In previous studies an increased prevalence of cerebral white matter lesions was found in formerly eclamptic and preeclamptic women compared with women after normotensive pregnancies.1,2 Although the pathogenesis of white matter lesions remains to be elucidated, the increased propensity for cerebrovascular and cardiovascular disease in formerly preeclamptic women3 may be an associated factor. We hypothesize that an episode of posterior reversible encephalopathy syndrome, which is considered the underlying cause of the neurologic symptoms in eclamptic as well as some preeclamptic patients, may play an additional role.4 In posterior reversible encephalopathy syndrome, severe vasogenic edema has been suggested to potentially progress to such an extent that regional cerebral perfusion decreases, leading to areas of cytotoxic edema, infarction, and development of white matter lesions in the long term.5,6
In elderly individuals, white matter lesions are associated with cognitive decline and dementia7 and are mainly located in the frontal and parietal lobe.8–10 Although impaired subjective cognitive functioning in formerly eclamptic women has been reported,11,12 no significant differences were found for objective measures of sustained attention and executive functioning after eclampsia.13 Moreover, in former patients with posterior reversible encephalopathy syndrome, permanent clinical symptoms have been found including impaired self-perceived as well as objective neurocognitive functioning and visual disturbances,11,12,14–16 partly thought to be related to permanent cerebral lesions. However, the clinical implications of white matter lesions in formerly preeclamptic and eclamptic women remain so far unclear.
To get insight into the pathophysiology and possible consequences of white matter lesions, this study assessed the distribution of such lesions in women who had eclampsia or preeclampsia compared with women who had normotensive pregnancies several years prior.
MATERIALS AND METHODS
Participants were enrolled in this retrospective cohort study as part of ongoing follow-up studies assessing cerebral long-term consequences of preeclampsia and eclampsia such as white matter lesions and neurocognitive functioning.1 Three groups of women were recruited for these studies, ie, formerly eclamptic, formerly preeclamptic, and parous control women.
Women with a diagnosis of eclampsia in their medical history between 1988 and 2005 were identified from the electronic admission, diagnosis, and delivery databases of the University Medical Center Groningen. Recruitment and selection criteria have been published previously.1,2 In the meantime, additional formerly eclamptic women have been recruited to participate in our follow-up studies through collaboration with two other tertiary referral centers: the VU University Medical Center Amsterdam and Isala Clinics Zwolle. In addition, six formerly eclamptic women who delivered in other hospitals and who had heard about this study requested to participate in the current study, which was allowed. Recruitment and selection criteria of participating women with a diagnosis of preeclampsia or normotensive pregnancies in their medical history were reported previously.2 Briefly, medical records of formerly eclamptic and preeclamptic women were reviewed for accurateness of diagnosis and to extract clinical and demographic characteristics. Both eclampsia and preeclampsia were defined according to the definition of the International Society for the Study of Hypertension in Pregnancy.17 Parous women in the control group were recruited through either the department's electronic delivery database or among hospital employees and their family members. Their records were evaluated to confirm that the pregnancy was indeed uneventful and normotensive. Exclusion criteria included contraindication for magnetic resonance image (MRI) scanning, a history of epilepsy, cerebrovascular accident, demyelinating disorders, intracranial infections or any cranial neurosurgical procedure, or the inability to understand Dutch. Only women who did not meet any of the exclusion criteria were invited to participate in the current study by mail.
After the MRI procedure and after a period of rest, blood pressure was measured manually using a aneroid sphygmomanometer. Patients with a systolic blood pressure of 140 mmHg or greater, diastolic blood pressure 90 mmHg or greater, or both or currently using antihypertensive medication or both were designated as currently hypertensive.18
Approval for this project was obtained from the Medical Ethics Committee of the University Medical Center Groningen and all participants signed informed consent.
