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CHAPTER 13

Cerebrovascular Pathophysiology
in Preeclampsia and Eclampsia

MARILYN J. CIPOLLA, GERDA G. ZEEMAN AND F. GARY CUNNINGHAM

Editors comment: A single chapter focusing on the brain renaissance of neuroanatomy and pathology, intracranial
in normal pregnancy and preeclampsia appeared in edi- hemorrhages and generalized cerebral edema were promi-
tion 3 and this is its first revision. New additions include nently emphasized.
animal model observations that suggest explanations for Neuroanatomical emphasis culminated in the seminal
changes in cerebral physiology during normal pregnancy work of Sheehan and Lynch and their autopsy series of
and hypertensive complications. New findings in the human eclamptic women.1 This work is unique as the brains stud-
disease regarding volume status and the eclamptic convul- ied were from autopsies performed within 2 hours after
sion are discussed and there is further clarification of that death, eliminating most of the postmortem changes that rap-
new but loosely thrown around term posterior reversible idly occur in brain tissue and might confound interpretation.
encephalopathy syndrome and in both areas our authors By then, it was appreciated that women with fatal eclampsia
have made recent seminal contributions. One does not need frequently had brain abnormalities, but that these caused
an editors comment to realize that cerebral involvement in death in a minority of such cases. As deaths from eclamp-
preeclampsia, and especially eclampsia, is a purveyor of sia declined over the last half of the 20th century, interest
serious disease. In this regard discussions regarding pre- in cerebral pathology waned also because there were few
vention and management of cerebral symptoms, especially avenues from which to approach appropriate investigation.
eclampsia, can be found in Chapters 12 and 20, the first This gap was filled by the development of computed tomog-
reviewing trials with magnesium sulfate, the latter the treat- raphy (CT) in the 1970s, which allowed noninvasive brain
ment of impending or actual eclampsia. imaging. Doppler studies of cerebral blood flow (CBF)
velocity reawakened interests in cerebrovascular perturba-
tions in the preeclampsia syndrome. More recently, the use
INTRODUCTION of MRI has opened wider the vista to study neuroanatomi-
cal changes as well as to more accurately measure cerebral
The brain has a central role in the preeclampsiaeclampsia perfusion. These technologies, combined with reproduc-
syndrome. For many centuries, convulsions in the preg- ible animal models to better study cerebral blood flow and
nant woman were the most recognizable event of what we its alterations, have allowed a heretofore unknown look at
now know to be a generalized disorder that affects virtu- cerebrovascular pathology provoked by the preeclampsia
ally every organ system. In his first edition of Hypertensive syndrome.
Disorders in Pregnancy, Chesley chronicled the histori- In this chapter we correlate the earlier neuropathologi-
cal evolution of theories concerning causes of convulsions cal observations of eclampsia with the noninvasive imag-
in women with eclampsia. Since the times of Hippocrates ing findings derived from CT scanning and MR imaging.
and Galen, the two main theories were either cerebral We also correlate cerebrovascular abnormalities induced
congestion repletion, or cerebral anemia depletion. by preeclampsiaeclampsia and measured with direct and
Beliefs concerning repletion led to the widespread practice indirect noninvasive methods such as MRI technology and
of phlebotomy during the 1700s and 1800s. And through- Doppler velocimetry. And finally, we review hypertensive
out much of the last century, as therapeutic measures were effects on cerebral perfusion in both pregnant and non-
aimed at either halting or preventing convulsions, evidence pregnant animal models from which we draw a composite
began to accrue leading to insights into the cerebrovascu- description of the effects of the preeclampsia syndrome on
lar pathophysiology of eclampsia. For example, during the the brain. Finally this chapter is designed to specifically

Chesleys Hypertensive Disorders in Pregnancy. DOI: http://dx.doi.org/10.1016/B978-0-12-407866-6.00013-4


ISBN: 978-0-12-407866-6 269 2015
2014 Elsevier Inc. All rights reserved.

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270 Chesleys Hypertensive Disorders in Pregnancy

describe cerebral pathology and pathophysiology in pre- cortical infarctions are described as well.1,4 These infarcts
eclampsia/eclampsia. Clinical aspects of the preeclampsia vary from about 0.3 to 1.0mm in diameter and are some-
syndrome are discussed in Chapters 2 (clinical spectrum), times confluent. The classical microscopic vascular lesions
12 (prevention), and 20 (management). consist of fibrinoid necrosis of the arterial wall and perivas-
cular microinfarcts and hemorrhages.

NEUROANATOMICAL FINDINGS
WITH ECLAMPSIA NEUROIMAGING IN ECLAMPSIA

Most neuroanatomical descriptions of the brain in eclamp- A number of neuroimaging techniques have been used
tic women are taken from eras when mortality rates were to better understand the cerebrovascular mechanism(s)
quite high. One consistent finding was that brain pathology involved in the preeclampsia syndrome. These include angi-
accounted for only about a third of fatal cases such as the ography, CT, and MRI techniques. Specifically, the ever-
one shown in Fig. 13.1.2 In the majority of cases, however, increasing development of MRI techniques has especially
death was from pulmonary edema, and the brain lesions been useful to provide information concerning the patho-
were coincidental. Thus, while gross intracerebral hemor- genesis of cerebral manifestations of preeclampsia.
rhage was seen in up to 60% of eclamptic women, it was
fatal in only half.1,3,4 As shown in Fig. 13.2, other princi-
Computed Tomography (CT)
pal lesions found at autopsy consisted of cortical and sub-
cortical petechial hemorrhages. Histologically, these are Localized hypodense lesions at the graywhite matter junc-
composed of numerous small hemorrhages, 0.31.0mm tion, primarily in the parieto-occipital lobes, are typically
in diameter, arranged in streaks of 24cm running radially found in eclampsia (Fig. 13.3). Such lesions may also be
in the cortex. They may appear anywhere on the gyral sur- seen in the frontal and inferior temporal lobes, as well as
face and are most common in the occipital lobes and least the basal ganglia and thalamus.58 The spectrum of involve-
common in the temporal lobes. Many occur in the border ment is wide, and with increasing radiological involvement,
zones between cerebral arterial territories. Other frequently either of the occipital lobes or with diffuse cerebral edema,
described major macroscopic lesions include subcorti- symptoms such as lethargy, confusion, and blindness will
cal edema, multiple nonhemorrhagic areas of softening develop.9,10 In these cases, widespread edema shows as
throughout the brain, hemorrhagic areas in the white mat- a marked compression or even obliteration of the cerebral
ter, and hemorrhage in the basal ganglia or pons, often with ventricles (Fig. 13.4). Such women may develop signs of
rupture into the ventricles. In some cases, numerous small impending life-threatening transtentorial herniation.

FIGURE 13.2 Composite illustration showing location of cere-


bral hemorrhages and petechiae in women with eclampsia: (A)
FIGURE 13.1Hypertensive hemorrhage with eclampsia. pia-arachnoid hemorrhage; (B) cortical petechiae; (C) subcortical
(Reprinted, with permission, from Cunningham FG, etal.: Williams petechiae; and (D) focal softenings or petechiae in midbrain or
Obstetrics, 20th ed. Stamford, CT: Appleton & Lange; 1997.) white matter.1

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 271

Most reports describe reversibility of cerebral edema.11,12


In a few women with eclampsia, however, cerebral infarctions
have been described.13 And cerebral hemorrhagic transforma-
tion may also develop from areas of ischemic infarction.14
These findings raise important issues regarding both the
pathogenesis of preeclampsia-related intracranial hemorrhage
as well as its prevention.

Magnetic Resonance Imaging (MRI)


There are a number of MRI acquisitions that are used to
study cerebrovascular anatomy and function in eclamp-
tic women. Common findings are hyperintense T2 lesions
in the subcortical and cortical regions of the parietal and
occipital lobes, with occasional involvement of basal gan-
glia and/or brainstem.5,15,16 Some examples are shown in
Figs. 13.5A and 13.6A. While these lesions of the posterior
FIGURE 13.3 Cranial CT of a woman with eclampsia. Radio reversible encephalopathy syndrome are almost universal
graphic low-density areas (arrow) are seen in the right occipital lobe. in women with eclampsia, their incidence in women with

FIGURE 13.4 Computed tomographs in a woman with cerebral edema following acutely exacerbated severe hypertension. The radiograph
on the left shows slit-like effaced ventricles as well as sharply demarcated graywhite interface, both indicating parenchymal swelling. The
radiograph on the right taken 10 days later shows diminished edema manifest by larger ventricles and loss of graywhite interface demarcation.

