Publisher Summary
Pre-eclampsia and eclampsia are not distinct disorders but are differentiated according to the severity of the clinical symptoms. The mildest disorder in this continuum is pregnancy-induced hypertension (PIH). In pre-eclampsia, hypertension and proteinuria are present, and when convulsions occur in addition to these signs, the condition is referred to as eclampsia. By definition, the central nervous system (CNS) is commonly affected in patients with pre-eclampsia/eclampsia and is a cause of significant morbidity and possibly death in those affected. Death from pre-eclampsia/eclampsia is usually attributable to cerebral hemorrhage in patients with thrombocytopenia either in isolation or as part of HELLP syndrome. Fortunately, the neurologic deficits often are reversible. Headache is the most common neurologic symptom in pre-eclampsia/eclampsia, reported in 7 8–83% of the patients. Visual symptoms may occur in 40% of pre-eclamptic women and they present in a variety of ways from blurred vision, diplopia, homonymous hemianopsia, to cortical blindness. Cerebral hemorrhage is reported to be the most common cause of death in patients with eclampsia. SAH occasionally is reported in pre-eclampsia/eclampsia. Nontraumatic SAH usually results from rupture of a berry aneurysm or arteriovenous malformation (AVM). A large case-crossover study did not find an increased risk of aneurysmal SAH or AVM during pregnancy, delivery, or puerperium.
The hallmarks of preeclampsia are hypertension and proteinuria in a pregnant woman. Unfortunately, this relatively common complication of pregnancy, affecting 2–8% of all pregnancies depending on the criteria used for diagnosis , can evolve into the far more serious eclampsia in which one sees encephalopathy with seizures and the potential for a fatal outcome. Naturally, by definition, eclampsia is intimately associated with neurologic manifestations that can be quite varied. This chapter will provide a compilation of the type of complications that can be seen in the realm of neurology both in preeclampsia and eclampsia. Such presentations are not at all uncommon for the neurology consultant on the Obstetrics Service and should be recognized in a timely fashion, as effective intervention can have an important impact on outcome. Topics to be discussed will include the pathophysiology as well as the neurologic manifestations including headache, stroke, and seizures.
Pathophysiology
There are certain risk factors for the development of hypertension and proteinuria in later stages of pregnancy. There are several identified contributing factors to an increased risk of pre-eclampsia. It is now generally acknowledged that the initial pathogenesis appears to be tied in with the placenta. As the human embryo is implanted within the uterus, there is pronounced decidualization of the endometrium while the embryo produces trophoblastic invasion of the maternal spiral arteries in order to maintain adequate placental nutrition to the developing fetus. In the normal pregnancy, the trophoblast becomes embedded in the vessel wall and the muscular and elastic components of the affected vessels become disrupted. This remodeling of the spiral arteries results in dilated, low-resistance vessels that are unable to constrict when exposed to vasoactive stimulation . This ensures that there is adequate circulation for the placenta and fetus. There is impairment of this physiologic process in pre-eclampsia with the trophoblastic invasion disrupted. This is associated with retention, by the spiral arteries, of their endothelial lining and musculature. There is resultant compromise of perfusion into the intervillous space, which adversely affects blood flow to the placenta and fetus, which can lead to ischemic hypoxia and oxidative stress.
Although often self-limited, pre-eclampsia is not necessarily benign for the fetus. There is commonly intrauterine growth retardation as well as low birth weight, prematurity, and risk of perinatal stroke. Furthermore, the potential systemic manifestations of pre-eclampsia can evolve into an encephalopathy with predisposition to seizures, and even death; in the mother, this is termed eclampsia.
It is theorized that impaired perfusion of placental tissue results in toxic factors that are released into the systemic circulation with resultant damage to maternal endothelial cells . Susceptibility to such an occurrence includes premorbid risk factors such as underlying hypertension, glucose intolerance, and hyperlipidemia, which constitutes much of what has been termed the metabolic syndrome . Of particular note is the potential association of smoking with pre-eclampsia . However, somewhat surprisingly, there is roughly a one-third reduced risk of pre-eclampsia in smokers that has been theorized to be related to a possible protective effect of either heme oxygenase, an enzyme involved in the endogenous generation of carbon monoxide, or the carbon monoxide itself which is a by-product of the cigarette smoke .