Detailed MRI study protocols have been previously described.1 Briefly, participants underwent MRI on a 3-T MRI system using the following sequences: T1, proton density, T2, and fluid-attenuated inversion recovery using parameters as described previously.1 Transverse slice thickness was 5 mm with a 20% interslice gap. The presence, size, and number of white matter lesions were rated by an experienced neuroradiologist, who was blinded for patient category as previously described.1,19 White matter lesions were considered present if hyperintense on fluid-attenuated inversion recovery, T2- and proton density-weighted images and not hypointense on T1-weighted images. Subcortical white matter lesions were categorized according to their largest diameter as small (less than 3 mm), medium (3–10 mm), or large (greater than 10 mm). The number of lesions was evaluated per size category for the following locations: frontal, parietal, temporal, occipital, insular, brainstem, and cerebellum. Considering them spherical with a fixed diameter per size category, a total approximated volume for subcortical white matter lesions was determined.
For evaluation of prevalence and mean volume of lesions in each group, correction for inclusion of partial volume was performed as previously described.2 Briefly, for each participant, an arbitrary two small lesions were subtracted from the total number of small lesions. This means that women with only two small lesions or less were considered as white matter lesion–negative. Correction for partial volume was not possible for evaluation of regional distribution because it is not feasible to determine from which brain region(s) the partial volume correction (ie, two small lesions) should be subtracted if a woman demonstrates small lesions in more than one region. Therefore, prevalence of white matter lesions according to brain region was evaluated in lesion-positive women only with inclusion of all lesions, ie, without correction of partial volume.
Descriptive statistics such as demographic information are presented as means±standard deviations for continuous variables and percentages for dichotomous variables.
Demographic data were compared among formerly eclamptic, preeclamptic, and control women using analysis of variance for normally distributed data, or Kruskal-Wallis test for data that were not normally distributed. Dichotomous variables, ie, presence of white matter lesions, current hypertension, current smoking, and nulliparity, were compared between the groups using χ2 with pair wise χ2 as the post hoc test. Lesion volume between formerly (pre)eclamptic and control women was compared using the Mann-Whitney test. To evaluate differences in presence of white matter lesions between brain regions, the proportion of women with lesions in the frontal lobe was compared with the proportion of women with lesions in the other brain regions using McNemar's test.
Differences were considered statistically significant at P≤.05. For evaluating differences in presence of white matter lesions between brain regions, a Bonferroni correction was applied to this α level. Data analyses were performed using SPSS statistical package for Windows 8.
The recruitment and inclusion process of the formerly preeclamptic women (n=74) and the women who had normotensive pregnancies (n=75) has recently been described in a report on presence and lesion load of white matter lesions.2 The group of formerly eclamptic women has been expanded since our last report,1 in which neuroimaging data of 39 formerly eclamptic women were presented. Therefore, we now provide detailed description of the recruitment of the entire group of women who had eclampsia. In total, 137 formerly eclamptic women were identified. Six of these women were excluded, one because diagnosis of eclampsia could not be confirmed, another because of a history of a cerebrovascular accident, and a third as a result of inability to understand Dutch. In addition, three women had died in the interim, two of whom were the result of cerebral complications resulting from eclampsia and one as a result of gynecologic cancer. Of the remaining 131 formerly eclamptic patients, 69 could be reached and were willing to participate. Six of them were subsequently excluded as a result of contraindications for MRI scanning. Three of the 63 women who were included in the formerly eclamptic group had not experienced tonic–clonic seizures. These three, however, had experienced generalized myoclonic twitches while conscious, suggesting cerebral involvement. Therefore, for this study, we describe the MRI findings of a total of 63 formerly eclamptic, 74 formerly preeclamptic, and 75 parous control participants.
Table 1 shows baseline characteristics of the study participants. Mean age at the time of participation was similar for all groups; all groups were in their late 30s. However, elapsed time since the index pregnancy was longer for the formerly eclamptic women (7.6±4.7 years) compared with both formerly preeclamptic women (5.2±4.1 years) and parous women in the control group (5.0±3.3 years). Furthermore, the percentage of women who were nulliparous at the time of the index pregnancy differed between the groups with most nulliparous women in the formerly eclamptic group (82.5%) followed by formerly preeclamptic (67.6%) and control women (46.7%). Estimated gestational age at delivery was more than 6 weeks shorter in formerly eclamptic and preeclamptic women compared with parous women in the control group. In addition, as expected, birth weight of the neonate was approximately 45% lower in the formerly eclamptic and preeclamptic group than the control group.
