Accepted Manuscript Incidence of posterior reversible encephalopathy syndrome in eclamptic and preeclamptic patients with neurological symptoms Michinori Mayama, MD, Kaname Uno, MD, Sho Tano, MD, Masato Yoshihara, MD, Mayu Ukai, MD, Yasuyuki Kishigami, MD, Yasuhiro Ito, MD, PhD, Hidenori Oguchi, MD, PhD PII:
S0002-9378(16)00339-2
DOI:
10.1016/j.ajog.2016.02.039
Reference:
YMOB 10963
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 1 December 2015 Revised Date:
28 January 2016
Accepted Date: 16 February 2016
Please cite this article as: Mayama M, Uno K, Tano S, Yoshihara M, Ukai M, Kishigami Y, Ito Y, Oguchi H, Incidence of posterior reversible encephalopathy syndrome in eclamptic and pre-eclamptic patients with neurological symptoms, American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/ j.ajog.2016.02.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Incidence of posterior reversible encephalopathy syndrome in eclamptic and
ACCEPTED MANUSCRIPT
pre-eclamptic patients with neurological symptoms
Michinori MAYAMA1,*, MD; Kaname UNO1, MD; Sho TANO1, MD; Masato
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YOSHIHARA1, MD; Mayu UKAI1, MD; Yasuyuki KISHIGAMI1, MD; Yasuhiro ITO2, MD, PhD; Hidenori OGUCHI1, MD, PhD
Department of Obstetrics, Perinatal Medical Center, TOYOTA Memorial Hospital,
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1
Toyota, Aichi, Japan
Department of Neurology, TOYOTA Memorial Hospital, Toyota, Aichi, Japan
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2
Disclosure: The authors received no financial support for this work and report no conflict
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of interest
* Corresponding author: Michinori Mayama
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Department of Obstetrics, Perinatal Medical Center, Toyota Memorial Hospital 20-2, Misato-cho, Toyota, Aichi, Japan
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Phone: +81-90-9527-4848 Fax: +81-565-24-7170
E-mail: [email protected] Word count: Abstract: 354 words; main text: 1840 words
Condensation: Posterior reversible encephalopathy syndrome was detected in 92.3% eclamptic and 19.2% pre-eclamptic patients with neurological symptoms, and these patients had similar clinical and radiological backgrounds.
2
Short running title: PRES in Eclampsia and Pre-eclampsia
ACCEPTED MANUSCRIPT
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We would like to include table 1 with the abstract in the printed version.
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ABSTRACT
ACCEPTED MANUSCRIPT Background: Posterior reversible encephalopathy syndrome is frequently observed in patients with eclampsia; however, it has also been reported in some pre-eclamptic patients. Objectives: The aim of this study was to determine the incidence of posterior reversible encephalopathy syndrome in pre-eclamptic and eclamptic patients and to assess whether
clinical and radiological characteristics.
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these two patient groups share similar pathophysiological backgrounds by comparing
Study Design: This was a retrospective cohort study of 4,849 pregnant patients. A total of 49 eclamptic and pre-eclamptic patients with neurological symptoms underwent magnetic
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resonance imaging and magnetic resonance angiography; 10 patients were excluded from further analysis because of a history of epilepsy or dissociative disorder. The age, parity,
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blood pressure, and routine laboratory data at the onset of symptoms were also recorded. Results: Among 39 patients with neurological symptoms, 12 out of 13 (92.3%) eclamptic patients and 5 out of 26 (19.2%) pre-eclamptic patients developed posterior reversible encephalopathy syndrome. Whereas age and blood pressure at onset were not significantly
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different between encephalopathic and nonencephalopathic patients, hematocrit, serum creatinine, aspartate transaminase, alanine transaminase, and lactate dehydrogenase values were significantly higher in patients with posterior reversible encephalopathy syndrome
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than those without magnetic resonance imaging abnormalities. In contrast, eclamptic patients with posterior reversible encephalopathy syndrome did not show any significant
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differences in clinical and laboratory data compared with pre-eclamptic patients with posterior reversible encephalopathy syndrome. In addition to the parieto-occipital regions, atypical regions such as the frontal and temporal lobes, and basal ganglia were also involved in both eclamptic and pre-eclamptic patients with posterior reversible encephalopathy syndrome. Finally, intraparenchymal hemorrhage was detected in one eclamptic patient, and subarachnoid hemorrhage was observed in one pre-eclamptic patient. Conclusions: Although the incidence of posterior reversible encephalopathy syndrome was high in eclamptic patients, nearly 20% pre-eclamptic patients with neurological symptoms also developed posterior reversible encephalopathy syndrome. The similarities in clinical and radiological findings of posterior reversible encephalopathy syndrome between the two
4
groups support the hypothesis that these two patient groups have a shared
ACCEPTED MANUSCRIPT pathophysiological background. Thus, magnetic resonance imaging studies should be considered for patients with the recent onset of neurological symptoms regardless of the development of eclampsia.