There appears to be a familial predisposition to pre-eclampsia that may well be reflective of a genetic predisposition to risk factors associated with pre-eclampsia including components of the metabolic syndrome. However, differential gene expression also might play a role. In a study of potential placental genes that might predispose to pre-eclampsia, Hoegh et al. reported what they viewed as a surprisingly low differential gene expression when comparing biopsies from 11 pre-eclamptic placentas when compared to 18 normal controls.
Neurologic Manifestations of Pre-eclampsia/Eclampsia
Spectrum of Manifestations
Pre-eclampsia and eclampsia are not distinct disorders but are differentiated according to the severity of the clinical symptoms. The mildest disorder in this continuum is pregnancy-induced hypertension (PIH). In pre-eclampsia, hypertension and proteinuria are present, and when convulsions occur in addition to these signs, the condition is referred to as eclampsia . Some patients may be diagnosed with PIH and never progress to a more severe presentation. Furthermore, up to 28% of patients with a diagnosis of eclampsia do not have pre-eclampsia or PIH preceding this presentation . Because pre-eclampsia and eclampsia are a continuum and possibly share the same pathophysiologic mechanisms, we will use the term pre-eclampsia/eclampsia.
By definition, the central nervous system (CNS) is commonly affected in patients with pre-eclampsia/eclampsia and is a cause of significant morbidity and possibly death in those affected . Death from pre-eclampsia/eclampsia is usually attributable to cerebral hemorrhage in patients with thrombocytopenia either in isolation or as part of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome . Fortunately, the neurologic deficits often are reversible.
Incidence and Prevalence
In the United States, pre-eclampsia affects roughly 5% of women, and eclampsia occurs in 5–7 of every 10,000 births (0.05–0.07%) with international rates, overall, approximately the same as the United States. However, eclampsia occurs in 0.17–1% of pregnant women in developing countries . The neurologic manifestations that may occur associated with pre-eclampsia/eclampsia syndrome are varied and are listed in Table 5.1 .
| Headache |
| Seizures |
| Visual disturbances |
| Reversible posterior leukoencephalopathy syndrome |
| Subarachnoid hemorrhage |
| Ischemic stroke |
| Cerebral venous thrombosis |
| Altered mental status |
| Cognitive dysfunction |
| Intracranial hypertension |
Headache
Headache is the most common neurologic symptom in pre-eclampsia/eclampsia, reported in 78–83% of the patients . New-onset headache may be the initial complaint in a pregnant woman presenting with pre-eclampsia/eclampsia. Progressive headache always precedes seizure activity in eclampsia and does not respond to routine over-the-counter remedies . The headache syndrome in pre-eclampsia/eclampsia has no typical characteristics. It has been described by patients as throbbing or pounding, pressure-like, or sharp like a knife. The location also varies. Aura usually is not seen . Rapid resolution of the headache associated with pre-eclampsia/eclampsia is seen with administration of magnesium sulfate .
If the patient experiences sudden onset of a severe headache (thunderclap headache) associated with nausea and vomiting, the physician should have a high index of suspicion for subarachnoid hemorrhage (SAH). A possible association between migraine headaches and pre-eclampsia has been suggested .
Visual Disturbances
Visual symptoms may occur in 40% of pre-eclamptic women and they present in a variety of ways from blurred vision, diplopia, homonymous hemianopsia, to cortical blindness . Anton’s and Balint syndrome have also been described in association with pre-eclampsia/eclampsia . Initially attributed to retinal arteriolar vasospasm or thrombosis, visual disturbances are now recognized to be associated with cerebral edema demonstrated on neuroimaging techniques by low-density areas on CT brain scan and by hyperintense lesions on T2-weighted and fluid attenuation inversion recovery (FLAIR) MRI .
Cortical blindness, when it occurs, is usually reversible and the majority of patients recover vision over a period ranging from 2 h to 21 days . Cerebral edema has been attributed to endothelial dysfunction and reversible posterior leukoencephalopathy syndrome (RPLS) ( Figure 5.1 ). Brief episodes of positive visual symptoms, such as scintillating scotomata, chromatopsia, as well as colored and mainly circular elementary visual hallucinations, should prompt rapid investigation to evaluate for possible occipital seizures .