FIGURE 13.5 Classic MRI pattern of vasogenic edema in eclampsia with associated subcortical infarction. (A) T2 hyperintensity on
FLAIR images indicates parieto-occipital distribution of vasogenic edema. (B) Within this volume is a smaller area of hyperintensity on
DWI (arrow). (C) That this signal is due to restricted diffusion is confirmed by hypointensity on the ADC map (arrow). (D) These findings
suggesting areas of subcortical infarction are supported by follow-up studies obtained 6 weeks later in which T2 hyperintensity on FLAIR
image and (E) corresponding low signal intensity on T1-weighted image (arrows) indicated evolution to gliosis.16

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272 Chesleys Hypertensive Disorders in Pregnancy

there are persistent findings in up to a fourth of eclamptic


women several weeks postpartum.16,19,20

Diffusion-Weighted MRI and Apparent


Diffusion Coefficient
From the foregoing, it is apparent that there are
two distinctly different types of cerebral edema in
eclampsia vasogenic and cytotoxic edema. Vasogenic
edema is associated with increased hydrostatic pressure
and ensuing capillary leak, while cytotoxic edema is asso-
ciated with ischemia and cell death with infarction. This
issue is critical because the former is usually reversible and
the latter may not be.21 It is not possible with conventional
CT and MRI techniques to differentiate between these two
forms of cerebral edema. To do so, a series of MRI acqui-
sitions were developed. These include diffusion-weighted
imaging (DWI) sequences and apparent diffusion coeffi-
cient (ADC) mapping. With these, it is possible to further
characterize the hyperintense lesions seen on T2 imaging
(Figs. 13.5BE and 13.6BE). Any predictions of the clini-
cal course of eclampsia based on DWI and ADC findings
remain currently speculative.22
DWI takes advantage of strong diffusion gradients that
detect changes in water molecule distribution in tissue.
Quantitative measurement of the diffusion property of a
tissue is expressed as the ADC. Vasogenic edema is char-
acterized by increased extracellular fluid with enhanced
water diffusion and may be seen as a combination of nor-
mal DWI with hyperintense T2 signal lesions and increased
apparent diffusion.23 Conversely, in the presence of an
ischemic event, cytotoxic edema is caused by sodium
pump failure, cell swelling, and eventually cell death. This
causes a reduction in proton diffusion, due to a shift of
FIGURE 13.6 MRI evidence of hypertensive encephalopathy water from the extracellular to the intracellular space, and
and lacunar infarctions in eclampsia. This case demonstrates the it elicits a hyperintense signal on DWI but with a decreased
occasional atypical distribution of signal abnormalities away from
ADC.24 It has been shown that ischemic brain regions
the parieto-occipital region. (A) Note on T2-weighted FLAIR
can be identified within minutes to hours after the onset
image that the predominant changes occur in the basal ganglia
regions bilaterally. (B) Small foci of cytotoxic edema are indi- of neurological symptoms.21,25 Furthermore, newer tech-
cated by the marked hyperintensity on DWIs. (C) Corresponding niques such as susceptibility-weighted imaging and diffu-
reduced ADC (arrows). (D) These small, presumed lacunar infarc- sion tensor imaging for assessing the structure of the white
tions show a typical evolution on repeat examination 6 weeks after matter are being developed, but their benefit for eclampsia
the initial events as T2 hyperintensity on FLAIR (arrows) and (E) is yet unclear.26
low signal intensity on T1-weighted image (arrows) in regions In women with eclampsia, studies using DWI sequences
corresponding to DWI evidence of infarct (see B and C) on the showed that the origin of cerebral edema is primarily
initial studies. Hypertensive encephalopathy is neither necessarily vasogenic, but that less commonly there are ischemic and
posterior nor reversible.16 cytotoxic changes, i.e., infarction. These latter cases have
DWI hyperintense T2 lesions and decreased ADC super-
preeclampsia is not known. Intuitively, however, they are imposed on the pattern of vasogenic edema.16,20 In related
more likely found in women who have more severe dis- animal studies, Tamaki et al.27 showed that bloodbrain
ease and who have neurological symptoms.1719 And they barrier (BBB) disruption due to marked local hydro-
are although usually reversible, it is now known that some static pressure precedes decreased tissue perfusion and
of these hyperintense lesions appear as infarctions and that ischemia.

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 273

PATHOGENESIS OF CEREBRAL The second theory is that eclampsia represents a form of


MANIFESTATIONS IN (PRE)ECLAMPSIA hypertensive encephalopathy such that sudden elevations in
systemic blood pressure exceed the normal cerebrovascular
Pregnancy-induced changes of cerebrovascular autoregulatory capacity.8,3133 The decrease in cerebrovas-
hemodynamics have not been well studied, and thus the cular resistance (CVR) causes disruption of end-capillary
pathogenesis of cerebral manifestations of the preeclamp- hydrostatic pressure, hyperperfusion, and extravasation of
sia syndrome is also unclear. Much of this is because of the plasma and red cells through opening of the endothelial
various challenges associated with in vivo studies of cere- tight junctions with increased pinocytosis leading to the
bral blood flow in human pregnancy (see below). And while accumulation of vasogenic edema.3133 Regions of forced
central nervous system histopathology is mainly based on vasodilatation and vasoconstriction develop, especially
autopsy data as discussed, most hemodynamic data are in arterial boundary zones, as is prominent in hyperten-
invariably from surviving women. Although this presents sive encephalopathy.31 Figure 13.7 shows a brain biopsy
some difficulty in relating histopathological with hemody- of a patient with hypertensive encephalopathy, a condition
namic findings, an accurate picture is emerging. that may relate to eclampsia. This mechanism has gained
When taken clinically, data taken from the past several much attention over the last decade, especially since it
decades include pathological and neuroimaging findings was described as reversible posterior leukoencephalopa-
that have led to two general theories to explain cerebral thy syndrome.34 More recently, it is usually referred to as
abnormalities associated with eclampsia. Importantly and the posterior reversible encephalopathy syndrome (PRES)
as emphasized throughout this edition endothelial cell to incorporate the posterior nature of the condition.35 The
dysfunction that characterizes the preeclampsia syndrome normal structure of the neurovascular unit comprises capil-
may play a key role in both theories. lary endothelial cells in close association with basal lamina,
The first theory suggests that in response to acute severe astrocytic endfeet, and pericytes (Fig. 13.8). It is largely
hypertension cerebrovascular overregulation leads to vaso-
spasm.28 This presumption was based on the angiographic
appearance of diffuse or multifocal segmental narrowings
suggestive of vasospasm of the cerebral vasculature in
women with severe preeclampsia and eclampsia.29 In this
scheme, diminished CBF is hypothesized to result in isch-
emia, cytotoxic edema, and eventually tissue infarction.
Finally, the reversible cerebral vasoconstriction syndrome
has been reported to be associated with preeclampsia,30 but
whether this causes eclampsia is not known.

FIGURE 13.7 Cerebral biopsy of a 60-year-old man with hyper- FIGURE 13.8 Schematic of the neurovascular unit. Increased
tensive encephalopathy from blood pressure 220/120 mmHg. hydrostatic (capillary lumen) pressure causes extravasation of
The white matter shows mild, diffuse vacuolization with minimal plasma and red cells through endothelial tight junctions with peri-
inflammatory reaction characterized by scattered macrophages. vascular edema. Reprinted with permission from del Zoppo GJ.
Abundant reactive astrocytes were evident. (From Schiff and Lopes. New Engl J Med. 2006;354:553555. (This figure is reproduced in
Neurocrit Care. 2005;2(3):303305, with permission.) color in the color plate section.)

