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Neuroradiology |
1 From the Departments of Radiology (R.B.S., J.F.P., A.I., K.M.B., R.A.K., S.M.B.), Neurology (S.K.F., U.D.), and Pathology (U.D.), Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; the Department of Radiology, Massachusetts General Hospital, Boston (R.Y.C.C.); and the Department of Obstetrics and Gynecology, University of Nebraska School of Medicine, Omaha (J.T.R.). Received March 31, 1998; revision requested May 19; final revision received March 13, 2000; accepted March 24. R.Y.C.C. was supported by a 1995 RSNA Medical Student Award. Address correspondence to R.B.S. (e-mail: rbschwartz@partners.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Twenty-eight patients with preeclampsia-eclampsia and neurologic symptoms underwent magnetic resonance (MR) imaging. Clinical parameters recorded at the time of MR imaging included serum electrolytes and various indices of hematologic, renal, and hepatic function. Several data were available 1 week prior to the development of neurologic symptoms in 11 patients. Univariate analysis and multivariate logistic regression analyses were performed to study possible associations between these parameters and brain edema at MR imaging.
RESULTS: The 20 patients with brain edema at MR imaging had a significantly greater incidence of abnormal red blood cell morphology (14 [82%] of 17 patients vs two [25%] of eight, P < .005) and higher levels of lactic dehydrogenase (LDH) (339 U/L ± 65 [SD] vs 258 U/L ± 65, P = .007) than the eight with normal MR imaging findings; multivariate logistic regression analysis showed a strong association with red blood cell morphology only. Moreover, LDH levels were elevated before the development of neurologic abnormalities (P < .05). Blood pressures were not significantly different between groups at any time.
CONCLUSION: Brain edema at MR imaging in patients with preeclampsia-eclampsia was associated with abnormalities in endothelial damage markers and not with hypertension level.
Index terms: Brain, abnormalities, 10.59, 10.862 • Brain, MR, 10.121413, 10.12143 • Hypertension • Pregnancy, complications
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Clinical and radiographic signs in patients with hypertensive encephalopathy are believed to be related to the effects of acutely increased systemic blood pressure on the autoregulation of the cerebral vasculature. Although once widely believed to reflect the effects of vasospasm and thrombosis (6,7), neurologic deficits in patients with hypertensive encephalopathy are now believed to be most commonly caused by vasogenic edema that arises from the escape of fluid from the intravascular compartment into the interstitium because of breakthrough of autoregulation (3,4,8,9). Furthermore, there is evidence that other factors in addition to systemic hypertension play a role in the development of hypertensive encephalopathy in patients with preeclampsia-eclampsia. Hypertensive encephalopathy is a relatively uncommon complication of preeclampsia-eclampsia, even in patients with severe hypertension (4). Also, blood pressure measurements in patients with preeclampsia-eclampsia who develop hypertensive encephalopathy generally are lower than those in patients who are not pregnant and have hypertensive encephalopathy (10). The purpose of our study was to investigate the clinical parameters that are associated with the development of the brain edema of hypertensive encephalopathy in patients with preeclampsia-eclampsia.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MR imaging was performed by using a Signa 1.5-T system (GE Medical Systems, Milwaukee, Wis); in each case, sagittal and transverse T1-weighted images (repetition time, 600 msec; echo time, 25 msec [600/25] and transverse T2-weighted images (3,000/30 or 80) were acquired, with 5-mm contiguous sections. Fluid-attenuated inversion recovery (FLAIR) imaging was performed in five patients; diffusion-weighted imaging, in four. Five patients received intravenous gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ) prior to undergoing transverse T1-weighted imaging. All images were originally read prospectively as part of the routine clinical practice at the Brigham and Women’s Hospital by neuroradiologists who were aware of the clinical indication for the study.
