Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia




Keywords

eclampsia, cerebral edema, cerebral hemodynamics, posterior reversible encephalopathy syndrome

 


Editors’ comment: A single chapter focusing on the brain in normal pregnancy and preeclampsia appeared in edition 3 and this is its first revision. New additions include animal model observations that suggest explanations for changes in cerebral physiology during normal pregnancy and hypertensive complications. New findings in the human disease regarding volume status and the eclamptic convulsion are discussed and there is further clarification of that new but loosely thrown around term “posterior reversible encephalopathy syndrome” and in both areas our authors have made recent seminal contributions. One does not need an editors’ comment to realize that cerebral involvement in preeclampsia, and especially eclampsia, is a purveyor of serious disease. In this regard discussions regarding prevention and management of cerebral symptoms, especially eclampsia, can be found in Chapter 12 , Chapter 20 , the first reviewing trials with magnesium sulfate, the latter the treatment of impending or actual eclampsia.




Introduction


The brain has a central role in the preeclampsia–eclampsia syndrome. For many centuries, convulsions in the pregnant woman were the most recognizable event of what we now know to be a generalized disorder that affects virtually every organ system. In his first edition of Hypertensive Disorders in Pregnancy , Chesley chronicled the historical evolution of theories concerning causes of convulsions in women with eclampsia. Since the times of Hippocrates and Galen, the two main theories were either cerebral congestion repletion , or cerebral anemia depletion . Beliefs concerning repletion led to the widespread practice of phlebotomy during the 1700s and 1800s. And throughout much of the last century, as therapeutic measures were aimed at either halting or preventing convulsions, evidence began to accrue leading to insights into the cerebrovascular pathophysiology of eclampsia. For example, during the renaissance of neuroanatomy and pathology, intracranial hemorrhages and generalized cerebral edema were prominently emphasized.


Neuroanatomical emphasis culminated in the seminal work of Sheehan and Lynch and their autopsy series of eclamptic women. This work is unique as the brains studied were from autopsies performed within 2 hours after death, eliminating most of the postmortem changes that rapidly occur in brain tissue and might confound interpretation. By then, it was appreciated that women with fatal eclampsia frequently had brain abnormalities, but that these caused death in a minority of such cases. As deaths from eclampsia declined over the last half of the 20th century, interest in cerebral pathology waned also because there were few avenues from which to approach appropriate investigation. This gap was filled by the development of computed tomography (CT) in the 1970s, which allowed noninvasive brain imaging. Doppler studies of cerebral blood flow (CBF) velocity reawakened interests in cerebrovascular perturbations in the preeclampsia syndrome. More recently, the use of MRI has opened wider the vista to study neuroanatomical changes as well as to more accurately measure cerebral perfusion. These technologies, combined with reproducible animal models to better study cerebral blood flow and its alterations, have allowed a heretofore unknown look at cerebrovascular pathology provoked by the preeclampsia syndrome.


In this chapter we correlate the earlier neuropathological observations of eclampsia with the noninvasive imaging findings derived from CT scanning and MR imaging. We also correlate cerebrovascular abnormalities induced by preeclampsia–eclampsia and measured with direct and indirect noninvasive methods such as MRI technology and Doppler velocimetry. And finally, we review hypertensive effects on cerebral perfusion in both pregnant and nonpregnant animal models from which we draw a composite description of the effects of the preeclampsia syndrome on the brain. Finally this chapter is designed to specifically describe cerebral pathology and pathophysiology in preeclampsia/eclampsia. Clinical aspects of the preeclampsia syndrome are discussed in Chapter 2 , Chapter 12 , Chapter 20 .




Neuroanatomical Findings with Eclampsia


Most neuroanatomical descriptions of the brain in eclamptic women are taken from eras when mortality rates were quite high. One consistent finding was that brain pathology accounted for only about a third of fatal cases such as the one shown in Fig. 13.1 . In the majority of cases, however, death was from pulmonary edema, and the brain lesions were coincidental. Thus, while gross intracerebral hemorrhage was seen in up to 60% of eclamptic women, it was fatal in only half. As shown in Fig. 13.2 , other principal lesions found at autopsy consisted of cortical and subcortical petechial hemorrhages. Histologically, these are composed of numerous small hemorrhages, 0.3–1.0 mm in diameter, arranged in streaks of 2–4 cm running radially in the cortex. They may appear anywhere on the gyral surface and are most common in the occipital lobes and least common in the temporal lobes. Many occur in the border zones between cerebral arterial territories. Other frequently described major macroscopic lesions include subcortical edema, multiple nonhemorrhagic areas of “softening” throughout the brain, hemorrhagic areas in the white matter, and hemorrhage in the basal ganglia or pons, often with rupture into the ventricles. In some cases, numerous small cortical infarctions are described as well. These infarcts vary from about 0.3 to 1.0 mm in diameter and are sometimes confluent. The classical microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular microinfarcts and hemorrhages.