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magnetic resonance imaging, cerebral vasoconstriction
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Keywords: posterior reversible encephalopathy syndrome, eclampsia, pre-eclampsia,
5
INTRODUCTION
ACCEPTED MANUSCRIPT Posterior reversible encephalopathy syndrome (PRES) refers to reversible vasogenic brain edema accompanied with acute neurological symptoms such as seizure, impaired consciousness, and visual disturbance; brain imaging studies commonly reveal vasogenic edema predominantly involving the bilateral parieto-occipital regions.1 The pathophysiology of PRES is suggested to involve the failure of cerebral blood flow
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autoregulation, and endothelial dysfunction is implicated to play an important role in its development.1, 2 Eclampsia and pre-eclampsia are also associated with endothelial
dysfunction. Importantly, recent studies reported that PRES was frequently observed in
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eclamptic patients, and PRES has been suggested as an essential component of
eclampsia-mediated primary central nervous system injury.3, 4 However, PRES was also
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reported in patients with severe pre-eclampsia.5 Thus, we hypothesized that pre-eclamptic and eclamptic patients presenting with neurological symptoms such as severe headaches, visual disturbances, impaired consciousness, or seizures might be suffering from a similar pathophysiological condition and that this clinical presentation could be radiologically
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identified as PRES. We conducted magnetic resonance imaging (MRI) studies in patients presenting with neurological symptoms during the peripartum period to determine the incidence of PRES. We also assessed cerebrovascular condition in these patients using
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magnetic resonance angiography (MRA). Finally, we analyzed the available clinical and
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radiological findings to confirm our hypotheses.
MATERIALS AND METHODS This study was a retrospective cohort study conducted in a single medical center at the TOYOTA Memorial Hospital and was approved by the Ethics Committee of the TOYOTA Memorial Hospital. We enrolled pre-eclamptic and eclamptic patients with severe headaches, visual disturbances, impaired consciousness, or seizures during the peripartum period; all the patients underwent MRI within 24 h of the onset of symptoms. The severity of headache was determined clinically, and questionnaires and pain scales were not used due to the emergency situation. Of a total of 4,849 women who gave birth between February 2007 and July 2015, 49 patients were evaluated using MRI for the onset of new
6
neurological symptoms; of these, three patients were excluded because of history of
ACCEPTED MANUSCRIPT epilepsy and seven patients were excluded because of the diagnosis of dissociative disorder. Therefore, 39 patients were included in the final analysis of this study. Maternal characteristics, such as age, parity, blood pressure, laboratory data, and radiological findings were evaluated. All patients underwent MRI and MRA without contrast using a 1.5 tesla system
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within 24 h after the onset of symptoms, and follow-up MRI and MRA studies were
conducted within 3 months. The diagnosis of PRES was made based on MRI findings, which showed cortical or subcortical fluid-attenuated inversion recovery (FLAIR) and
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T2-weighted hyperintensities within the posterior predominance that resolved or
significantly improved on follow-up MRI. Pre-eclampsia was diagnosed based on the
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diagnostic criteria established by the American College of Obstetrics and Gynecology.6 Eclampsia was defined as the occurrence of seizures that could not be attributed to other causes in pregnant patients with pre-eclampsia.7
For data that were considered to be normally distributed, unpaired t test or Welch’s
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test was used based on the homogeneity of variances. Otherwise, the Mann–Whitney U test was used for continuous data, and Fisher’s exact test was used for categorical data. A P
RESULTS
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value of less than 0.05 was considered as statistically significant.
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Among a total of 39 patients fulfilling the criteria, 13 patients were diagnosed with eclampsia. Of these, 12 patients (92.3%) were diagnosed with PRES; four PRES patients (30.8%) also developed cerebral vasoconstriction. Thus, only one eclampsia patient did not exhibit any abnormal MRI findings. On the other hand, among 26 patients who developed neurological symptoms such as severe headaches, visual disturbances, or impaired consciousness in pre-eclamptic patients, five patients (19.2%) were diagnosed with PRES; of those, two (7.7%) developed cerebral vasoconstriction. Comparison of clinical and laboratory data at the onset between patients with PRES and patients without MRI abnormalities is shown in Table 1A. Maternal age, frequency of primiparas, blood pressure, platelet counts, blood urea nitrogen, and total bilirubin were not
7
significantly different between the two groups. However, hematocrit, serum creatinine,
ACCEPTED aspartate transaminase, alanine transaminase,MANUSCRIPT and lactate dehydrogenase values were significantly higher in patients with PRES than in those without MRI abnormalities. Table 1B shows the comparison of clinical and laboratory data between eclamptic and pre-eclamptic PRES patients. No significant differences were noted in the clinical and laboratory data between the two groups. At the onset, severe hypertension of 160/110 mm
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Hg or over was observed in eight out of 12 (66.7%) eclamptic patients with PRES, in all
five (100%) pre-eclamptic patients with PRES and in 14 out of 20 (70.0%) patients without MRI abnormalities.