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274 Chesleys Hypertensive Disorders in Pregnancy

unknown how these cells and structures are affected dur- CEREBRAL BLOOD FLOW
ing preeclampsia that may contribute to brain pathologies AUTOREGULATION
including hemorrhage and edema.
Autoregulation is the process by which cerebral blood flow
(CBF) remains relatively constant in the face of alterations
ECLAMPSIA AS POSTERIOR REVERSIBLE in cerebral perfusion pressure.45 Put another way, when
ENCEPHALOPATHY SYNDROME (PRES) cerebral perfusion pressure declines, cerebrovascular resis-
tance (CVR) decreases due to myogenic vasodilatation of
It is currently thought that preeclampsia is one of the dis- pial arteries and arterioles and hypoxic vasodilatation, thus
orders that share a common etiopathogenesis and that augmenting perfusion. Alternatively, if cerebral perfusion
comprise PRES. Its clinical, pathological, as well as neu- pressure increases, the autoregulatory response increases
roimaging features reflect the rapid and dynamic fluctua- CVR by vasoconstriction, resulting in relatively constant
tions in cerebral blood flow and water content.34,36 In fact, CBF. Thus, autoregulation is a physiological protective
nearly all patients with eclampsia had PRES as determined mechanism that prevents brain ischemia during drops in
by MRI.5,16 In nonpregnant and pregnant patients, PRES is pressure and prevents capillary damage and edema from
usually an acute cerebral illness which may present with hyperperfusion during pressure increases.45 In normoten-
headache, nausea, altered mental function, visual distur- sive adults, CBF is maintained at approximately 50mL per
bances, and seizures. 37 In preeclampsiaeclampsia related 100g of brain tissue per minute (mL/100g/min), provided
PRES, headaches are more frequent than altered mental perfusion pressure is in the range ~60160mm Hg.45,46
status as the initial PRES-related symptom compared to Above and below these limits, autoregulation is lost and
nonpregnant PRES patients. The convulsions are com- CBF becomes dependent on mean arterial pressure in a lin-
monly but not exclusively occipital in onset and corre- ear fashion.45,46
late with the characteristic predominantly posterior imaging Significant brain injury occurs when autoregulatory
abnormalities seen with MRI in women with eclampsia. mechanisms are lost. For example, during acute hyperten-
The arterial boundary zones, located at the territorial lim- sion at mean pressures above the autoregulatory limit
its of the major arteries, are commonly affected sites. These about 160mm Hg in the otherwise healthy patient the
zones are known as the border zone or watershed areas. myogenic vasoconstriction of vascular smooth muscle is
In the human, the most frequently affected region in the overcome by excessive intravascular pressure and forced
cortex is at the parieto-occipital sulci, which represent the dilatation of cerebral vessels occurs.47,48 The loss of myo-
boundary zone of the anterior, middle, and posterior cere- genic tone during forced dilatation decreases CVR and
bral arteries. Involvement of the cerebral cortex may also be increases CBF, a result that produces hyperperfusion, BBB
seen in PRES and lesions may extend to the brainstem, cer- disruption, and acute edema formation.4749
ebellum, basal ganglia, and the more anterior brain regions The relationship between autoregulation, CBF, and BBB
such as the frontal lobes.36,38,39 However, eclampsia-related disruption has been extensively studied. Numerous inves-
PRES cases demonstrate less frequent involvement of the tigators have found a positive correlation between loss of
thalamus, midbrain, and pons compared to nonpregnant autoregulation, increased perfusion, and BBB permeability
PRES cases.37 that leads to cerebral edema.45,46,49,50 Importantly, mecha-
Some patients with PRES have only convulsions and do nisms that increase resistance, such as sympathetic nerve
not manifest traditional prodromal signs and symptoms of stimulation or inward remodeling of cerebral arterioles dur-
hypertensive encephalopathy.40 In addition, the dramatic ing chronic hypertension, attenuate increases in CBF dur-
blood pressure increases that typify hypertensive encepha- ing acute hypertension and are protective of the BBB.5052
lopathy are not necessarily seen and there may be only In general, when CBF is compared in areas with and with-
mild to moderate blood pressure increases with PRES.41 out albumin extravasation in the same brain, the regions of
Importantly, PRES may develop with only mild hyperten- increased permeability have the highest blood flow, indi-
sion,, which may involve endothelial damage. This has been cating loss of autoregulation and decreased CVR.46,49,53
described in the thrombotic microangiopathy syndromes Together, these findings suggest that decreased resistance
hemolytic uremic syndrome and thrombotic thrombocy- and hyperperfusion during acute hypertension cause BBB
topenic purpura as well as with systemic lupus erythema- disruption, whereas increased resistance is protective of
tosus, with immunosuppressive drug toxicity, or with the the microcirculation. In fact, decreased CVR that leads to
use of certain chemotherapeutic agents that include meth- hyperperfusion during acute hypertension is considered the
otrexate and cisplatin.37,42,43 Finally, it is important to rec- primary cause of edema during hypertensive encephalopa-
ognize PRES because the neurological disorder is readily thy and eclampsia.8,18,33,46,5457
treatable by lowering any dangerously elevated blood pres- When severe experimental hypertension is induced by
sures and correction of the underlying medical condition intravenous infusion of vasogenic agents, arterioles develop
that caused endothelial cell injury.44 a pattern of alternating constrictions and dilatations, giving

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 275

rise to the so-called sausage-string appearance.4749,58 This important than absolute blood pressure. Thus, it is possible
vascular pattern has been demonstrated in small blood ves- that it is the acuteness of the blood pressure rise or relative
sels in various vascular beds, including the brain. In the change in pressure from baseline in the setting of endothe-
cerebral circulation, the development of the sausage-string lial dysfunction that disrupts the delicate balance between
pattern is linked to the development of vascular damage, capillary and cerebral perfusion pressures in eclampsia.
specifically in the dilated regions of the vessel as they fail Understanding cerebral hemodynamic changes associated
to maintain myogenic vasoconstriction, with resulting endo- with pregnancy and preeclampsia is challenging, necessitat-
thelial hyperpermeability and extravasation of macromol- ing the use of animal models in some instances. Thus, the
ecules into the brain parenchyma.4749 following sections will review both animal and clinical stud-
ies on changes in cerebral hemodynamics during pregnancy
and preeclampsia.
CEREBRAL BLOOD FLOW AUTOREGULATION
AND HEMODYNAMICS IN PREGNANCY
Animal Studies
The effect of pregnancy on cerebral hemodynamics and Many women who develop eclampsia do so at pressures
cerebral blood flow autoregulation is of significant inter- that are considerably lower than those reported for poste-
est mostly because impaired cerebral autoregulation is rior reversible encephalopathy syndrome or hypertensive
thought to be a major contributor to the development of encephalopathy.58,6063 These findings suggest that the cere-
eclampsia.8,18,33,47,54,58,59 The adaptation of the cerebral bral blood flow autoregulatory curve is shifted to the lower
circulation to pregnancy has recently been extensively range of pressures during pregnancy. Studies in anesthe-
reviewed.59 From clinical observations, it is known that tized rats found that this was not the case. When the upper
eclampsia can develop with only mild or even absent hyper- limit of CBF autoregulation was compared between non-
tension. While it is tempting to hypothesize that the upper pregnant and late-pregnant rats, there was no difference in
limit of cerebral autoregulation is reduced with the pre- the pressure of autoregulatory breakthrough64 (Fig. 13.9A).
eclampsia syndrome, evidence for this is lacking. It seems In fact. more recent studies in rats found that both the upper
much more likely that perivascular edema develops at a and lower limits of CBF autoregulation were extended.65,66
much lower capillary hydrostatic pressure, possibly as a Importantly, however, only the pregnant animals developed
function of endothelial activation known to accompany the significant edema formation in response to acute hyperten-
preeclampsia syndrome. That said, failure of autoregulatory sion64,65 and autoregulatory breakthrough, suggesting that
mechanisms may occur in response to either an acute and/or the endothelium is more susceptible to hydrostatic edema
relatively large blood pressure increase, which seems more during pregnancy (Fig. 13.9B).

