorrhages from arteriovenous malformations are more likely to occur in younger women (18–25 years) and are uniformly distributed throughout gestation, with a higher risk during labor and the puerperium.

Subarachnoid hemorrhage in a pregnant woman, as in a patient who is not pregnant, may be associated with severe headache, nausea, vomiting, focal neurologic signs, and seizures. Transient hypertension and proteinuria are often present and must be differentiated from pre-eclampsia/ eclampsia. Diagnosis is established based on the clinical presentation and CT of the brain. If the brain CT findings are negative and intracranial hemorrhage is still suspected, then a lumbar puncture to detect hemorrhage is indicated. If hemorrhage is detected, the patient requires either an MR angiogram or four-vessel angiography, depending on the institution’s technical capabilities and experience, and a brain MRI to evaluate for aneurysms and arteriovenous malformations.

Intracerebral hemorrhage in pregnancy is most often attributable to hypertension occurring in the setting of eclampsia. Other causes include bleeding from an arteriovenous malformation, hemorrhagic transformation of an ischemic stroke, cocaine or alcohol abuse, and coagulopathies. The presenting symptoms of intracerebral hemorrhage are usually focal neurologic deficits, headache, nausea, vomiting, and seizures. A noncontrast CT of the head is generally the imaging test of first choice, followed by MRI to detect any structural lesion underlying the hemorrhage.

Treatment of seizures in the setting of subarachnoid or intracranial hemorrhage does not differ in pregnant and nonpregnant patients. The risk for teratogenic effects of antiepileptic drugs is far outweighed by the risk for repeated hemorrhage following a major motor seizure.

Patients with immunologic and rheumatologic diseases, such as systemic lupus erythematosus (SLE), may experience an exacerbation of CNS disease during pregnancy.⁴¹ Unlike most rheumatologic disorders, which spare the CNS, SLE involves the CNS in as many as one half of patients.¹² Neurologic disease is the second-leading cause of death in SLE⁵³ and frequently causes neuropsychiatric disturbances such as seizures, encephalopathies, psychosis, and lateralized motor deficits.²⁰ The risk for development of pre-eclampsia, hypercoagulability, and antiphospholipid antibodies is also increased in SLE. The CNS lesion in SLE is principally a small-vessel vasculitis with vascular hyalinization, endothelial proliferation, thrombosis, and capillary wall thickening.¹ Low-dose corticosteroids are the preferred treatment for SLE, with or without aspirin or heparin. Lupus of the CNS may require treatment with higher doses of corticosteroids. Antiepileptic drugs for seizures may be required only during acute flares.

Antiphospholipid antibodies may be associated with neurologic disease, either in the context of SLE (30% of patients) or within the primary antiphospholipid antibody syndrome.³⁵ The syndrome is characterized by deep venous and arterial thrombosis and stroke, repeated miscarriages, and thrombocytopenia. Seizures may occur. Cerebral events during pregnancy associated with anticardiolipin antibodies are generally treated with heparin anticoagulation. Seizures usually require antiepileptic treatment.

Thrombotic thrombocytopenic purpura is a rare disorder that may occur more frequently during pregnancy. Presenting features are thrombocytopenic purpura, microangiopathic hemolytic anemia, renal disease, and neurologic symptoms, which may include headache, encephalopathy, paresis, visual disturbance, and paresthesias. Seizures occur
in 20% of patients and are treated acutely with antiepileptic drugs.⁴⁸ The outcome of thrombotic thrombocytopenic purpura has substantially improved with plasmapheresis and plasma exchange.⁵⁵

The types of brain tumors that occur in pregnant women are not different from those in nonpregnant women—most commonly gliomas, then meningiomas and acoustic neuromas.¹¹ Pregnancy does not appear to be a risk for development of a specific neoplasm, but it can exacerbate tumor growth. Symptoms associated with increased intracranial pressure, such as nausea and vomiting, may be confused with “morning sickness,” especially during the first trimester. However, persistent headache and neurologic deficits should raise concern for neoplasia. Seizures are a common presenting symptom of cranial neoplasms and may be partial or generalized. Any patient who has a seizure and in whom neurologic signs and symptoms are present warrants evaluation with an MRI.

Seizures may be the presenting symptom of infections of the CNS during pregnancy. The frequency of viral meningitis and encephalitis is not increased during pregnancy. However, pregnant women are at higher risk for infections caused by intracellular organisms because specific immune responses are altered to permit maternal adaptation to fetal and placental antigens.²³ The agents most likely to cause CNS infections and seizures during pregnancy include bacteria (Mycobacterium tuberculosis, Listeria monocytogenes), fungi (Coccidioides immitus), protozoa (Toxoplasma, Plasmodium), and viruses (influenza, varicella-zoster [chicken pox only], and polio).²⁷ The increased incidence of HIV seropositivity and AIDS in pregnancy should prompt consideration of this entity in any pregnant patient with opportunistic infections of the CNS. Treatment of these infections is the same as for nonpregnant women, with choice of antibiotic guided by information regarding the relative teratogenicity. Seizures are treated with antiepileptic drugs as required during the acute illness.

Pre-eclampsia and eclampsia are diseases of pregnancy that occur most often in nulliparous women. Most seizures occurring during pregnancy are a sign of eclampsia. Eclampsia is defined as the development of convulsions and/or unexplained coma during pregnancy or postpartum in patients with signs or symptoms of pre-eclampsia. Pre-eclampsia is a multisystem disorder associated with hypertension, proteinuria, edema, hemoconcentration, hypoalbuminemia, abnormalities of hepatic function or coagulation, and increased urate levels.³² In a recent study, 3.9% of 467 women with untreated pre-eclampsia progressed to seizures (eclampsia).⁷

Eclampsia is associated with seizures, cerebral bleeding, and death. The diagnosis of eclampsia is made when an antepartum or postpartum woman presents with generalized edema, hypertension, proteinuria, and convulsions. The spectrum of presentation, however, includes severe to minimal or even no hypertension, proteinuria, or edema.

Eclampsia most commonly occurs at or beyond week 28 of pregnancy. However, some cases occur between weeks 21 and 27 (7.5%) or at 20 weeks’ or earlier (1.5%). Eclampsia occurring before 20 weeks’ gestation is usually associated with molar or hydropic degeneration of the placenta. Eclampsia may also present within 48 hours postpartum and even as late as 4 weeks postpartum.

The incidence of eclampsia in Europe and other developed countries is 1/2,000 deliveries. In developing countries, estimates vary from 1/100 to 1/1,700. Maternal mortality ranges from 1.8% to 5%.^10,16 Eclampsia accounts for approximately 50,000 maternal deaths and is a leading cause of maternal deaths in the United States, Scandinavia, Iceland, Finland, and the United Kingdom.⁵⁰