Figure 13.1


Hypertensive hemorrhage with eclampsia.

(Reprinted, with permission, from Cunningham FG, et al.: Williams Obstetrics , 20th ed. Stamford, CT: Appleton & Lange; 1997.)



Figure 13.2


Composite illustration showing location of cerebral hemorrhages and petechiae in women with eclampsia: (A) pia-arachnoid hemorrhage; (B) cortical petechiae; (C) subcortical petechiae; and (D) focal softenings or petechiae in midbrain or white matter.




Neuroimaging in Eclampsia


A number of neuroimaging techniques have been used to better understand the cerebrovascular mechanism(s) involved in the preeclampsia syndrome. These include angiography, CT, and MRI techniques. Specifically, the ever-increasing development of MRI techniques has especially been useful to provide information concerning the pathogenesis of cerebral manifestations of preeclampsia.


Computed Tomography (CT)


Localized hypodense lesions at the gray–white matter junction, primarily in the parieto-occipital lobes, are typically found in eclampsia ( Fig. 13.3 ). Such lesions may also be seen in the frontal and inferior temporal lobes, as well as the basal ganglia and thalamus. The spectrum of involvement is wide, and with increasing radiological involvement, either of the occipital lobes or with diffuse cerebral edema, symptoms such as lethargy, confusion, and blindness will develop. In these cases, widespread edema shows as a marked compression or even obliteration of the cerebral ventricles ( Fig. 13.4 ). Such women may develop signs of impending life-threatening transtentorial herniation.




Figure 13.3


Cranial CT of a woman with eclampsia. Radiographic low-density areas (arrow) are seen in the right occipital lobe.



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 gray–white interface, both indicating parenchymal swelling. The radiograph on the right taken 10 days later shows diminished edema manifest by larger ventricles and loss of gray–white interface demarcation.


Most reports describe reversibility of cerebral edema. In a few women with eclampsia, however, cerebral infarctions have been described. And cerebral hemorrhagic transformation may also develop from areas of ischemic infarction. 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 eclamptic women. Common findings are hyperintense T2 lesions in the subcortical and cortical regions of the parietal and occipital lobes, with occasional involvement of basal ganglia and/or brainstem. Some examples are shown in Figs. 13.5A and 13.6A . While these lesions of the posterior reversible encephalopathy syndrome are almost universal in women with eclampsia, their incidence in women with preeclampsia is not known. Intuitively, however, they are more likely found in women who have more severe disease and who have neurological symptoms. And they are although usually reversible, it is now known that some of these hyperintense lesions appear as infarctions and that there are persistent findings in up to a fourth of eclamptic women several weeks postpartum.




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.



Figure 13.6


MRI evidence of hypertensive encephalopathy and lacunar infarctions in eclampsia. This case demonstrates the occasional atypical distribution of signal abnormalities away from the parieto-occipital region. (A) Note on T2-weighted FLAIR image that the predominant changes occur in the basal ganglia regions bilaterally. (B) Small foci of cytotoxic edema are indicated by the marked hyperintensity on DWIs. (C) Corresponding reduced ADC (arrows). (D) These small, presumed lacunar infarctions show a typical evolution on repeat examination 6 weeks after the initial events as T2 hyperintensity on FLAIR (arrows) and (E) low signal intensity on T1-weighted image (arrows) in regions corresponding to DWI evidence of infarct (see B and C) on the initial studies. Hypertensive encephalopathy is neither necessarily posterior nor reversible.