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Neurological symptoms at onset are shown in Table 2. Impaired consciousness was only detected in patients with eclampsia or in those with MRI abnormalities; however, the
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incidence of severe headaches and visual disturbances were not different between these patients and the patients without MRI abnormalities. Although the number of patients was small, the frequencies of severe headache and visual disturbances were not different between those with eclampsia and those with pre-eclampsia. However, impaired
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consciousness was more frequently observed in those with eclampsia than in those with pre-eclampsia.
Figure 1 shows the distribution of affected regions in PRES. In both eclamptic and
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pre-eclamptic patients, vasogenic edema was frequently detected in the occipital and parietal regions, which are typically involved in PRES. Atypical regions such as the frontal
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and temporal lobes and basal ganglia were also involved in both groups, although only eclamptic patients exhibited signs of vasogenic edema in the brain stem and cerebellum. Among a total of 17 patients with PRES in our cohort, hemorrhagic complications were only observed in 2 (11.8%) patients; both patients developed concurrent cerebral vasoconstriction.
COMMENT Improvements in imaging modalities have led to an increase in the diagnosis of PRES. In this study, PRES was frequently observed in patients with eclampsia, which was consistent with the findings of a previous study.4 High PRES incidence in patients with eclampsia
8
lends further support to the hypothesis that PRES is a primary component of central
ACCEPTED MANUSCRIPT nervous system injury in eclampsia. However, our results also revealed that PRES was also present in patients without eclampsia. Endothelial activation and damage cause numerous complications in pre-eclampsia.8 Hemolysis occurring due to endothelial damage induces lactate dehydrogenase elevation and fluid leakage resulting in increased hematocrit levels.9 Furthermore, glomerular endothelial dysfunction triggers protein loss and kidney damage
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with increased creatine levels, whereas hepatic dysfunction induced by reduced perfusion leads to elevated liver enzymes.8 The differences in laboratory data including hematocrit, serum creatinine, aspartate transaminase, alanine transaminase, and lactate dehydrogenase
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between patients with PRES and those without imply that patients with PRES may have more severe endothelial damage than the unaffected patients. On the other hand, the
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similarities in clinical and laboratory data between pre-eclamptic and eclamptic PRES patients indicated a shared pathophysiological background, which was further supported by MRI findings that were common to both patient groups.
Cerebral circulation has an autoregulatory mechanism to maintain a steady
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cerebral blood flow. However, severe hypertension can overwhelm this system, resulting in blood–brain barrier (BBB) dysfunction.1 However, previous studies reported that nearly 50% patients with PRES showed mean arterial pressure (MBP) of less than the upper limit
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of autoregulation, which is 140–160 mm Hg.2, 10 In addition to hypertension, circulating cytokines also cause endothelial dysfunction.11 A study by Amburgey et al. demonstrated
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that plasma from pre-eclamptic women increased BBB permeability in vitro and that vascular endothelial growth factor had an important role in this change.12 In this study, the average MBP of patients with PRES was less than the upper limit of autoregulation and was not significantly different from the average MBP of patients without MRI abnormalities. Therefore, endothelial dysfunction caused by circulating cytokines may have a more important role than hypertension in the development of PRES in eclamptic as well as pre-eclamptic patients, and this hypothesis is supported by the difference in laboratory data of patients with and without PRES. Autoregulation of cerebral circulation is mediated in part by neurogenic control. As minimal sympathetic innervation exists in the posterior fossa, posterior brain regions are
9
particularly susceptible to hypertension.1 Cytokine-mediated endothelial dysfunction might
ACCEPTED MANUSCRIPT have a relatively significant impact on the development of BBB breakdown in eclamptic and pre-eclamptic patients; this might explain the involvement of atypical brain regions such as the basal ganglia and frontal lobe that were frequently affected in PRES patients in our cohort. One previous report proposed that the involvement of deep brain structures such as the cerebellum, brain stem, and basal ganglia was indicative of severe PRES.13 In our
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patients, deep brain structures such as the brain stem and cerebellum were found to be
affected only in eclamptic patients. In addition, multiple regional involvement was more
likely to be observed in eclamptic patients. These findings indicate that seizures may be a
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result of worsening PRES.