(A) 3.5 (B)


79.0
NP (n=7) Basal pressure *
LP (n=8) Acute HTN
3.0
78.5
% Water content

2.5
78.0
rCBF

2.0
77.5

1.5 77.0

1.0 76.5

0.5 76.0
100 110 120 130 140 150 160 170 180 190 200 210 220 230 (n=3) (n=6) (n=4) (n=7)
Pressure (mmHg) Nonpregnant Late-pregnant
FIGURE 13.9 (A) Graph of cerebral blood flow autoregulatory curves in anesthetized nonpregnant (NP, closed squares) and late-
pregnant (LP, open squares) rats. The curves were determined using laser Doppler to measure relative changes in cerebral blood flow
during constant infusion of phenylephrine to raise mean arterial pressure. Notice there is no difference in autoregulation or the pressure at
which breakthrough occurred. (B) Graph showing percent water content as a measure of cerebral edema formation in the same groups of
animals as shown in (A). In nonpregnant animals, water content was similar at basal pressure (black bars) and after autoregulatory break-
through (gray bars). In late-pregnant animals, however, acute hypertension that caused autoregulatory breakthrough caused a significant
increase in water content (p<0.05 vs. basal; p<0.05 vs. NP). Thus, under these conditions, pregnancy alone predisposes the brain to
edema formation.64

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276 Chesleys Hypertensive Disorders in Pregnancy

200 pressures and to maintain tissue perfusion when blood pres-


NP (n=7)
LP (n=10)
sure falls.68,69 The cerebral circulation is a unique vascular
180
PP (n=8) bed in that large extracranial and intracranial pial vessels
** contribute about 50% to total CVR.70 Studies of isolated
160
** cerebral arteries from nonpregnant, late-pregnant, and post-
Diameter (m)

140 partum animals suggest that forced dilatation occurs at lower


pressures during pregnancy and postpartum (Fig. 13.10).71
120 This may be a contributory mechanism by which pregnancy
decreases CVR during acute increases in pressure.
100 Although these changes in larger pial arteries may
contribute to decreased CVR and increased microvascu-
80
lar pressure noted in late-pregnant animals, the response
60
of smaller parenchymal arterioles is a critical determi-
0 25 50 75 100 125 150 175 200 nant of distal capillary pressure and a major determinant
Intravascular pressure (mmHg) of BBB changes. In fact, previous studies have shown
FIGURE 13.10 Graph showing pressure versus diameter that differences in resistance of small vessels in the brain
curves of posterior cerebral arteries from nonpregnant (NP, parenchyma can account for regional differences in BBB
closed triangles), late-pregnant (LP, closed circles), and post- permeability during acute hypertension.70,72 Because late-
partum (PP, closed squares) animals. Arteries from all groups of pregnant animals developed edema in response to auto-
animals constricted in response to increased pressure within the regulatory breakthrough and elevated hydrostatic pressure,
pressure range 50125mm Hg, demonstrating myogenic reactiv- it seems likely that small-vessel resistance is reduced and
ity. Arteries from LP and PP animals, however, underwent forced contributes to edema. In studies to specifically examine
dilatation at significantly lower pressure compared with NP brain parenchymal arterioles, vessels from late-pregnant
animals this is noted by the large increase in diameter in
animals were shown to have larger diameters compared
response to increased pressure (**p<0.01 vs. NP). The increase
with those from nonpregnant animals.67 Thus, there is a
in diameter during forced dilatation is a primary event in the
development of hydrostatic brain edema in which cerebrovascular gestation-induced effect to cause outward remodeling of
resistance is decreased. Reprinted with permission.71 parenchymal arterioles (Fig. 13.11A). Subsequent stud-
ies showed that selective enlargement of brain parenchy-
mal arterioles was due to relaxin-induced activation of
It is important to note that the autoregulatory curves in the transcription factor peroxisome proliferator-activated
these studies were determined using laser Doppler meth- receptor-gamma (PPAR).73Although such structural
ods to measure CBF and they thus only provide relative changes may not influence resting CBF, they would have
changes in blood flow. Other studies using microspheres to a significant impact on local hemodynamics under condi-
measure absolute CBF showed that acutely increased pres- tions when vessels are markedly dilated such as during
sures in late pregnancy were associated with significantly breakthrough of autoregulation and the resulting forced
decreased CVR and increased CBF when compared with dilatation. Importantly, outward remodeling of parenchy-
nonpregnant animals.67 Specifically, pregnancy was asso- mal arterioles in the brain appears to be at the expense of
ciated with a 40% decrease in CVR compared with that the vascular wall, which becomes significantly thinner dur-
in nonpregnant animals with the same change in pressure. ing pregnancy (Fig. 13.11B). Therefore, the significance of
Because increased CVR in response to elevated cerebral outward remodeling of cerebral arteries and arterioles dur-
perfusion pressure is a protective mechanism in the brain ing pregnancy may not be limited to decreased CVR dur-
that prevents transmission of harmful hydrostatic pressure ing acute hypertension, but may also predispose the brain to
to the microcirculation, diminished CVR during pregnancy hemorrhage, another pathological finding of eclampsia, due
in response to acute hypertension could promote BBB dis- to severely increased wall stress.
ruption and vasogenic edema, similar to what is seen during
eclampsia.
Human Studies
The mechanism by which pregnancy decreases CVR
during acute hypertension is not clear, but may be related to In 1949, McCall first described cerebral blood flow changes
structural changes that affect arterial and arteriolar diameter. in women with eclampsia using an inhalation technique of a
Resistance and flow regulation are principally determined by gaseous mixture containing nitrogen, nitric oxide, and oxy-
vessel caliber because they are inversely related to the fourth gen.74 Internal jugular arterial and venous blood was col-
power of vessel radius. The innate myogenic behavior of the lected and the Fick principle applied by measuring serum
cerebrovascular smooth muscle is crucial for establishment concentrations. In eclamptic women, while the delivery of
of an appropriate CVR, which serves to protect downstream oxygen and CBF were normal, there was a 20% decrease in
arterioles and capillaries in the face of changing perfusion oxygen utilization. Other than these studies, there are none

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 277

(A) Transcranial Doppler (TCD)


80 Ultrasonography
Doppler ultrasonography is the most widely used noninva-
70 * sive technique to assess the intracerebral circulation. It has
Lumen diameter (m)

60
been employed extensively in neurosurgical patients for the
early detection of cerebral vasospasm following subarach-
50 noid hemorrhage.75 TCD studies in the middle cerebral
artery provide information on changes in flow velocity of
40 red blood cells and, when combined with blood pressure,
an index of relative cerebral perfusion and cerebrovascu-
30
lar resistance is derived in the downstream arterioles.76 It
20 has been assumed that vascular constriction significantly
NP (n=6) LP (n=6) increases the resistance met by blood inflowing from arter-
ies supplying the microvasculature. Resistance to flow is
(B) 10 inversely proportional to the fourth power of vessel radius
NP (n=6)
LP (n=6) provided that there is steady-state laminar flow. When
8 extrapolating CBF using transcranial Doppler from veloc-
Wall thickness (m)