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 associated with ischemia and cell death with infarction. This issue is critical because the former is usually reversible and the latter may not be. 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 acquisitions were developed. These include diffusion-weighted imaging (DWI) sequences and apparent diffusion coefficient (ADC) mapping. With these, it is possible to further characterize the hyperintense lesions seen on T2 imaging ( Figs. 13.5B–E and 13.6B–E ). Any predictions of the clinical course of eclampsia based on DWI and ADC findings remain currently speculative.


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 characterized by increased extracellular fluid with enhanced water diffusion and may be seen as a combination of normal DWI with hyperintense T2 signal lesions and increased apparent diffusion. 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 water from the extracellular to the intracellular space, and it elicits a hyperintense signal on DWI but with a decreased ADC. It has been shown that ischemic brain regions can be identified within minutes to hours after the onset of neurological symptoms. Furthermore, newer techniques such as susceptibility-weighted imaging and diffusion tensor imaging for assessing the structure of the white matter are being developed, but their benefit for eclampsia is yet unclear.


In women with eclampsia, studies using DWI sequences showed that the origin of cerebral edema is primarily vasogenic, but that less commonly there are ischemic and cytotoxic changes, i.e., infarction. These latter cases have DWI hyperintense T2 lesions and decreased ADC superimposed on the pattern of vasogenic edema. In related animal studies, Tamaki et al. showed that blood–brain barrier (BBB) disruption due to marked local hydrostatic pressure precedes decreased tissue perfusion and ischemia.




Pathogenesis of Cerebral Manifestations in (PRE)Eclampsia


Pregnancy-induced changes of cerebrovascular hemodynamics have not been well studied, and thus the pathogenesis of cerebral manifestations of the preeclampsia syndrome is also unclear. Much of this is because of the various challenges associated with in vivo studies of cerebral blood flow in human pregnancy (see below). And while central nervous system histopathology is mainly based on autopsy data as discussed, most hemodynamic data are invariably from surviving women. Although this presents some difficulty in relating histopathological with hemodynamic findings, an accurate picture is emerging.


When taken clinically, data taken from the past several decades include pathological and neuroimaging findings that have led to two general theories to explain cerebral abnormalities associated with eclampsia. Importantly – and as emphasized throughout this edition – endothelial cell dysfunction that characterizes the preeclampsia syndrome may play a key role in both theories.


The first theory suggests that in response to acute severe hypertension cerebrovascular overregulation leads to vasospasm. 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. In this scheme, diminished CBF is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarction. Finally, the reversible cerebral vasoconstriction syndrome has been reported to be associated with preeclampsia, but whether this causes eclampsia is not known.


The second theory is that eclampsia represents a form of hypertensive encephalopathy such that sudden elevations in systemic blood pressure exceed the normal cerebrovascular autoregulatory capacity. The decrease in cerebrovascular resistance (CVR) causes disruption of end-capillary hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through opening of the endothelial tight junctions with increased pinocytosis leading to the accumulation of vasogenic edema. Regions of forced vasodilatation and vasoconstriction develop, especially in arterial boundary zones, as is prominent in hypertensive encephalopathy. Figure 13.7 shows a brain biopsy of a patient with hypertensive encephalopathy, a condition that may relate to eclampsia. This mechanism has gained much attention over the last decade, especially since it was described as reversible posterior leukoencephalopathy syndrome . More recently, it is usually referred to as the posterior reversible encephalopathy syndrome (PRES) to incorporate the posterior nature of the condition. The normal structure of the neurovascular unit comprises capillary endothelial cells in close association with basal lamina, astrocytic endfeet, and pericytes ( Fig. 13.8 ). It is largely unknown how these cells and structures are affected during preeclampsia that may contribute to brain pathologies including hemorrhage and edema.




Figure 13.7


Cerebral biopsy of a 60-year-old man with hypertensive encephalopathy from blood pressure 220/120 mmHg. The white matter shows mild, diffuse vacuolization with minimal inflammatory reaction characterized by scattered macrophages. Abundant reactive astrocytes were evident.

(From Schiff and Lopes. Neurocrit Care. 2005;2(3):303–305, with permission.)



Figure 13.8


Schematic of the neurovascular unit. Increased hydrostatic (capillary lumen) pressure causes extravasation of plasma and red cells through endothelial tight junctions with perivascular edema.

Reprinted with permission from del Zoppo GJ. New Engl J Med . 2006;354:553–555. (This figure is reproduced in color in the color plate section.)