Contrary to what the term implies, PRES is not entirely reversible; hemorrhagic
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complications are reported in 9%–33% cases of PRES.14, 15, 16 In this study, two PRES patients with cerebral vasoconstriction developed hemorrhagic complications. Although recent studies reported the co-occurrence of cerebral vasoconstriction in patients with PRES,2, 14, 15, 17 the incidence varied from 16.2% to 85.0%, and only 30%–50% of PRES
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patients underwent angiographic imaging in those studies. In the current study, all participants were evaluated using MRA, which detected cerebral vasoconstriction in five of 17 (29.4%) PRES patients. Cerebral vasoconstriction is considered to be a consequence of
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cerebral vascular tone deregulation caused by sympathetic overactivity and endothelial dysfunction.17, 18 Although PRES and cerebral vasoconstriction may have overlapping
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pathophysiological mechanisms, it is still unclear whether the coexistence of cerebral vasoconstriction increases the risk of hemorrhagic complications in patients with PRES. This study was conducted at a single hospital, and therefore, included a small
number of patients. A future study with larger sample size is necessary to confirm the findings of this study. However, the strength of our study is the inclusion criteria that included patients who developed neurological symptoms; PRES is characterized not only by radiological findings but also by a new onset of neurological symptoms. PRES is associated with many comorbidities such as severe hypertension, renal disease, autoimmune disorders, cytotoxic medications, post-transplantation immunosuppression, sepsis, and eclampsia.2, 14, 16, 17 Most past studies investigating PRES included patients from
10
various backgrounds and with various comorbidities. In contrast, our study determined the
ACCEPTED MANUSCRIPT incidence of PRES and cerebral vasoconstriction in a specific patient population, patients with eclampsia or pre-eclampsia. In conclusion, the shared similarities in clinical and radiological findings between eclamptic and pre-eclamptic PRES patients supported our hypothesis that eclampsia represented one neurological symptom of PRES. In addition, our findings implied that
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endothelial dysfunction played a more important role than hypertension in the development of PRES in eclamptic and pre-eclamptic patients. Even though eclampsia may be the most severe form of PRES in the obstetrical field, our study revealed that in addition to the
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19.2% of patients who developed PRES, 7.7% of pre-eclamptic patients developed cerebral vasoconstriction concurrent with neurological symptoms. Thus, MRI and MRA studies
of the development of eclampsia.
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Acknowledgments
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should be considered for patients with the recent onset of neurological symptoms regardless
The authors thank the neurologists and radiologists at our hospital for reviewing the medical charts and MRI findings to confirm patient diagnoses. We also would like to show
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our greatest appreciation to the medical staff of our department for their contribution to data
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collection. The authors would like to thank Enago (www.enago.jp) for the English language review.
References 1.) Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015;14:914-25. 2.) Li Y, Gor D, Walicki D, et al. Spectrum and potential pathogenesis of reversible posterior leukoencephalopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:873-82.
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3.) Wagner SJ1, Acquah LA, Lindell EP, et al. Posterior reversible encephalopathy
ACCEPTED MANUSCRIPT syndrome and eclampsia: pressing the case for more aggressive blood pressure control. Mayo Clin Proc 2011;86:851-6. 4.) Brewer J, Owens MY, Wallace K, et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol 2013;208:468.e1-6. 5.) Matsuda H, Sakaguchi K, Shibasaki T, et al. Cerebral edema on MRI in severe
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preeclamptic women developing eclampsia. J Perinat Med 2005;33:199–205.
6.) American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of
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Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122-31.
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7.) 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. 8.) Hypertensive disorders of pregnancy. In: Cunningham FG, Gant NF, Leveno KJ, et al, eds. Williams Obstetrics. 21st ed. New York: McGraw Hill;2001:567-618.
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9.) Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29:1043-9.
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10.) Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65:205-10.
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11.) Marra A, Vargas M, Striano P, Del Guercio L, Buonanno P, Servillo G. Posterior reversible encephalopathy syndrome: the endothelial hypotheses. Med Hypotheses 2014;82:619-22.
12.) Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ. Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension. 2010;56:1003-8. 13.) McKinney AM, Short J, Truwit CL, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am Roentgenol 2007;189:904-12.
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14.) Burnett MM, Hess CP, Roberts JP, Bass NM, Douglas VC, Josephson SA.
ACCEPTED MANUSCRIPTsyndrome in patients on Presentation of reversible posterior leukoencephalopathy calcineurin inhibitors. Clin Neurol Neurosurg 2010;112:886-91. 15.) Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 2010;85:427-32.
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16.) Liman TG, Bohner G, Heuschmann PU, Endres M, Siebert E. The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES study. J Neurol 2012;259:155-64.
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17.) Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR
perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol
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2008;29:447-55.
18.) Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D. Reversible Cerebral Vasoconstriction Syndrome, Part 1: Epidemiology, Pathogenesis, and Clinical Course.
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AJNR Am J Neuroradiol. 2015;36:1392-9.
Table 1. Comparison of clinical and laboratory data at the onset of symptoms between
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PRES patients and patients without MRI abnormalities (A) and between eclamptic and
(A)
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pre-eclamptic PRES patients (B).