Current weight and the percentage of women who currently smoke were comparable among the three groups. Systolic and diastolic blood pressures were higher and hypertension occurred four times more often in formerly eclamptic and preeclamptic women than in parous women in the control group.
Although formerly eclamptic (n=20 [31.7%]) and preeclamptic women (n=27 [36.5%]) appeared to have subcortical white matter lesions more often than parous women in the control group (n=16 [21.3%]), these differences did not reach significance (P=.11). However, when grouped together, the (pre)eclamptic group had lesions significantly more often than parous women in the control group (34.4% compared with 21.3%; P<.05). In addition, lesion load was more than threefold in formerly preeclamptic and eclamptic women (mean volume 0.07 mL, range 0.00–2.35 mL) compared with women in the control group (mean volume 0.02 mL, range 0.00–0.13 mL, P<.05).
The cerebral regional distribution of lesions in white matter lesion–positive women was comparable for all groups (Fig. 1). In all three groups, the majority of lesions was located in the frontal lobes (P<.005; frontal lobe compared with any other brain region). In the formerly preeclamptic group, all women with lesions (n=27) demonstrated these in the frontal lobes. Eighty-five percent (n=17) of the formerly eclamptic women with lesions had these lesions in the frontal lobe; for control participants, this was 87.5% (n=14). The parietal lobe was the second most affected region by white matter lesions, that is, in 35% of formerly eclamptic (n=7), 29.6% of formerly preeclamptic (n=8), and 25% of control women (n=4). In addition, three formerly preeclamptic women (11.1%) and one control woman (6.3%) demonstrated lesions in the temporal lobes. The insular lobes were affected by white matter lesions in four formerly eclamptic women (20.0%) and two women in the control group (12.5%). One formerly eclamptic woman (5.0%) had a lesion located within the cerebellum. White matter lesions in more than one brain region were observed in 40.0% of the formerly eclamptic (n=5), 33.3% of formerly preeclamptic (n=9), and only in 25.0% of control women (n=4). In all participants, except for three formerly eclamptic and two women in the control group, lesions in the parietal, temporal, or insular lobe and cerebellum were accompanied by lesions in the frontal lobes. None of the participants showed involvement of the occipital lobe or brainstem.
Periventricular white matter lesions were present in only one formerly eclamptic woman. She did not demonstrate any subcortical white matter lesions. In five formerly preeclamptic women, periventricular lesions were observed. These women all demonstrated subcortical lesions in addition. None of the control women had periventricular white matter lesions. In all women demonstrating periventricular white matter lesions, these lesions were considered mild, a pencil thin lining surrounding only part of the ventricles.
In the formerly eclamptic group, one woman demonstrated a lacunar infarct and two women had cortical infarcts. Two of these women also demonstrated subcortical white matter lesions. In the formerly preeclamptic group, two women had lacunar infarcts and one woman demonstrated a cortical infarct. These three women all had subcortical white matter lesions in addition to the infarcts. None of the control women had cerebral infarcts.
The pathophysiology of white matter lesions in formerly preeclamptic and eclamptic women remains speculative and by assessing their distribution, we aimed to provide insight into their development. Previously, we have hypothesized that such white matter lesions may be related to posterior reversible encephalopathy syndrome.1,2 In posterior reversible encephalopathy syndrome, an acute increase in blood pressure may cause loss of cerebral autoregulation, resulting in blood–brain barrier disruption, vasogenic edema formation, and neurologic symptoms.20–22 Severe vasogenic edema in the acute phase of posterior reversible encephalopathy syndrome may reduce blood flow to ischemic levels, resulting in cytotoxic edema.5 This may later appear as infarction or white matter lesions on MRI.5,6 We expected a similar white matter lesion distribution to that of cerebral edema in posterior reversible encephalopathy syndrome. However, although the edema in posterior reversible encephalopathy syndrome is typically located in the occipitoparietal lobes,23 this study demonstrates only few women with lesions in the posterior brain regions. In fact, the majority of lesions were located in the frontal lobes. Moreover, this distribution was similar between women who had posterior reversible encephalopathy syndrome, ie, the formerly eclamptic women, and women without posterior reversible encephalopathy syndrome, ie, the parous women in the control group. Therefore, a direct causal relationship between the cerebral edema of posterior reversible encephalopathy syndrome and white matter lesions in formerly preeclamptic and eclamptic women seems unlikely.