Eclampsia as Posterior Reversible Encephalopathy Syndrome (PRES)


It is currently thought that preeclampsia is one of the disorders that share a common etiopathogenesis and that comprise PRES. Its clinical, pathological, as well as neuroimaging features reflect the rapid and dynamic fluctuations in cerebral blood flow and water content. In fact, nearly all patients with eclampsia had PRES as determined by MRI. In nonpregnant and pregnant patients, PRES is usually an acute cerebral illness which may present with headache, nausea, altered mental function, visual disturbances, and seizures. In preeclampsia–eclampsia related PRES, headaches are more frequent than altered mental status as the initial PRES-related symptom compared to nonpregnant PRES patients. The convulsions are commonly – but not exclusively – occipital in onset and correlate with the characteristic predominantly posterior imaging abnormalities seen with MRI in women with eclampsia. The arterial boundary zones, located at the territorial limits of the major arteries, are commonly affected sites. These zones are known as the border zone or watershed areas . In the human, the most frequently affected region in the cortex is at the parieto-occipital sulci, which represent the boundary zone of the anterior, middle, and posterior cerebral arteries. Involvement of the cerebral cortex may also be seen in PRES and lesions may extend to the brainstem, cerebellum, basal ganglia, and the more anterior brain regions such as the frontal lobes. However, eclampsia-related PRES cases demonstrate less frequent involvement of the thalamus, midbrain, and pons compared to nonpregnant PRES cases.


Some patients with PRES have only convulsions and do not manifest traditional prodromal signs and symptoms of hypertensive encephalopathy. In addition, the dramatic blood pressure increases that typify hypertensive encephalopathy are not necessarily seen and there may be only mild to moderate blood pressure increases with PRES. Importantly, PRES may develop with only mild hypertension,, which may involve endothelial damage. This has been described in the thrombotic microangiopathy syndromes – hemolytic uremic syndrome and thrombotic thrombocytopenic purpura – as well as with systemic lupus erythematosus, with immunosuppressive drug toxicity, or with the use of certain chemotherapeutic agents that include methotrexate and cisplatin. Finally, it is important to recognize PRES because the neurological disorder is readily treatable by lowering any dangerously elevated blood pressures and correction of the underlying medical condition that caused endothelial cell injury.




Cerebral Blood Flow Autoregulation


Autoregulation is the process by which cerebral blood flow (CBF) remains relatively constant in the face of alterations in cerebral perfusion pressure. Put another way, when cerebral perfusion pressure declines, cerebrovascular resistance (CVR) decreases due to myogenic vasodilatation of pial arteries and arterioles and hypoxic vasodilatation, thus augmenting perfusion. Alternatively, if cerebral perfusion pressure increases, the autoregulatory response increases CVR by vasoconstriction, resulting in relatively constant CBF. Thus, autoregulation is a physiological protective mechanism that prevents brain ischemia during drops in pressure and prevents capillary damage and edema from hyperperfusion during pressure increases. In normotensive adults, CBF is maintained at approximately 50 mL per 100 g of brain tissue per minute (mL/100 g/min), provided perfusion pressure is in the range ~60–160 mm Hg. Above and below these limits, autoregulation is lost and CBF becomes dependent on mean arterial pressure in a linear fashion.


Significant brain injury occurs when autoregulatory mechanisms are lost. For example, during acute hypertension at mean pressures above the autoregulatory limit – about 160 mm Hg in the otherwise healthy patient – the myogenic vasoconstriction of vascular smooth muscle is overcome by excessive intravascular pressure and forced dilatation of cerebral vessels occurs. The loss of myogenic tone during forced dilatation decreases CVR and increases CBF, a result that produces hyperperfusion, BBB disruption, and acute edema formation.


The relationship between autoregulation, CBF, and BBB disruption has been extensively studied. Numerous investigators have found a positive correlation between loss of autoregulation, increased perfusion, and BBB permeability that leads to cerebral edema. Importantly, mechanisms that increase resistance, such as sympathetic nerve stimulation or inward remodeling of cerebral arterioles during chronic hypertension, attenuate increases in CBF during acute hypertension and are protective of the BBB. In general, when CBF is compared in areas with and without albumin extravasation in the same brain, the regions of increased permeability have the highest blood flow, indicating loss of autoregulation and decreased CVR. Together, these findings suggest that decreased resistance and hyperperfusion during acute hypertension cause BBB disruption, whereas increased resistance is protective of the microcirculation. In fact, decreased CVR that leads to hyperperfusion during acute hypertension is considered the primary cause of edema during hypertensive encephalopathy and eclampsia.