*
ity data, several assumptions are made, one of which is the
6 caliber or cross-sectional area of the artery studied, which is
likely to change dynamically.
*
4 Studies in normal pregnant women have demonstrated
a decrease in mean velocity in the middle cerebral artery
2 as pregnancy progresses, with return to nonpregnant val-
ues in the puerperium.7779 The decreased mean velocity
0 is presumed secondary to decreased vascular resistance,
5 75 which could imply the presence of more distal arteriolar
Intravascular pressure (mm Hg) vasodilatation and is in agreement with studies demon-
FIGURE 13.11 (A) Effect of pregnancy on the diameter of strating outward remodeling of small vessels in the brain
small penetrating arterioles in the brain. Measurements were during pregnancy.67 A recent cross-sectional study used
taken using video microscopy, ex vivo and fully relaxed in papav- dual-beam angle-independent digital ultrasound, which can
erine solution to inhibit smooth muscle contraction at a pressure measure changes in artery diameter and thus obtain abso-
of 5mm Hg. Measuring diameter at low pressure when changes lute CBF measurements, to measure blood flow changes in
in distensibility are minimal provides a more accurate assessment the internal carotid artery over the course of pregnancy in
of arteriole remodeling and growth. Graph shows arteriolar lumen healthy women.80 This study found CVR decreased from
diameter from nonpregnant (NP, black bar) and late-pregnant (LP,
a nonpregnant value of 0.141 to 0.112mm Hg mL/100g/
gray bar) animals. Pregnancy causes outward remodeling of cere-
min in the third trimester, with CBF increasing 22%
bral arterioles (*p < 0.05 vs. NP). This effect likely decreases
small-vessel resistance under conditions when the vasculature from 42.2 mL/100 g/min in nonpregnant women to
is fully dilated, such as during acute hypertension and forced 51.8mL/100g/min in the third trimester. This study is lim-
dilatation. (B) Effect of pregnancy on arteriolar wall thickness. ited by a cross-sectional analysis and there were eight-fold
Measurements were taken similarly to those shown in (A) at pres- more patients studied in the third trimester compared with
sures of 5 and 75mm Hg. Graph shows wall thickness of arterioles nonpregnant women, and five-fold more than in the first tri-
from nonpregnant (NP, black bar) and late-pregnant (LP, gray bar) mester.80 The discrepancies in these studies demonstrate the
animals. Notice that in addition to causing outward remodeling of difficulties in measuring CBF during pregnancy especially
arterioles that increases lumen diameter, pregnancy also causes because plasma volume and hematocrit change so dramati-
arterioles to have significantly thinner walls (*p < 0.05 vs. NP). cally, influencing velocity measurements.
This effect on arteriolar wall thickness would be expected to cause
A number of investigators have shown increased middle
a significant elevation in wall stress, especially under conditions of
cerebral artery blood flow velocity in preeclampsia.78,81,82
acute hypertension when both lumen diameter and arteriolar pres-
sure are severely increased.73 Moreover, symptomatic preeclamptic women with visual
disturbances or headaches were found to have the high-
est velocities.83 Increased velocity was also reported for
reported that used invasive methods to assess pregnancy- women with eclamptic seizures.84 Low maternal middle
related CBF in humans. In fact, there are obvious major cerebral artery resistance indices in the second trimester
challenges encountered when assessing CBF in the human, may be predictive of the subsequent development of pre-
and accurate methods are either invasive or require radioac- eclampsia.85 Along the same lines, a lower ophthalmic
tive substances. artery resistive index in preeclamptic women who presented

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278 Chesleys Hypertensive Disorders in Pregnancy

with clinical characteristics of PRES is suggested as a clini- was another significant fall at term (Fig. 13.12). Taken
cally applicable biomarker for cerebral overperfusion.86 together, there is a 20% decrease in CBF at term. Middle
Increasing velocity with preeclampsia is assumed second- and posterior cerebral artery diameters remained unchanged
ary to high resistance in downstream arterioles. In chroni- throughout pregnancy and postpartum. These findings
cally hypertensive women without preeclampsia, however, are in agreement with most TCD studies in which middle
there was not substantively increased CBF velocity despite cerebral arterial flow velocities decreased and vessel wall
elevated mean arterial pressure.87 Also, CBF velocity in tone diminished as pregnancy advanced.77,79 A longitudi-
preeclampsia was reduced by both antihypertensive therapy nal TCD study demonstrated a decrease in cerebral perfu-
and magnesium sulfate.88,89 Because of this observation, sion pressure in mid pregnancy and after delivery in women
many favored the vasospasm model for the etiopathogenesis with uncomplicated pregnancies.94 The underlying cause of
of eclampsia. Alternatively, these findings can be ascribed these changes that result in diminished CBF during preg-
to relief of cerebral vasospasm. nancy is not clear. It is hypothesized that downstream resis-
Dynamic CBF autoregulation testing using TCD meth- tance arterioles become more dilated in order to maintain
ods is based on the response of CBF velocity to small phys- constant blood flow at the tissue level. However, changes
iological changes in arterial blood pressure. Women with in plasma volume during pregnancy that affect the hydro-
preeclampsia demonstrate impaired dynamic cerebral auto- gen ion content of water may also have influenced the MR
regulation capacity.90 However, a recent study found that measurement. As newer MR sequences are developed, the
changes in dynamic CBF autoregulation in pregnant women physiological adaptation of pregnancy, especially changes
were not predictive of preeclampsia.91 in water, will need to be accounted for.
In women with severe preeclampsia, CBF determined
Velocity-Encoded Phase Contrast at term with velocity-encoded phase contrast MRI is sig-
MRI and Perfusion-Weighted Imaging nificantly increased when compared with normotensive
In contrast to relative changes in CBF, velocity-encoded pregnant controls.95 Increased CBF is not related to vaso-
MRI can determine absolute blood flow and has been used dilatation of the large cerebral arteries because the diam-
to measure intracranial, renal, and cardiopulmonary circu- eter of the four main vessels remains unchanged. These
lations.92 Velocity-encoded phase contrast MRI is based on observations also are similar to those obtained with TCD
the principle that hydrogen nuclei in blood moving through studies.96 It remains speculative whether increased CBF is
a magnetic field gradient accumulate a phase shift which is from changes in resistance of downstream resistance arte-
proportional to their velocity. Blood flow is then calculated rioles, increased cardiac output, increased mean arterial
by multiplying blood flow velocity and the cross-sectional pressure, or central nervous system factors that control
area of the vessel under study. Due to the high spatial reso- autoregulation.
lution for vessel localization and cross-sectional area, flow MR perfusion-weighted imaging (PWI) has been used
measurements are highly accurate. in preeclampsia and findings suggest that there is hyperper-
Physiological normative data of CBF in the large cere- fusion-induced vasogenic edema without cerebrovascular
bral vessels in both hemispheres longitudinally across nor- spastic changes.97 These conflicting observations with the
mal pregnancy and postpartum have been described.19,93
With this type of measurement, however, CBF is not cor-
rected to mL/min/100g cerebral tissue, so the numbers 160 4
are not comparable and are larger than those shown for
the animal models and other human studies that have 140
Blood flow (mL/min)

Diameter (mL/min)
measured CBF. As shown in Table 13.1, CBF was signifi-
3
cantly reduced by the end of the first trimester. Flow then 120
remained constant until 3638 weeks, at which time there
100
2
TABLE 13.1 Cerebral Blood Flow (mL/min) 80 Flow
at Four Time Intervals Diameter
Artery 1416 wks 2832 wks 3638 wks Postpartum 60 1
1416 2832 3638 6Wpp
(68 wks) Weeks gestation
MCA 135.25.5 132.54.6 118.2 4.6 147.9 5.0 * p<.05 compared to 6 weeks pp
PCA 52.4 2.9 51.2 2.4 44.2 2.4 55.8 2.7 FIGURE 13.12 Middle cerebral arterial blood flow and ves-
93
From Zeeman etal., 2003, with permission. sel diameter determined longitudinally during pregnancy and
Values are expressed as the mean SE. compared with nonpregnant postpartum values in nine healthy
MCA = middle cerebral artery; PCA = posterior cerebral artery. women.93