Alternatively, in the general population, the presence of hypertension is associated with cerebral white matter lesions,24–26 which may also explain the higher prevalence of such lesions in our preeclamptic and eclamptic women. Preeclampsia is associated with an increased risk for vascular disease later in life, including hypertension, ischemic and hemorrhagic stroke, and ischemic heart disease.3 In this context, the cardiovascular and metabolic demands of normal pregnancy are considered a physiologic “stress test.”27 Predisposed women fail this test and develop preeclampsia during pregnancy, thereby revealing their increased lifetime risk for cerebrovascular and cardiovascular disease. In this scheme, an underlying predisposition for cardiovascular disease may result in development of both white matter lesions and preeclampsia without a direct causal relationship between the two. The higher prevalence of current hypertension in formerly preeclamptic and eclamptic women is in line with this “stress test” theory and epidemiologic data. Moreover, the regional distribution of white matter lesions in these women is similar to what has been found in other conditions that are associated with vascular disease such as dementia and migraine.8,9,28
In the elderly, white matter lesions are associated with stroke, cognitive decline, and dementia.7 The clinical implications of such lesions in our relatively young cohort of preeclamptic and eclamptic women are currently unknown. Whether cognitive functioning may sooner or later also be affected is currently under investigation. Because a role for posterior reversible encephalopathy syndrome in the development of white matter lesions cannot be completely ruled out, also clinical follow-up of former patients with posterior reversible encephalopathy syndrome is of interest. In a rather small percentage of such patients, persistent neurocognitive complaints and neuroimaging abnormalities have been described. Self-perceived cognitive functioning is impaired in formerly eclamptic women.11,12 Furthermore, diminished objective neurocognitive functioning, visual disturbances, and epilepsy have been described after both eclampsia-related as well as nonobstetric posterior reversible encephalopathy syndrome.14–16,29 However, comprehensive longitudinal studies concerning neurocognitive functioning after posterior reversible encephalopathy syndrome are lacking.
A few limitations of the current study should be noted. First, because neuroimaging is not a standard procedure during preeclampsia and eclampsia, the location of cerebral edema in the acute phase of posterior reversible encephalopathy syndrome cannot be individually related to the distribution of lesions years later. Furthermore, which preeclamptic women potentially had posterior reversible encephalopathy syndrome is not known. Second, white matter lesions may have been present before the index pregnancy, but this information is obviously not available. Third, we might have slightly overestimated the prevalence of lesions per brain region because it is technically not feasible to correct for inclusion of partial volume.
This study describes the regional distribution of white matter lesions in formerly preeclamptic and eclamptic women as well as parous women who never exhibited pregnancy-related hypertension. The regional distribution of white matter lesions, mostly in the frontal lobe, may be a reflection of the predisposition for vascular disease in formerly eclamptic and preeclamptic women. The difference in chronic hypertension incidence between women in the control group and study patients may explain a major part of the difference in the presence of subcortical lesions and future study should explore the role of chronic hypertension and brain white matter lesions in individuals in the reproductive age group. Whether a history of posterior reversible encephalopathy syndrome plays an additional role remains speculative but is less likely. These findings may add to the existing literature concerning the importance of evaluation of vascular risk factors in formerly preeclamptic and eclamptic women.
1. Aukes AM, de Groot JC, Aarnoudse JG, Zeeman GG. Brain lesions several years after eclampsia. Am J Obstet Gynecol 2009;200:504.e1–5.