When severe experimental hypertension is induced by intravenous infusion of vasogenic agents, arterioles develop a pattern of alternating constrictions and dilatations, giving rise to the so-called sausage-string appearance. This vascular pattern has been demonstrated in small blood vessels in various vascular beds, including the brain. In the cerebral circulation, the development of the sausage-string pattern is linked to the development of vascular damage, specifically in the dilated regions of the vessel as they fail to maintain myogenic vasoconstriction, with resulting endothelial hyperpermeability and extravasation of macromolecules into the brain parenchyma.




Cerebral Blood Flow Autoregulation and Hemodynamics in Pregnancy


The effect of pregnancy on cerebral hemodynamics and cerebral blood flow autoregulation is of significant interest mostly because impaired cerebral autoregulation is thought to be a major contributor to the development of eclampsia. The adaptation of the cerebral circulation to pregnancy has recently been extensively reviewed. From clinical observations, it is known that eclampsia can develop with only mild or even absent hypertension. While it is tempting to hypothesize that the upper limit of cerebral autoregulation is reduced with the preeclampsia syndrome, evidence for this is lacking. It seems much more likely that perivascular edema develops at a much lower capillary hydrostatic pressure, possibly as a function of endothelial activation known to accompany the preeclampsia syndrome. That said, failure of autoregulatory mechanisms may occur in response to either an acute and/or relatively large blood pressure increase, which seems more important than absolute blood pressure. Thus, it is possible that it is the acuteness of the blood pressure rise or relative change in pressure from baseline in the setting of endothelial dysfunction that disrupts the delicate balance between capillary and cerebral perfusion pressures in eclampsia. Understanding cerebral hemodynamic changes associated with pregnancy and preeclampsia is challenging, necessitating the use of animal models in some instances. Thus, the following sections will review both animal and clinical studies on changes in cerebral hemodynamics during pregnancy and preeclampsia.


Animal Studies


Many women who develop eclampsia do so at pressures that are considerably lower than those reported for posterior reversible encephalopathy syndrome or hypertensive encephalopathy. These findings suggest that the cerebral blood flow autoregulatory curve is shifted to the lower range of pressures during pregnancy. Studies in anesthetized rats found that this was not the case. When the upper limit of CBF autoregulation was compared between nonpregnant and late-pregnant rats, there was no difference in the pressure of autoregulatory breakthrough ( Fig. 13.9A ). In fact. more recent studies in rats found that both the upper and lower limits of CBF autoregulation were extended. Importantly, however, only the pregnant animals developed significant edema formation in response to acute hypertension and autoregulatory breakthrough, suggesting that the endothelium is more susceptible to hydrostatic edema during pregnancy ( Fig. 13.9B ).




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 breakthrough (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.


It is important to note that the autoregulatory curves in these studies were determined using laser Doppler methods to measure CBF and they thus only provide relative changes in blood flow. Other studies using microspheres to measure absolute CBF showed that acutely increased pressures in late pregnancy were associated with significantly decreased CVR and increased CBF when compared with nonpregnant animals. Specifically, pregnancy was associated with a 40% decrease in CVR compared with that in nonpregnant animals with the same change in pressure. Because increased CVR in response to elevated cerebral perfusion pressure is a protective mechanism in the brain that prevents transmission of harmful hydrostatic pressure to the microcirculation, diminished CVR during pregnancy in response to acute hypertension could promote BBB disruption and vasogenic edema, similar to what is seen during eclampsia.


The mechanism by which pregnancy decreases CVR during acute hypertension is not clear, but may be related to structural changes that affect arterial and arteriolar diameter. Resistance and flow regulation are principally determined by vessel caliber because they are inversely related to the fourth power of vessel radius. The innate myogenic behavior of the cerebrovascular smooth muscle is crucial for establishment of an appropriate CVR, which serves to protect downstream arterioles and capillaries in the face of changing perfusion pressures and to maintain tissue perfusion when blood pressure falls. The cerebral circulation is a unique vascular bed in that large extracranial and intracranial pial vessels contribute about 50% to total CVR. Studies of isolated cerebral arteries from nonpregnant, late-pregnant, and postpartum animals suggest that forced dilatation occurs at lower pressures during pregnancy and postpartum ( Fig. 13.10 ). This may be a contributory mechanism by which pregnancy decreases CVR during acute increases in pressure.