PRES (n = 17)
No MRI abnormalities (n = 20)
P value
Age (y) * Primipara ¶ SBP (mmHg) * DBP (mmHg) *
35.4 ± 5.5 12 (70.6) 176 ± 24 104 ± 17
33.9 ± 4.8 8 (40.0) 168 ± 19 100 ± 14
0.36 0.10 0.25 0.48
MBP (mmHg) * Ht (%)* Plt (104/µL) †
128± 18 38.8 ± 5.9 12.7 (6.1–36.7)
123 ± 15 33.7 ± 5.5 20.2 (12.0–29.1)
0.34
BUN (mg/dL) † Cre (mg/dL) * AST (IU/L) † ALT (IU/L) †
11.0 (4.0–35.0) 0.76 ± 0.26 43.0 (18.0–1042.0) 29.0 (8.0–1008.0)
9.0 (5.0–17.0) 0.56 ± 0.14 18.0 (11.0–124.0) 10.0 (5.0–139.0)
0.01 0.09 0.37
S0002-9378(16)00339-2
DOI:
10.1016/j.ajog.2016.02.039
Reference:
YMOB 10963
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 1 December 2015 Revised Date:
28 January 2016
Accepted Date: 16 February 2016
Please cite this article as: Mayama M, Uno K, Tano S, Yoshihara M, Ukai M, Kishigami Y, Ito Y, Oguchi H, Incidence of posterior reversible encephalopathy syndrome in eclamptic and pre-eclamptic patients with neurological symptoms, American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/ j.ajog.2016.02.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Incidence of posterior reversible encephalopathy syndrome in eclamptic and
ACCEPTED MANUSCRIPT
pre-eclamptic patients with neurological symptoms
Michinori MAYAMA1,*, MD; Kaname UNO1, MD; Sho TANO1, MD; Masato
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YOSHIHARA1, MD; Mayu UKAI1, MD; Yasuyuki KISHIGAMI1, MD; Yasuhiro ITO2, MD, PhD; Hidenori OGUCHI1, MD, PhD
Department of Obstetrics, Perinatal Medical Center, TOYOTA Memorial Hospital,
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1
Toyota, Aichi, Japan
Department of Neurology, TOYOTA Memorial Hospital, Toyota, Aichi, Japan
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2
Disclosure: The authors received no financial support for this work and report no conflict
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of interest
* Corresponding author: Michinori Mayama
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Department of Obstetrics, Perinatal Medical Center, Toyota Memorial Hospital 20-2, Misato-cho, Toyota, Aichi, Japan
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Phone: +81-90-9527-4848 Fax: +81-565-24-7170
E-mail: [email protected] Word count: Abstract: 354 words; main text: 1840 words
Condensation: Posterior reversible encephalopathy syndrome was detected in 92.3% eclamptic and 19.2% pre-eclamptic patients with neurological symptoms, and these patients had similar clinical and radiological backgrounds.
2
Short running title: PRES in Eclampsia and Pre-eclampsia
ACCEPTED MANUSCRIPT
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We would like to include table 1 with the abstract in the printed version.
3
ABSTRACT
ACCEPTED MANUSCRIPT Background: Posterior reversible encephalopathy syndrome is frequently observed in patients with eclampsia; however, it has also been reported in some pre-eclamptic patients. Objectives: The aim of this study was to determine the incidence of posterior reversible encephalopathy syndrome in pre-eclamptic and eclamptic patients and to assess whether
clinical and radiological characteristics.
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these two patient groups share similar pathophysiological backgrounds by comparing
Study Design: This was a retrospective cohort study of 4,849 pregnant patients. A total of 49 eclamptic and pre-eclamptic patients with neurological symptoms underwent magnetic
SC
resonance imaging and magnetic resonance angiography; 10 patients were excluded from further analysis because of a history of epilepsy or dissociative disorder. The age, parity,
M AN U
blood pressure, and routine laboratory data at the onset of symptoms were also recorded. Results: Among 39 patients with neurological symptoms, 12 out of 13 (92.3%) eclamptic patients and 5 out of 26 (19.2%) pre-eclamptic patients developed posterior reversible encephalopathy syndrome. Whereas age and blood pressure at onset were not significantly
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different between encephalopathic and nonencephalopathic patients, hematocrit, serum creatinine, aspartate transaminase, alanine transaminase, and lactate dehydrogenase values were significantly higher in patients with posterior reversible encephalopathy syndrome
EP
than those without magnetic resonance imaging abnormalities. In contrast, eclamptic patients with posterior reversible encephalopathy syndrome did not show any significant
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differences in clinical and laboratory data compared with pre-eclamptic patients with posterior reversible encephalopathy syndrome. In addition to the parieto-occipital regions, atypical regions such as the frontal and temporal lobes, and basal ganglia were also involved in both eclamptic and pre-eclamptic patients with posterior reversible encephalopathy syndrome. Finally, intraparenchymal hemorrhage was detected in one eclamptic patient, and subarachnoid hemorrhage was observed in one pre-eclamptic patient. Conclusions: Although the incidence of posterior reversible encephalopathy syndrome was high in eclamptic patients, nearly 20% pre-eclamptic patients with neurological symptoms also developed posterior reversible encephalopathy syndrome. The similarities in clinical and radiological findings of posterior reversible encephalopathy syndrome between the two
4
groups support the hypothesis that these two patient groups have a shared
ACCEPTED MANUSCRIPT pathophysiological background. Thus, magnetic resonance imaging studies should be considered for patients with the recent onset of neurological symptoms regardless of the development of eclampsia.