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 279

different techniques probably indicate the difficulty of inter- hemorrhage, edema, and brain herniation, and they also
preting hemodynamic changes in preeclampsia. predispose to epilepsy and cognitive impairment later in
life.107109 Acutely, seizures have significant effects on the
Single Photon Emission cerebrovasculature, including BBB disruption and unreg-
Computed Tomography ulated, excessive cerebral blood flow.106,110 Glutamate
The technique of single photon emission computed tomog- receptor activation of vascular smooth muscle and endo-
raphy (SPECT) involves intravenous injection of a radio- thelium can cause potent cerebral vasodilatation, dimin-
isotope to determine alterations in regional CBF. The ished cerebrovascular resistance (CVR), and autoregulatory
effect of early pregnancy was assessed in women between failure106,110113 In this regard, the effects of seizures are
7 and 19 weeks who planned termination. Regional flow similar to those of hypertensive encephalopathy and PRES.
in the cerebral frontal, temporal, and parietal lobes, as While the cause of the eclamptic seizure is not cer-
well as in the basal ganglia and cerebellum, was found to tain, it is thought to be stimulated by an acute rise in blood
be increased about 10% during pregnancy compared with pressure superimposed on capillary interendothelial leak-
repeat studies done post abortion.79 Case reports of SPECT age from the preeclampsia syndrome, further discussed
used in women with preeclampsia described hyperemia in in Chapter 9. However, it is well established that de novo
the posterior, temporal, lateral occipital, and inferior pari- seizures can occur at relatively normal blood pressures
etal cortex.98 In a study of SPECT imaging in 63 eclamp- and even in women with seemingly uncomplicated preg-
tic women, all demonstrated perfusion deficits in watershed nancies, that is, without preeclampsia.61,63,114116 In fact,
areas.99 And with a similar method, xenon CT, diffuse women who develop eclampsia exhibit a wide spectrum of
cerebral hyperperfusion and vasogenic edema without evi- signs and symptoms ranging from severe hypertension and
dence of vasospasm were demonstrated in a woman with proteinuria to mild or absent hypertension with no protein-
eclampsia.100 uria.57,61,63,115 For example, in one study of 53 pregnancies
complicated by eclampsia, only seven women (13%) had
severe preeclampsia prior to seizure,61 and in another study
Proton MR Spectroscopy 16% of women were considered normotensive.63 It is there-
The noninvasive method of proton MR spectroscopy (MRS) fore important to consider that the adaptation to normal
is used to investigate cerebral metabolism. Specifically, pregnancy may predispose the brain to seizure.
intracellular metabolite diffusion has been used to study An important aspect to consider is how pregnancy might
women with preeclampsia. Increased choline was reported change the excitability state of the brain. Pioneering work
in edematous areas of the brain, and thought to reflect rela- in the 1940s established that certain progesterone metabo-
tive cerebral ischemia without infarction.101,102 A lactate lites were potent sedatives and anesthetics that act too
peak in eclampsia, even after complete reversibility of rapidly to be due to a genomic effect.117,118 For example,
imaging abnormalities, suggested the presence of infarc- some progesterone metabolites enhance the interaction
tion. A marked decline in N-acetyl-aspartate (NAA) in a of -aminobutyric acid (GABA) the major inhibitory
follow-up study of eclampsia correlated with the develop- receptor in the brain with its receptor, but have mini-
ment of cerebral atrophy resulting from gross neuronal mal action on glutamate receptors.119 Fluctuations in
damage. neurosteroid levels during pregnancy result in selective
changes in the expression and function of GABAA recep-
Near-Infrared Spectroscopy(NIRS) tors that cause neuronal hyperexcitability.120,121 Moreover,
This is an optical technique that allows real-time assess- animal studies demonstrate late-pregnancy is associated
ment of changes in tissue oxygenation and cerebral blood with decreased expression of the subunit of the GABAA
flow. Using this technique in women with several stages of receptor and increased neuronal excitability of acute brain
hypertension, women with severe preeclampsia showed an slices.120,121 And a recent study of genome-wide meth-
increase in CBF with posture changes.103 ylation found that leukocytes obtained from women with
preeclampsia had hypermethylation of GABRA1, the 1
subunit of the GABAA receptor.122 Although implications
MECHANISMS OF SEIZURE DURING of this are not clear, because the hypermethylation was
PREGNANCY AND PREECLAMPSIA genome-wide, it is possible that preeclampsia is a state
of altered neuronal GABAA receptor function as well,
Seizures consist of excessive release of excitatory neu- further making the brain hyperexcitable. These studies sug-
rotransmitters (especially glutamate), massive depolariza- gest that pregnancy is a state of decreased seizure threshold
tion of network neurons, and bursts of action potentials.104 that may partially explain unheralded seizure in seem-
Clinical and experimental evidence suggests that extended ingly normal pregnancy, whereas preeclampsia may have
seizures can cause significant brain injury and later brain an even lowered seizure threshold due to altered GABAA
dysfunction.104106 In the brain, seizures can cause stroke, function.

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280 Chesleys Hypertensive Disorders in Pregnancy

ROLE OF CIRCULATING FACTORS it prevented the increase in excitability. It was also deter-
IN ECLAMPSIA mined that TNF- levels were not different between preg-
nant vs. nonpregnant serum, but the late-pregnant serum
During pregnancy, large amounts of hormones, including caused microglial activation (Fig. 13.13). This study
growth factors, cytokines and chemokines, are produced, importantly demonstrates that when applied directly to
mostly by the fetal-placental unit, and secreted into the mater- hippocampal slices, serum from late-pregnant animals
nal circulation.123,124 Eclamptic seizures occur almost exclu- causes neuronal excitability mediated by TNF-, likely
sively in the last half of pregnancy, and often during late from microglia. However, seizures do not normally occur
gestation when levels of these circulating hormones are high- in intact animals during pregnancy despite the presence of
est.61,63,115,116 In addition, there is a high propensity for seizure hyperexcitable factor(s) in serum. This finding points to a
to occur in multi-fetal gestations when the levels of hormones critical role of the BBB in protecting the brain from sei-
are elevated even further, suggesting a role for these circulating zure-provoking circulating factors. How the BBB adapts
proinflammatory mediators in eclampsia.114,125 The effect of to pregnancy or is altered by preeclampsia is just becom-
circulating factors on the excitability of hippocampal neurons ing understood. In addition, circulating factors have a
was investigated by exposing brain slices in culture to serum significant effect on BBB permeability, which is discussed
from nonpregnant and late-pregnant rats.126 After 48 hours of more below.
exposure, evoked network potentials were measured and quan-
tified by a graded scale that represented a range from normal to
seizure activity. Exposure to nonpregnant serum did not affect BloodBrain Barrier
slice excitability relative to control conditions. But serum from This unique structure is made up of the cerebral endo-
late-pregnant animals caused hyperexcitability in the hippo- thelium, which is characterized by high electrical resis-
campal slices. tance tight junctions and low hydraulic conductivity.127,128
When soluble TNF- receptor type 1 (sTNF-R1) was Together, these provide a barrier through which there is
added to the serum to inhibit TNF--dependent signaling, little ionic or solute flux, which minimizes the effect of

FIGURE 13.13 Relative neuronal excitability and microglial activation of hippocampal slices after exposure to nonpregnant or late-
pregnant rat serum. (A) Graded scale for which neuronal network excitability was measured. (B) Graph showing relative excitability of
neuronal networks after replacement of horse serum with nonpregnant or late-pregnant rat serum for 48 hours in the absence ( sTNFR1)
and presence ( + sTNFR1) of soluble tumor necrosis factor receptor 1 to inhibit TNF- signaling. Late-pregnant serum increased neuronal
excitability, which was prevented by sTNFR1. (C) Microglial activation of slices in response to the different serums. Late-pregnant serum
caused microglial activation. Reprinted with permission.126

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 281

hydrostatic pressure on capillary filtration and thus has a seen that late-pregnant animals had greater permeability
protective influence against vasogenic brain edema. An compared with nonpregnant animals. This suggests that at
acute rise in blood pressure that causes cerebrovascu- the same hydrostatic pressure, there is greater BBB perme-
lar resistance to decrease, however, can severely increase ability to Lucifer Yellow during pregnancy. These in vitro
hydrostatic pressure in the microcirculation, and this in turn studies were followed up with in vivo measures of BBB
disrupts the BBB, resulting in hydrostatic brain edema.129 permeability in nonpregnant and late-pregnant rats. It was
One mechanism by which cerebral edema forms with found that pregnancy caused a significant increase in BBB
eclampsia is by increased BBB permeability due to patho- permeability to both large and small tracers in response to
logically increased vascular hydrostatic pressure a form of acute hypertension.67
vasogenic edema or hydrostatic brain edema.129,130 These observations are significant for several reasons.
First, they suggest that, independent of changes in vascu-
BloodBrain Barrier in Pregnancy lar resistance, pregnancy affects the cerebral endothelium,
It appears that cerebrovascular adaptation to normal preg- making it more permeable in response to increased pres-
nancy may actually predispose to development of hydro- sure. Second, Lucifer Yellow is a polar compound com-
static brain edema when blood pressure is acutely elevated. monly used to measure fluid-phase endocytosis. Therefore,
Outward remodeling of parenchymal arterioles, discussed increased permeability suggests that transcellular transport
above, likely decreases small-vessel resistance in the brain. may be a major contributor to BBB permeability during
In addition, pregnancy appears to cause greater BBB per- acute elevations in pressure. In addition, while these experi-
meability and/or hydraulic conductivity in response to ments used cerebral arteries to measure BBB permeability,
identical hydrostatic pressures, which may play a major other studies have shown that it is the cerebral veins that
role in development of cerebral edema. A number of ani- disrupt first during acute hypertension.131,132 Importantly,
mal studies illustrate this principle. BBB permeability to a recent study in rats found that pregnancy causes cerebral
Lucifer Yellow, a polar tracer that does not pass through veins to enlarge with a thinner wall, similar to brain paren-
tight junctions, was measured in pregnancy.67 These stud- chymal arterioles.133 This type of remodeling may promote
ies were conducted on isolated and pressurized cerebral rupture (due to the thinner wall) or stasis of blood (due to
arteries from nonpregnant and late-pregnant rats such that enlargement of the lumen) and contribute to brain patholo-
permeability in response to the same change in hydrostatic gies during pregnancy.
pressure could be measured. The permeability of the BBB
in response to pressure is shown in Fig. 13.14. It can be Proinflammatory and Antiangiogenic
Factors and the BloodBrain Barrier
A major factor in the pathogenesis of preeclampsia is the
20
presence of circulating proinflammatory and antiangio-
genic factors that are thought to produce maternal vascular
inflammation and cause the endothelial dysfunction that
Permeability (ng/mL/mm Hg)