Figure 13.10


Graph showing pressure versus diameter curves of posterior cerebral arteries from nonpregnant (NP, closed triangles), late-pregnant (LP, closed circles), and postpartum (PP, closed squares) animals. Arteries from all groups of animals constricted in response to increased pressure within the pressure range 50–125 mm Hg, demonstrating myogenic reactivity. Arteries from LP and PP animals, however, underwent forced dilatation at significantly lower pressure compared with NP animals – this is noted by the large increase in diameter in response to increased pressure (** p <0.01 vs. NP). The increase in diameter during forced dilatation is a primary event in the development of hydrostatic brain edema in which cerebrovascular resistance is decreased.

Reprinted with permission.


Although these changes in larger pial arteries may contribute to decreased CVR and increased microvascular pressure noted in late-pregnant animals, the response of smaller parenchymal arterioles is a critical determinant of distal capillary pressure and a major determinant of BBB changes. In fact, previous studies have shown that differences in resistance of small vessels in the brain parenchyma can account for regional differences in BBB permeability during acute hypertension. Because late-pregnant animals developed edema in response to autoregulatory breakthrough and elevated hydrostatic pressure, it seems likely that small-vessel resistance is reduced and contributes to edema. In studies to specifically examine brain parenchymal arterioles, vessels from late-pregnant animals were shown to have larger diameters compared with those from nonpregnant animals. Thus, there is a gestation-induced effect to cause outward remodeling of parenchymal arterioles ( Fig. 13.11A ). Subsequent studies showed that selective enlargement of brain parenchymal arterioles was due to relaxin-induced activation of the transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ). Although such structural changes may not influence resting CBF, they would have a significant impact on local hemodynamics under conditions when vessels are markedly dilated such as during breakthrough of autoregulation – and the resulting forced dilatation. Importantly, outward remodeling of parenchymal arterioles in the brain appears to be at the expense of the vascular wall, which becomes significantly thinner during pregnancy ( Fig. 13.11B ). Therefore, the significance of outward remodeling of cerebral arteries and arterioles during pregnancy may not be limited to decreased CVR during acute hypertension, but may also predispose the brain to hemorrhage, another pathological finding of eclampsia, due to severely increased wall stress.




Figure 13.11


(A) Effect of pregnancy on the diameter of small penetrating arterioles in the brain. Measurements were taken using video microscopy, ex vivo and fully relaxed in papaverine solution to inhibit smooth muscle contraction at a pressure of 5 mm Hg. Measuring diameter at low pressure when changes in distensibility are minimal provides a more accurate assessment of arteriole remodeling and growth. Graph shows arteriolar lumen diameter from nonpregnant (NP, black bar) and late-pregnant (LP, gray bar) animals. Pregnancy causes outward remodeling of cerebral arterioles (* p <0.05 vs. NP). This effect likely decreases small-vessel resistance under conditions when the vasculature is fully dilated, such as during acute hypertension and forced dilatation. (B) Effect of pregnancy on arteriolar wall thickness. Measurements were taken similarly to those shown in (A) at pressures of 5 and 75 mm Hg. Graph shows wall thickness of arterioles from nonpregnant (NP, black bar) and late-pregnant (LP, gray bar) animals. Notice that in addition to causing outward remodeling of arterioles that increases lumen diameter, pregnancy also causes arterioles to have significantly thinner walls (* p <0.05 vs. NP). This effect on arteriolar wall thickness would be expected to cause a significant elevation in wall stress, especially under conditions of acute hypertension when both lumen diameter and arteriolar pressure are severely increased.


Human Studies


In 1949, McCall first described cerebral blood flow changes in women with eclampsia using an inhalation technique of a gaseous mixture containing nitrogen, nitric oxide, and oxygen. Internal jugular arterial and venous blood was collected and the Fick principle applied by measuring serum concentrations. In eclamptic women, while the delivery of oxygen and CBF were normal, there was a 20% decrease in oxygen utilization. Other than these studies, there are none reported that used invasive methods to assess pregnancy-related CBF in humans. In fact, there are obvious major challenges encountered when assessing CBF in the human, and accurate methods are either invasive or require radioactive substances.