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EP
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SC
magnetic resonance imaging, cerebral vasoconstriction
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Keywords: posterior reversible encephalopathy syndrome, eclampsia, pre-eclampsia,
5
INTRODUCTION
ACCEPTED MANUSCRIPT Posterior reversible encephalopathy syndrome (PRES) refers to reversible vasogenic brain edema accompanied with acute neurological symptoms such as seizure, impaired consciousness, and visual disturbance; brain imaging studies commonly reveal vasogenic edema predominantly involving the bilateral parieto-occipital regions.1 The pathophysiology of PRES is suggested to involve the failure of cerebral blood flow
RI PT
autoregulation, and endothelial dysfunction is implicated to play an important role in its development.1, 2 Eclampsia and pre-eclampsia are also associated with endothelial
dysfunction. Importantly, recent studies reported that PRES was frequently observed in
SC
eclamptic patients, and PRES has been suggested as an essential component of
eclampsia-mediated primary central nervous system injury.3, 4 However, PRES was also
M AN U
reported in patients with severe pre-eclampsia.5 Thus, we hypothesized that pre-eclamptic and eclamptic patients presenting with neurological symptoms such as severe headaches, visual disturbances, impaired consciousness, or seizures might be suffering from a similar pathophysiological condition and that this clinical presentation could be radiologically
TE D
identified as PRES. We conducted magnetic resonance imaging (MRI) studies in patients presenting with neurological symptoms during the peripartum period to determine the incidence of PRES. We also assessed cerebrovascular condition in these patients using
EP
magnetic resonance angiography (MRA). Finally, we analyzed the available clinical and
AC C
radiological findings to confirm our hypotheses.
MATERIALS AND METHODS This study was a retrospective cohort study conducted in a single medical center at the TOYOTA Memorial Hospital and was approved by the Ethics Committee of the TOYOTA Memorial Hospital. We enrolled pre-eclamptic and eclamptic patients with severe headaches, visual disturbances, impaired consciousness, or seizures during the peripartum period; all the patients underwent MRI within 24 h of the onset of symptoms. The severity of headache was determined clinically, and questionnaires and pain scales were not used due to the emergency situation. Of a total of 4,849 women who gave birth between February 2007 and July 2015, 49 patients were evaluated using MRI for the onset of new
6
neurological symptoms; of these, three patients were excluded because of history of
ACCEPTED MANUSCRIPT epilepsy and seven patients were excluded because of the diagnosis of dissociative disorder. Therefore, 39 patients were included in the final analysis of this study. Maternal characteristics, such as age, parity, blood pressure, laboratory data, and radiological findings were evaluated. All patients underwent MRI and MRA without contrast using a 1.5 tesla system
RI PT
within 24 h after the onset of symptoms, and follow-up MRI and MRA studies were
conducted within 3 months. The diagnosis of PRES was made based on MRI findings, which showed cortical or subcortical fluid-attenuated inversion recovery (FLAIR) and
SC
T2-weighted hyperintensities within the posterior predominance that resolved or
significantly improved on follow-up MRI. Pre-eclampsia was diagnosed based on the
M AN U
diagnostic criteria established by the American College of Obstetrics and Gynecology.6 Eclampsia was defined as the occurrence of seizures that could not be attributed to other causes in pregnant patients with pre-eclampsia.7
For data that were considered to be normally distributed, unpaired t test or Welch’s
TE D
test was used based on the homogeneity of variances. Otherwise, the Mann–Whitney U test was used for continuous data, and Fisher’s exact test was used for categorical data. A P
RESULTS
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value of less than 0.05 was considered as statistically significant.
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Among a total of 39 patients fulfilling the criteria, 13 patients were diagnosed with eclampsia. Of these, 12 patients (92.3%) were diagnosed with PRES; four PRES patients (30.8%) also developed cerebral vasoconstriction. Thus, only one eclampsia patient did not exhibit any abnormal MRI findings. On the other hand, among 26 patients who developed neurological symptoms such as severe headaches, visual disturbances, or impaired consciousness in pre-eclamptic patients, five patients (19.2%) were diagnosed with PRES; of those, two (7.7%) developed cerebral vasoconstriction. Comparison of clinical and laboratory data at the onset between patients with PRES and patients without MRI abnormalities is shown in Table 1A. Maternal age, frequency of primiparas, blood pressure, platelet counts, blood urea nitrogen, and total bilirubin were not
7
significantly different between the two groups. However, hematocrit, serum creatinine,
ACCEPTED aspartate transaminase, alanine transaminase,MANUSCRIPT and lactate dehydrogenase values were significantly higher in patients with PRES than in those without MRI abnormalities. Table 1B shows the comparison of clinical and laboratory data between eclamptic and pre-eclamptic PRES patients. No significant differences were noted in the clinical and laboratory data between the two groups. At the onset, severe hypertension of 160/110 mm
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Hg or over was observed in eight out of 12 (66.7%) eclamptic patients with PRES, in all
five (100%) pre-eclamptic patients with PRES and in 14 out of 20 (70.0%) patients without MRI abnormalities.