2. Aukes AM, De Groot JC, Wiegman MJ, Aarnoudse JG, Sanwikarja GS, Zeeman GG. Long-term cerebral imaging after pre-eclampsia. BJOG 2012;119:1117–22.
3. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974.
4. Cipolla MJ, Kraig RP. Seizures in women with preeclampsia: mechanisms and management. Fetal Matern Med Rev 2011;22:91–108.
5. Zeeman GG, Fleckenstein JL, Twickler DM, Cunningham FG. Cerebral infarction in eclampsia. Am J Obstet Gynecol 2004;190:714–20.
6. Koch S, Rabinstein A, Falcone S, Forteza A. Diffusion-weighted imaging shows cytotoxic and vasogenic edema in eclampsia. AJNR Am J Neuroradiol 2001;22:1068–70.
7. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666.
8. Gootjes L, Teipel SJ, Zebuhr Y, Schwarz R, Leinsinger G, Scheltens P, et al.. Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 2004;18:180–8.
9. Barber R, Scheltens P, Gholkar A, Ballard C, McKeith I, Ince P, et al.. White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 1999;67:66–72.
10. de Groot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and subjective cognitive dysfunction: the Rotterdam Scan Study. Neurology 2001;56:1539–45.
11. Aukes AM, Wessel I, Dubois AM, Aarnoudse JG, Zeeman GG. Self-reported cognitive functioning in formerly eclamptic women. Am J Obstet Gynecol 2007;197:365.e1–6.
12. Andersgaard AB, Herbst A, Johansen M, Borgstrom A, Bille AG, Øian P. Follow-up interviews after eclampsia. Gynecol Obstet Invest 2009;67:49–52.
13. Postma IR, Wessel I, Aarnoudse JG, Zeeman GG. Neurocognitive functioning in women with a history of eclampsia: executive functioning and sustained attention. Am J Perinatol 2010;27:685–90.
14. Stroescu I, Salinas CM, Nahab FB, Stringer AY. Long-term neurocognitive and neuroimaging outcomes in posterior reversible encephalopathy syndrome: two case reports and implications. Clin Neuropsychol 2011;25:1386–402.
15. Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J 2005;35:83–90.
16. Moseman CP, Shelton S. Permanent blindness as a complication of pregnancy induced hypertension. Obstet Gynecol 2002;100:943–5.
17. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.
18. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560–72.
19. de Groot JC, de Leeuw FE, Oudkerk M, van Gijn J, Hofman A, Jolles J, et al.. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol 2000;47:145–51.
20. Easton JD. Severe preeclampsia/eclampsia: hypertensive encephalopathy of pregnancy? Cerebrovasc Dis 1998;8:53–8.
21. Johansson BB. The blood-brain barrier and cerebral blood flow in acute hypertension. Acta Med Scand Suppl 1983;678:107–12.
22. Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia. Hypertension 2007;50:14–24.
23. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al.. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500.
24. Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D'Agostino RB, et al.. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke 2004;35:1857–61.
25. de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, et al.. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125:765–72.
26. Kuller LH, Margolis KL, Gaussoin SA, Bryan NR, Kerwin D, Limacher M, et al.. Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the Women's Health Initiative Memory Study (WHIMS)-MRI trial. J Clin Hypertens (Greenwich) 2010;12:203–12.
27. Craici I, Wagner S, Garovic VD. Preeclampsia and future cardiovascular risk: formal risk factor or failed stress test? Ther Adv Cardiovasc Dis 2008;2:249–59.
28. Rossato G, Adami A, Thijs VN, Cerini R, Pozzi-Mucelli R, Mazzucco S, et al.. Cerebral distribution of white matter lesions in migraine with aura patients. Cephalalgia 2010;30:855–9.
29. Lucchini G, Grioni D, Colombini A, Contri M, De Grandi C, Rovelli A, et al.. Encephalopathy syndrome in children with hemato-oncological disorders is not always posterior and reversible. Pediatr Blood Cancer 2008;51:629–33.