* characterizes the preeclampsia syndrome.134136 Recent


15
studies have investigated how circulating factors produced
during pregnancy and preeclampsia affect the BBB. Plasma
obtained from women with severe preeclampsia was found
10
to increase BBB permeability, which was prevented by
nonselective inhibition of vascular endothelial growth fac-
tor (VEGF) receptors.137 A subsequent study found that
5
plasma from women with early-onset preeclampsia, but
not late-onset preeclampsia, had elevated levels of oxi-
dized low-density lipoprotein (oxLDL) that were causative
0
NP (n=7) LP (n=7)
in increasing BBB permeability.138 The increase in BBB
permeability was prevented by inhibitory antibodies to
FIGURE 13.14 The effect of pregnancy on bloodbrain bar- lectin-like oxLDL (LOX-1) receptors. It was subsequently
rier permeability in response to elevated hydrostatic pressure. determined that the mechanism by which oxLDL activation
Permeability to Lucifer Yellow was assessed in cerebral arteries
of LOX-1 caused increased BBB permeability was through
in response to increases in pressure from 60 to 200mm Hg. These
data represent the average slope of the regression lines of the pres-
generation of the reactive oxygen and nitrogen species per-
sure versus permeability curves, or the rate of permeability in oxynitrite.139 This finding also explains why VEGF recep-
response to pressure, from nonpregnant (NP, black bar) and late- tor inhibition also prevented the increase in permeability in
pregnant (LP, gray bar) animals. Notice that pregnancy causes a response to preeclamptic plasma VEGF inhibition would
significant increase in bloodbrain barrier permeability in response decrease nitric oxide, one of the two factors needed for per-
to the same change in hydrostatic pressure (*p<0.05 vs. NP).67 oxynitrite generation.

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282 Chesleys Hypertensive Disorders in Pregnancy

Aquaporins and Cerebral Edema mechanism by which magnesium acts to prevent convul-
During Pregnancy sions is not clear. Some studies have suggested that magne-
sium acts on the cerebrovasculature to cause vasodilatation
The aquaporins are a family of channel-forming transmem- and relief of vasospasm.155157 Yet other studies have shown
brane proteins that facilitate the movement of water, glyc- magnesium sulfate treatment has little effect on cerebral
erol, and other solutes across cell membranes.140,141 Three hemodynamics and CBF.88,158 The mechanism of action
aquaporins AQP1, AQP4, and AQP9 have been identified of magnesium sulfate in prevention of eclampsia has been
in the brain.142144 AQP4 is the predominant aquaporin in the reviewed.159 In a study using isolated and pressurized cere-
brain, and it is mainly localized in the endfeet of astrocytes bral arteries, magnesium was shown to have a modest vaso-
surrounding blood vessels, the glial limitans membranes, dilatory effect, but the sensitivity of the response decreased
and ependyma.145147 Given its location, AQP4 is thought to during pregnancy and postpartum.160 Also, a clinical trial
facilitate the movement of water at the bloodbrain interface found that when compared with the calcium-channel
and at the bloodcerebrospinal fluid barrier.142,146,148 blocker nimodipine, magnesium sulfate was more effective
All three aquaporins are expressed in the brain dur- in preventing eclamptic convulsions.161 These findings sug-
ing pregnancy.144,149 Importantly, AQP4 has expression gest that the primary action of magnesium sulfate to prevent
levels that are significantly increased during pregnancy eclampsia is not an effect on vasospasm.
compared with the nonpregnant state when studied with There have been numerous reports that treatment with
quantitative PCR and Western blot.144,149 These findings magnesium sulfate decreases BBB permeability and edema
have led to the suggestion that pregnancy alone is a state formation in a variety of brain injury conditions, including
of altered brain water homeostasis. Because AQP4 has not traumatic brain injury, septic encephalopathy, and hypogly-
been found in cerebral endothelia, however, it is unlikely to cemia.162164 Euser et al.165 demonstrated that magnesium
affect hydraulic conductivity of the BBB. It is more likely sulfate treatment during pregnancy decreased BBB per-
that increased AQP4 expression during pregnancy is more meability to Evans blue in response to acute hypertension
related to edema resolution, as recently shown in brain (Fig. 13.15). The effect was most pronounced in the poste-
injury models.150 Genetic variations in AQP4 might serve to rior brain, a region that is most susceptible to edema forma-
explain why some women with preeclampsia develop cere- tion during eclampsia.
bral edema and eclampsia while others do not.
An increase in AQP4 in the brain during pregnancy has 5000
Sham
several implications related to eclampsia. AQP4 has been
shown to affect K+ homeostasis in the brain and modulate HTN
Fluorescence (CPS/g)

4000
seizure activity. AQP4 knockout mice have a decreased sei- HTN + Mg *
zure threshold when exposed to the chemoconvulsant pentyl-
3000
enetetrozol or to electrically stimulated seizure.151,152 This is
thought to be mediated by altered brain K+ homeostasis.153 * *
Thus, increased AQP4 expression during pregnancy may be 2000

another mechanism by which the seizure threshold is lowered.


Increased AQP4 may also be important for clearing poten- 1000
tially damaging and seizure-provoking serum factors that
gain entry to the brain through a disrupted BBB during pre- 0
eclampsia. AQP4 only transports water, not solute; however, Anterior Posterior
cerebrum cerebrum
a role for AQP4 in cerebrospinal fluid (CSF) and interstitial Brain region
solute clearance has recently been demonstrated.154 Because
FIGURE 13.15 Graph showing bloodbrain barrier perme-
the brain lacks a lymphatic circulation, bulk fluid flow driven
ability to Evans blue after acute hypertension and autoregula-
by AQP4 in astrocytic endfeet clears solute and regulates tory breakthrough in late-pregnant animals that were either sham
extracellular levels of protein in the brain. Thus, while normal controls (Sham, open bar), untreated (HTN, black bar), or treated
pregnancy is associated with increased AQP4 that may serve with 270mg/kg magnesium sulfate every 4 hours for 24 hours by
to clear solute that is elevated in the brain during pregnancy, intraperitoneal injection (HTN + Mag, gray bar). Permeability
if AQP4 is decreased during preeclampsia there may be accu- was measured by in situ perfusion in the anterior and posterior
mulation of damaging factors in the brain. The expression of brain regions. Bloodbrain barrier permeability was significantly
AQP4 in the brain during preeclampsia is not known. increased with acute hypertension and autoregulatory break-
through compared with sham controls (*p < 0.05). The increase
in permeability was greater in the posterior versus anterior brain
Effect of Magnesium Sulfate Treatment region (p < 0.05). Magnesium sulfate treatment significantly
decreased bloodbrain barrier treatment in posterior cerebrum
As discussed in Chapters 12 and 20, magnesium sulfate in response to acute hypertension (p < 0.05). Reprinted with
is used for prevention and treatment of eclampsia. The permission.165