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Neurological symptoms at onset are shown in Table 2. Impaired consciousness was only detected in patients with eclampsia or in those with MRI abnormalities; however, the
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incidence of severe headaches and visual disturbances were not different between these patients and the patients without MRI abnormalities. Although the number of patients was small, the frequencies of severe headache and visual disturbances were not different between those with eclampsia and those with pre-eclampsia. However, impaired
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consciousness was more frequently observed in those with eclampsia than in those with pre-eclampsia.
Figure 1 shows the distribution of affected regions in PRES. In both eclamptic and
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pre-eclamptic patients, vasogenic edema was frequently detected in the occipital and parietal regions, which are typically involved in PRES. Atypical regions such as the frontal
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and temporal lobes and basal ganglia were also involved in both groups, although only eclamptic patients exhibited signs of vasogenic edema in the brain stem and cerebellum. Among a total of 17 patients with PRES in our cohort, hemorrhagic complications were only observed in 2 (11.8%) patients; both patients developed concurrent cerebral vasoconstriction.
COMMENT Improvements in imaging modalities have led to an increase in the diagnosis of PRES. In this study, PRES was frequently observed in patients with eclampsia, which was consistent with the findings of a previous study.4 High PRES incidence in patients with eclampsia
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lends further support to the hypothesis that PRES is a primary component of central
ACCEPTED MANUSCRIPT nervous system injury in eclampsia. However, our results also revealed that PRES was also present in patients without eclampsia. Endothelial activation and damage cause numerous complications in pre-eclampsia.8 Hemolysis occurring due to endothelial damage induces lactate dehydrogenase elevation and fluid leakage resulting in increased hematocrit levels.9 Furthermore, glomerular endothelial dysfunction triggers protein loss and kidney damage
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with increased creatine levels, whereas hepatic dysfunction induced by reduced perfusion leads to elevated liver enzymes.8 The differences in laboratory data including hematocrit, serum creatinine, aspartate transaminase, alanine transaminase, and lactate dehydrogenase
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between patients with PRES and those without imply that patients with PRES may have more severe endothelial damage than the unaffected patients. On the other hand, the
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similarities in clinical and laboratory data between pre-eclamptic and eclamptic PRES patients indicated a shared pathophysiological background, which was further supported by MRI findings that were common to both patient groups.
Cerebral circulation has an autoregulatory mechanism to maintain a steady
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cerebral blood flow. However, severe hypertension can overwhelm this system, resulting in blood–brain barrier (BBB) dysfunction.1 However, previous studies reported that nearly 50% patients with PRES showed mean arterial pressure (MBP) of less than the upper limit
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of autoregulation, which is 140–160 mm Hg.2, 10 In addition to hypertension, circulating cytokines also cause endothelial dysfunction.11 A study by Amburgey et al. demonstrated
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that plasma from pre-eclamptic women increased BBB permeability in vitro and that vascular endothelial growth factor had an important role in this change.12 In this study, the average MBP of patients with PRES was less than the upper limit of autoregulation and was not significantly different from the average MBP of patients without MRI abnormalities. Therefore, endothelial dysfunction caused by circulating cytokines may have a more important role than hypertension in the development of PRES in eclamptic as well as pre-eclamptic patients, and this hypothesis is supported by the difference in laboratory data of patients with and without PRES. Autoregulation of cerebral circulation is mediated in part by neurogenic control. As minimal sympathetic innervation exists in the posterior fossa, posterior brain regions are
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particularly susceptible to hypertension.1 Cytokine-mediated endothelial dysfunction might
ACCEPTED MANUSCRIPT have a relatively significant impact on the development of BBB breakdown in eclamptic and pre-eclamptic patients; this might explain the involvement of atypical brain regions such as the basal ganglia and frontal lobe that were frequently affected in PRES patients in our cohort. One previous report proposed that the involvement of deep brain structures such as the cerebellum, brain stem, and basal ganglia was indicative of severe PRES.13 In our
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patients, deep brain structures such as the brain stem and cerebellum were found to be
affected only in eclamptic patients. In addition, multiple regional involvement was more
likely to be observed in eclamptic patients. These findings indicate that seizures may be a
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result of worsening PRES.