Transcranial Doppler (TCD) Ultrasonography


Doppler ultrasonography is the most widely used noninvasive technique to assess the intracerebral circulation. It has been employed extensively in neurosurgical patients for the early detection of cerebral vasospasm following subarachnoid hemorrhage. TCD studies in the middle cerebral artery provide information on changes in flow velocity of red blood cells and, when combined with blood pressure, an index of relative cerebral perfusion and cerebrovascular resistance is derived in the downstream arterioles. It has been assumed that vascular constriction significantly increases the resistance met by blood inflowing from arteries supplying the microvasculature. Resistance to flow is inversely proportional to the fourth power of vessel radius provided that there is steady-state laminar flow. When extrapolating CBF using transcranial Doppler from velocity data, several assumptions are made, one of which is the caliber or cross-sectional area of the artery studied, which is likely to change dynamically.


Studies in normal pregnant women have demonstrated a decrease in mean velocity in the middle cerebral artery as pregnancy progresses, with return to nonpregnant values in the puerperium. The decreased mean velocity is presumed secondary to decreased vascular resistance, which could imply the presence of more distal arteriolar vasodilatation and is in agreement with studies demonstrating outward remodeling of small vessels in the brain during pregnancy. A recent cross-sectional study used dual-beam angle-independent digital ultrasound, which can measure changes in artery diameter and thus obtain absolute CBF measurements, to measure blood flow changes in the internal carotid artery over the course of pregnancy in healthy women. This study found CVR decreased from a nonpregnant value of 0.141 to 0.112 mm Hg×mL/100 g/min in the third trimester, with CBF increasing 22% from 42.2 mL/100 g/min in nonpregnant women to 51.8 mL/100 g/min in the third trimester. This study is limited by a cross-sectional analysis and there were eight-fold more patients studied in the third trimester compared with nonpregnant women, and five-fold more than in the first trimester. The discrepancies in these studies demonstrate the difficulties in measuring CBF during pregnancy especially because plasma volume and hematocrit change so dramatically, influencing velocity measurements.


A number of investigators have shown increased middle cerebral artery blood flow velocity in preeclampsia. Moreover, symptomatic preeclamptic women with visual disturbances or headaches were found to have the highest velocities. Increased velocity was also reported for women with eclamptic seizures. Low maternal middle cerebral artery resistance indices in the second trimester may be predictive of the subsequent development of preeclampsia. Along the same lines, a lower ophthalmic artery resistive index in preeclamptic women who presented with clinical characteristics of PRES is suggested as a clinically applicable biomarker for cerebral overperfusion. Increasing velocity with preeclampsia is assumed secondary to high resistance in downstream arterioles. In chronically hypertensive women without preeclampsia, however, there was not substantively increased CBF velocity despite elevated mean arterial pressure. Also, CBF velocity in preeclampsia was reduced by both antihypertensive therapy and magnesium sulfate. Because of this observation, many favored the vasospasm model for the etiopathogenesis of eclampsia. Alternatively, these findings can be ascribed to relief of cerebral vasospasm.


Dynamic CBF autoregulation testing using TCD methods is based on the response of CBF velocity to small physiological changes in arterial blood pressure. Women with preeclampsia demonstrate impaired dynamic cerebral autoregulation capacity. However, a recent study found that changes in dynamic CBF autoregulation in pregnant women were not predictive of preeclampsia.


Velocity-Encoded Phase Contrast MRI and Perfusion-Weighted Imaging


In contrast to relative changes in CBF, velocity-encoded MRI can determine absolute blood flow and has been used to measure intracranial, renal, and cardiopulmonary circulations. Velocity-encoded phase contrast MRI is based on the principle that hydrogen nuclei in blood moving through a magnetic field gradient accumulate a phase shift which is proportional to their velocity. Blood flow is then calculated by multiplying blood flow velocity and the cross-sectional area of the vessel under study. Due to the high spatial resolution for vessel localization and cross-sectional area, flow measurements are highly accurate.