Cerebrovascular Disease
Intracranial Bleed
Cerebral hemorrhage is reported to be the most common cause of death in patients with eclampsia . SAH occasionally is reported in pre-eclampsia/eclampsia . Nontraumatic SAH usually results from rupture of a berry aneurysm or arteriovenous malformation (AVM). A large case-crossover study did not find an increased risk of aneurysmal SAH or AVM during pregnancy, delivery, or puerperium . SAH in pre-eclampsia/eclampsia is thought to be the result of rupture of cortical petechiae over the surface of the brain or rupture of small pial veins, as a complication of RPLS, and usually carries a favorable prognosis . Patients usually present with sudden onset of severe headache associated with signs of increased intracranial pressure, such as nausea, vomiting, loss of consciousness, cranial nerve palsies, and other focal neurologic deficits. Signs of meningeal irritation may be present early in some patients, such as neck pain, neck stiffness, low back pain, and bilateral leg pain . Mechanisms of SAH, outside of bleeding from aneurysms and AVMs, can include dissection , Moyamoya disease , and idiopathic perimesencephalic SAH .
Intraparenchymal bleed is more common in older women with underlying chronic hypertension. The areas most frequently affected include the striatocapsular area, thalamus, cerebellum, and brain stem. Patients with longstanding uncontrolled hypertension and atherosclerosis also tend to bleed in these same locations. The presentation and outcome is very much reflective of the size and location of the hematoma. Typically, hemispheric hematomas greater than 30 cm 3 in size have a worse prognosis, while relatively small hematomas of the pons can be devastating.
Other Situations Associated with Intracranial Bleed
Patients with cerebral venous thrombosis (CVT) may also present with intracranial bleed. Other potential etiologies that are recognized, with or without pregnancy, include bleeding into a primary or metastatic brain tumor, bleeding secondary to vasculitis, septic embolism, vessel dissection, or hemorrhagic transformation of a cerebral infarction.
Reversible Posterior Leukoencephalopathy Syndrome
RPLS is an acute cerebral illness and was described in 1996 . In terms of clinico-radiologic correlation, RPLS is characterized by reversible vasogenic subcortical edema without infarction and, in the majority of cases, patients present with encephalopathy, seizures, headache, and visual abnormalities . Visual changes range from loss of acuity, visual neglect, or homonymous hemianopia to complete blindness. This syndrome usually happens in patients with underlying predisposing medical conditions and oftentimes a triggering factor can be identified .
In RPLS, the sudden increase of the systemic blood pressure is postulated to disrupt the cerebral vascular reactivity leading to vasogenic edema similar to the mechanism associated with eclampsia. Interestingly, the neurologic manifestations of eclampsia are identical to those of hypertensive encephalopathy and RPLS .
Pre-eclampsia/eclampsia is believed to be a dysfunction in placental implantation and poor placental perfusion inducing hypoxia with consequent release of vasoactive substances into the maternal circulation, causing endothelial dysfunction and systemic hypertension. The endothelial dysfunction may predispose to blood–brain barrier (BBB) disruption with increased permeability even with moderate changes in blood pressure. Both BBB disruption and endothelial dysfunction contribute to breakthrough of autoregulation, leading to extravasation of fluid and red blood cells out of the vessels and causing vasogenic edema and pericapillary hemorrhages . The occipital lobes are particularly more vulnerable to loss of autoregulation because the sympathetic innervations are relatively sparse in the posterior circulation . In addition, the distal terminal branches are more often involved compared to proximal main vessels. These theories help to explain the radiologic findings of symmetric hyperintensities seen on FLAIR MRI, usually in the posterior white and gray matter, seen in eclampsia and hypertensive encephalopathy or RPLS ( Figure 5.1 ). RPLS is now hypothesized to be the primary mechanism of injury in eclampsia.
Ischemic Stroke
Stroke is associated with greater than 12% of maternal deaths. Etiologic factors associated with ischemic stroke during pregnancy are varied and include hypercoagulability, cerebral sino-venous thrombosis (CVT), paradoxical cerebral embolism, postpartum cerebral angiopathy, peripartum cardiomyopathy, arrhythmias, and less specific vascular sequelae of pre-eclampsia/eclampsia . Pre-eclampsia/eclampsia are the most common cause of both cerebral infarct and intracranial hemorrhage in pregnancy and puerperium . Pre-eclampsia/eclampsia is present in 24–47% of ischemic strokes and 14–44% of intracranial hemorrhages diagnosed during pregnancy .
It has long been assumed that most strokes associated with pregnancy are secondary to venous infarcts because these studies were collecting retrospective data before the advent of the newer imaging techniques . However, based on more recent information, pregnancy-related infarctions are most commonly attributable to arterial occlusion ( Figure 5.2 ). There is an increased risk of ischemic stroke in patients with pre-eclampsia/eclampsia and the risk appears to persist even beyond pregnancy and puerperium in these patients .