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 283

Cerebral Hemorrhage have now accrued, however, that support the view that com-
plete reversibility is not always the case.
As discussed previously, and shown in Fig. 13.2, nonlethal
intracranial hemorrhage is also frequently found in women
with eclampsia. In some women, sudden death occurs syn- Visual Functioning
chronously with the convulsion or follows shortly there-
Rarely, there may be permanent visual defects with severe
after, and is the result of massive cerebral hemorrhage (see
preeclampsia or eclampsia. There are two possible causes
Fig. 13.1). Such hemorrhage is more common in older
of these. One is retinal artery ischemia and infarction
women with underlying chronic hypertension and is thought
Purtscher retinopathy and the other is associated with
to be secondary to longstanding hypertension-induced lipo-
MR-imaging evidence of infarctions in the lateral genicu-
hyalinosis, which damages small or medium-sized cerebral
late nuclei.172174 In an examinination of visual fields in
arteries in the striatocapsular area, thalamus, cerebellum, and
over 40 women who had suffered eclampsia several years
brainstem.166 These changes are termed CharcotBouchard
previously none had evidence of visual field defects.175
aneuroforms or miliary aneuroforms.167,168
Vision-related quality of life impairment expressed by for-
Hemorrhage may also develop in areas of cerebral isch-
merly eclamptic women may therefore be related to prob-
emia or infarction that transform into a hemorrhagic infarc-
lems with higher-order visual functions.
tion. These are probably more common in young women
with HELLP syndrome and eclampsia.10,14 Women with pre-
eclampsia may also experience subarachnoid hemorrhage. Brain White Matter Lesions
In such cases a small amount of blood can be seen over the
In the strictest sense, posterior reversible encephalopathy
convexity of the frontal/parietal lobes extending into the syl-
syndrome (PRES) is inappropriate to describe the brain
vian fissure or interhemispheric tissue and is hypothesized to
edema seen with MRI and CT in eclamptic women since
be the result of rupture of cortical petechiae over the surface
it is not necessarily confined to the posterior cerebrum
of the brain or rupture of small pial veins.167 Only rarely is
and there may be incomplete resolution and even ensuing
intracerebral hemorrhage in women with preeclampsia due
infarction. Specifically, as discussed on p. 272, a quarter
to a ruptured aneurysm or arteriovenous malformation.169
of eclamptic women have restricted diffusion at time of
seizure. Persistent cerebral T2 hyperintensities can still be
visualized 68 weeks postpartum with MRI.16,20 Clinical
Cortical Blindness
parameters indicating eclampsia severity in women with or
Possibly due to the differential innervation of the poste- without such hyperintense lesions are shown in Table 13.2.
rior cerebral circulation as discussed, visual symptoms Focal gliosis has been described in 40 % of eclamptic
may manifest in 40% of preeclamptic women, and on rare women on average 9 days following the eclamptic sei-
occasions they may be the initial symptom.170,171 The older zure.176 The subsequent evolution of brain abnormalities
term used to describe loss of vision was amaurosis, and in in women who suffered eclampsia is unknown since lon-
addition there are scotomata, blurred vision, diplopia, and gitudinal follow-up studies are lacking. For nonpregnant
chromatopsia. Retinal abnormalities, including edema, vas- patients with PRES some information has become available
cular changes such as arteriolar vasospasm, thrombosis of describing neuroimaging follow-up. Imaging abnormali-
the central retinal artery, and retinal detachment can usually ties frequently consist of nonspecific white matter lesions
be ruled out. In addition, pupillary light reflexes and ocu- (WMLs), gliosis and infarction but may also include haem-
lar movements remain intact, and there are normal ophthal- orrhage (unpublished data).
mological findings. Focal occipital lobe edema, including In a long-term follow-up study of women with eclamp-
bilateral edema of the lateral geniculate nuclei, can be seen sia that averaged 7 years, there was a 41% prevalence of
on neuroimaging with this type of cortical blindness.172 The cerebral white matter lesions, which was significantly
majority of preeclamptic women with cortical blindness higher compared to the 17% found in age-matched women
recover vision over a period varying from 2 hours to 21 who had had a normotensive pregnancy177 (Fig. 13.16). The
days.170 Clinical recovery typically precedes normalization total volume of such lesions was significantly larger in the
of neuroimaging findings. previously eclamptic women. Women who suffered pre-
eclampsia without eclamptic seizures, on average 5 years
previously, also demonstrated such WMLs in 37 % of
REMOTE CEREBROVASCULAR HEALTH cases.178 Current hypertension and a history of early-onset
FOLLOWING PREECLAMPSIA preeclampsia (<37 weeks) were independently associated
AND ECLAMPSIA with the presence of such lesions (Fig. 13.17). Women with
term preeclampsia appeared to have an incidence of brain
Until recently, it was commonly held that seizures with pre- WMLs similar to control women who had normotensive
eclampsia have no significant long-term sequelae. Findings pregnancies. These atypical WMLs were predominantly

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284 Chesleys Hypertensive Disorders in Pregnancy

TABLE 13.2 Comparison of Clinical Parameters that Indicate Eclampsia Severity


in the Presence or Absence of Cerebral Infarctions
Factor Infarctions Present (n=6) Infarctions Absent (n=18) p Value

Age (y) 23.0 7.1 20.7 6.4 .465


Gestational age (wk) 36.2 2.4 39.0 2.1 .012
MAP (mm Hg) 123 10.8 112 11.1 <.001
MAP (mm Hg) 40.4 15.1 30.1 11.7 .096
Serum creatinine >0.9mg/dL 4 (67%) 2 (11%) .007
Proteinuria 3 + (dipstick) 4 (67%) 3 (17%) .020
Platelet count ( 1000/L)
Mean 105 53 203 63 .002
<150 4 (67%) 4 (22%) .046
<100 3 (50%) 1 (6%) .012
HELLP syndrome 3 (50%) 1 (6%) .012
Multiple seizures 5 (83%) 2 (11%) <.001
From Zeeman etal. 2004,16 with permission.
MAP = maximal mean arterial pressure in proximity to seizure(s); MAP = change in MAP from most recent prenatal visit
compared with MAP proximate to seizure; HELLP = hemolysis, elevated serum transaminase levels, low platelets.

FIGURE 13.17 Total volume of white matter lesions (WMLs)


in the control group, late-onset pre-eclamptic group, and early-
onset pre-eclamptic group. KruskalWallis test: p<0.01. Post-hoc
FIGURE 13.16 Magnetic resonance image (FLAIR) 7 years MannWhitney test: early-onset PE versus late-onset PE: p=0.01.
following eclampsia, demonstrating several white matter lesions Post-hoc MannWhitney test: early-onset PE versus controls:
(arrows). p<0.01. PE, pre-eclampsia. Reprinted with permission.178

found in the frontal lobes, followed by the parietal, insu- cases, progressive global brain edema may lead to further
lar, and temporal lobes, which are not the areas typically neurological deterioration, including blindness, mental status
involved in PRES.179 changes, coma, transtentorial herniation, and death.9,170
The exact pathophysiology underlying these morpho- The presence of atypical cerebral WMLs may indicate
logical brain changes in formerly preeclamptic and eclamptic that preeclampsia might be a risk marker for early cerebro-
women and their clinical relevance remain so far unknown. vascular damage. The predisposition of formerly preeclamp-
Cerebrovascular events in eclampsia appear to constitute a tic women to later cardiovascular and cerebrovascular
continuum characterized by an initial, reversible phase of disease may be an important factor for the development
vasogenic edema caused by hypertension along with endothe- of such lesions.180 In particular, the presence of hyperten-
lial dysfunction. In some cases, severe vasogenic edema may sion seems important for the development and progression
reduce cerebral perfusion to cause focal ischemia. Indeed, in of WMLs in elderly populations181 but also in younger
a quarter of eclamptic women, MRI documents a transition cohorts.182,183 Whether a history of posterior reversible
from reversible vasogenic edema to cytotoxic edema, irre- encephalopathy syndrome may be an additive risk factor for
versible cerebral ischemia, and infarction.16,20 In extreme the development of these lesions remains unknown.

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Chapter13Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia 285

Neurocognitive Functioning have preeclampsia compared with normotensive pregnant


women. In addition, there is a three- to five-fold increase in
There is scarce literature concerning long-term clinical con-
fatal stroke in previously preeclamptic women.169,195,196
sequences of PRES in either obstetrical or non-obstetrical
patients regarding neurocognitive status. Persistent brain
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