Physiological normative data of CBF in the large cerebral vessels in both hemispheres longitudinally across normal pregnancy and postpartum have been described. With this type of measurement, however, CBF is not corrected to mL/min/100 g cerebral tissue, so the numbers are not comparable and are larger than those shown for the animal models and other human studies that have measured CBF. As shown in Table 13.1 , CBF was significantly reduced by the end of the first trimester. Flow then remained constant until 36–38 weeks, at which time there was another significant fall at term ( Fig. 13.12 ). Taken together, there is a 20% decrease in CBF at term. Middle and posterior cerebral artery diameters remained unchanged throughout pregnancy and postpartum. These findings are in agreement with most TCD studies in which middle cerebral arterial flow velocities decreased and vessel wall tone diminished as pregnancy advanced. A longitudinal TCD study demonstrated a decrease in cerebral perfusion pressure in mid pregnancy and after delivery in women with uncomplicated pregnancies. The underlying cause of these changes that result in diminished CBF during pregnancy is not clear. It is hypothesized that downstream resistance arterioles become more dilated in order to maintain constant blood flow at the tissue level. However, changes in plasma volume during pregnancy that affect the hydrogen ion content of water may also have influenced the MR measurement. As newer MR sequences are developed, the physiological adaptation of pregnancy, especially changes in water, will need to be accounted for.



Table 13.1

Cerebral Blood Flow (mL/min) at Four Time Intervals






















Artery 14–16 wks 28–32 wks 36–38 wks Postpartum (6–8 wks)
MCA 135.2±5.5 132.5±4.6 118.2±4.6 147.9±5.0
PCA 52.4±2.9 51.2±2.4 44.2±2.4 55.8±2.7

Values are expressed as the mean±SE.

MCA=middle cerebral artery; PCA=posterior cerebral artery.

From Zeeman et al., 2003, with permission.



Figure 13.12


Middle cerebral arterial blood flow and vessel diameter determined longitudinally during pregnancy and compared with nonpregnant postpartum values in nine healthy women.


In women with severe preeclampsia, CBF determined at term with velocity-encoded phase contrast MRI is significantly increased when compared with normotensive pregnant controls. Increased CBF is not related to vasodilatation of the large cerebral arteries because the diameter of the four main vessels remains unchanged. These observations also are similar to those obtained with TCD studies. It remains speculative whether increased CBF is from changes in resistance of downstream resistance arterioles, increased cardiac output, increased mean arterial pressure, or central nervous system factors that control autoregulation.


MR perfusion-weighted imaging (PWI) has been used in preeclampsia and findings suggest that there is hyperperfusion-induced vasogenic edema without cerebrovascular spastic changes. These conflicting observations with the different techniques probably indicate the difficulty of interpreting hemodynamic changes in preeclampsia.


Single Photon Emission Computed Tomography


The technique of single photon emission computed tomography (SPECT) involves intravenous injection of a radioisotope to determine alterations in regional CBF. The effect of early pregnancy was assessed in women between 7 and 19 weeks who planned termination. Regional flow in the cerebral frontal, temporal, and parietal lobes, as well as in the basal ganglia and cerebellum, was found to be increased about 10% during pregnancy compared with repeat studies done post abortion. Case reports of SPECT used in women with preeclampsia described hyperemia in the posterior, temporal, lateral occipital, and inferior parietal cortex. In a study of SPECT imaging in 63 eclamptic women, all demonstrated perfusion deficits in watershed areas. And with a similar method, xenon CT, diffuse cerebral hyperperfusion and vasogenic edema without evidence of vasospasm were demonstrated in a woman with eclampsia.


Proton MR Spectroscopy


The noninvasive method of proton MR spectroscopy (MRS) is used to investigate cerebral metabolism. Specifically, intracellular metabolite diffusion has been used to study women with preeclampsia. Increased choline was reported in edematous areas of the brain, and thought to reflect relative cerebral ischemia without infarction. A lactate peak in eclampsia, even after complete reversibility of imaging abnormalities, suggested the presence of infarction. A marked decline in N -acetyl-aspartate (NAA) in a follow-up study of eclampsia correlated with the development of cerebral atrophy resulting from gross neuronal damage.


Near-Infrared Spectroscopy(NIRS)


This is an optical technique that allows real-time assessment of changes in tissue oxygenation and cerebral blood flow. Using this technique in women with several stages of hypertension, women with severe preeclampsia showed an increase in CBF with posture changes.

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Sep 20, 2018 | Posted by in GYNECOLOGY | Comments Off on Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia
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