Contrary to what the term implies, PRES is not entirely reversible; hemorrhagic
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complications are reported in 9%–33% cases of PRES.14, 15, 16 In this study, two PRES patients with cerebral vasoconstriction developed hemorrhagic complications. Although recent studies reported the co-occurrence of cerebral vasoconstriction in patients with PRES,2, 14, 15, 17 the incidence varied from 16.2% to 85.0%, and only 30%–50% of PRES
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patients underwent angiographic imaging in those studies. In the current study, all participants were evaluated using MRA, which detected cerebral vasoconstriction in five of 17 (29.4%) PRES patients. Cerebral vasoconstriction is considered to be a consequence of
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cerebral vascular tone deregulation caused by sympathetic overactivity and endothelial dysfunction.17, 18 Although PRES and cerebral vasoconstriction may have overlapping
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pathophysiological mechanisms, it is still unclear whether the coexistence of cerebral vasoconstriction increases the risk of hemorrhagic complications in patients with PRES. This study was conducted at a single hospital, and therefore, included a small
number of patients. A future study with larger sample size is necessary to confirm the findings of this study. However, the strength of our study is the inclusion criteria that included patients who developed neurological symptoms; PRES is characterized not only by radiological findings but also by a new onset of neurological symptoms. PRES is associated with many comorbidities such as severe hypertension, renal disease, autoimmune disorders, cytotoxic medications, post-transplantation immunosuppression, sepsis, and eclampsia.2, 14, 16, 17 Most past studies investigating PRES included patients from
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various backgrounds and with various comorbidities. In contrast, our study determined the
ACCEPTED MANUSCRIPT incidence of PRES and cerebral vasoconstriction in a specific patient population, patients with eclampsia or pre-eclampsia. In conclusion, the shared similarities in clinical and radiological findings between eclamptic and pre-eclamptic PRES patients supported our hypothesis that eclampsia represented one neurological symptom of PRES. In addition, our findings implied that
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endothelial dysfunction played a more important role than hypertension in the development of PRES in eclamptic and pre-eclamptic patients. Even though eclampsia may be the most severe form of PRES in the obstetrical field, our study revealed that in addition to the
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19.2% of patients who developed PRES, 7.7% of pre-eclamptic patients developed cerebral vasoconstriction concurrent with neurological symptoms. Thus, MRI and MRA studies
of the development of eclampsia.
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Acknowledgments
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should be considered for patients with the recent onset of neurological symptoms regardless
The authors thank the neurologists and radiologists at our hospital for reviewing the medical charts and MRI findings to confirm patient diagnoses. We also would like to show
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our greatest appreciation to the medical staff of our department for their contribution to data
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collection. The authors would like to thank Enago (www.enago.jp) for the English language review.
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3.) Wagner SJ1, Acquah LA, Lindell EP, et al. Posterior reversible encephalopathy
ACCEPTED MANUSCRIPT syndrome and eclampsia: pressing the case for more aggressive blood pressure control. Mayo Clin Proc 2011;86:851-6. 4.) Brewer J, Owens MY, Wallace K, et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol 2013;208:468.e1-6. 5.) Matsuda H, Sakaguchi K, Shibasaki T, et al. Cerebral edema on MRI in severe
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preeclamptic women developing eclampsia. J Perinat Med 2005;33:199–205.
6.) American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of
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Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122-31.
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7.) 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. 8.) Hypertensive disorders of pregnancy. In: Cunningham FG, Gant NF, Leveno KJ, et al, eds. Williams Obstetrics. 21st ed. New York: McGraw Hill;2001:567-618.
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9.) Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29:1043-9.
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10.) Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65:205-10.
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11.) Marra A, Vargas M, Striano P, Del Guercio L, Buonanno P, Servillo G. Posterior reversible encephalopathy syndrome: the endothelial hypotheses. Med Hypotheses 2014;82:619-22.
12.) Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ. Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension. 2010;56:1003-8. 13.) McKinney AM, Short J, Truwit CL, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am Roentgenol 2007;189:904-12.
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14.) Burnett MM, Hess CP, Roberts JP, Bass NM, Douglas VC, Josephson SA.
ACCEPTED MANUSCRIPTsyndrome in patients on Presentation of reversible posterior leukoencephalopathy calcineurin inhibitors. Clin Neurol Neurosurg 2010;112:886-91. 15.) Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 2010;85:427-32.
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16.) Liman TG, Bohner G, Heuschmann PU, Endres M, Siebert E. The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES study. J Neurol 2012;259:155-64.
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17.) Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR
perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol
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2008;29:447-55.
18.) Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D. Reversible Cerebral Vasoconstriction Syndrome, Part 1: Epidemiology, Pathogenesis, and Clinical Course.
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AJNR Am J Neuroradiol. 2015;36:1392-9.
Table 1. Comparison of clinical and laboratory data at the onset of symptoms between
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PRES patients and patients without MRI abnormalities (A) and between eclamptic and
(A)
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pre-eclamptic PRES patients (B).
PRES (n = 17)
No MRI abnormalities (n = 20)
P value
Age (y) * Primipara ¶ SBP (mmHg) * DBP (mmHg) *
35.4 ± 5.5 12 (70.6) 176 ± 24 104 ± 17
33.9 ± 4.8 8 (40.0) 168 ± 19 100 ± 14
0.36 0.10 0.25 0.48
MBP (mmHg) * Ht (%)* Plt (104/µL) †
128± 18 38.8 ± 5.9 12.7 (6.1–36.7)
123 ± 15 33.7 ± 5.5 20.2 (12.0–29.1)
0.34
BUN (mg/dL) † Cre (mg/dL) * AST (IU/L) † ALT (IU/L) †
11.0 (4.0–35.0) 0.76 ± 0.26 43.0 (18.0–1042.0) 29.0 (8.0–1008.0)
9.0 (5.0–17.0) 0.56 ± 0.14 18.0 (11.0–124.0) 10.0 (5.0–139.0)
0.01 0.09 0.37