In the primary analysis, patients were divided into two groups based on imaging findings: One group was composed of patients who had abnormal radiologic features that were indicative of brain edema (regions of increased signal intensity on T2-weighted images in the brain) and the other group was composed of patients who did not have these features. In each patient in both groups, the same selected clinical parameters were evaluated. The maximum blood pressure recorded just prior to the onset of the neurologic symptoms that prompted the radiographic study was recorded, if available. In those patients who were not at the hospital at the time of the neurologic event, the blood pressures obtained at admission were used. The highest blood pressure recorded during the 1st trimester of pregnancy was used as the baseline value. Mean arterial blood pressure and percentage change in mean arterial pressure were then calculated (mean arterial pressure is defined as 1/3 [systolic pressure + 2 · diastolic pressure], so that a blood pressure of 110/80 mm Hg, for example, is equivalent to a mean arterial blood pressure of 90 mm Hg). Other clinical parameters measured prior to or at the beginning of MR imaging included red blood cell morphology (abnormal morphology was defined as at least one schistocyte, anisocyte, or microspherocyte per high power field); white cell and platelet count; and hematocrit, serum albumin, calcium, magnesium, creatinine, blood urea nitrogen, lactic dehydrogenase (LDH), aspartame aminotransferase (AST), alanine aminotransferase (ALT), alkaline phophatase, uric acid, and urine protein levels. Ionized calcium and magnesium levels were unavailable.
Differences between the various laboratory values measured at the time of the neurologic event in the groups with or without MR imaging findings were determined by performing the two-tailed t test for independent samples (continuous variables) or 
2 analysis (dichotomous variables). A P value of .05 was considered to indicate a significant difference. Variances were calculated for each parameter and were found to be equal for each group in most cases. When differences between groups were tested, appropriate corrections were made for unequal variances where applicable. No corrections were made for multiple testing, since the analyses were exploratory in nature. Candidate variables (P < .05) were subsequently subjected to stepwise multiple logistic regression analysis, with MR imaging abnormality serving as the outcome variable. Analyses were performed with the aid of a standard statistical package (JMP; SAS Institute, Cary, NC).
Laboratory parameters in 11 patients (eight in the group with brain edema at MR imaging and three in the group without radiographic signs) were available 3–7 days prior to the onset of neurologic symptoms. These data were compared for both groups by performing the Wilcoxon rank sum test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The eight patients with negative MR imaging findings were 29–43 years of age (mean age, 32.4 years ± 8.5) and were not significantly different in age from those with positive findings. Seven of these patients had normal singleton pregnancies; one had twins. In four (50%) of these eight patients, neurologic symptoms occurred only after delivery (Table 1).
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Hypertensive encephalopathy–related brain edema often developed in patients with mild symptoms. The Figure shows serial images obtained in a patient; the extent of the radiographic findings of hypertensive encephalopathy correlated with the severity of the patient’s symptoms. The patient had a normal pregnancy but 2 days after delivery developed headache and blood pressure that increased to 150/90; her baseline blood pressure in the 1st trimester was 104/60. Her LDH level was 291 U/L (normal range, 107-231 U/L), and she had a normal peripheral smear and platelet count and minimal proteinuria and peripheral edema. The MR image in Figure part a was obtained after she experienced a seizure. Figure parts b and c, obtained 2 days later, when the patient had a blood pressure of 160/110 mm Hg, an LDH level of 373 U/L, anisocytes on her peripheral smear, 1+ proteinuria, and mild peripheral edema, show more extensive abnormalities.
The symptoms and radiologic abnormalities in most patients resolved completely within 2 weeks after restoration of normal blood pressure. One patient had small hemorrhages in the left occipital lobe and basal ganglia, and, at the time this article was written, slight contralateral weakness had persisted for 2 years after the event; another patient developed a small hemorrhage in the right occipital lobe, with a persistent residual field defect 1 year later.
Comparison of Patients with or without Brain Edema
There were few differences in symptoms and signs between the 20 patients with radiographic evidence of edema and the eight with negative radiologic findings. The incidences of headaches, visual changes, and other neurologic signs were similar in the two subgroups, but there was a significantly higher incidence of seizures in those with edema at MR imaging (Table 1). Baseline and maximal mean arterial blood pressures were not significantly different between the two groups, nor were the relative increases in blood pressures from 1st trimester levels (Table 2). All patients had mild to moderate (trace to 3+) proteinuria and signs of peripheral edema.
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There was a higher incidence of abnormal red blood cell morphology in peripheral smears in patients with radiographic findings versus those in patients without (14 (82%) of 17 vs two (25%) of eight, respectively; P < .005); three patients in the group with radiologic changes did not have red blood cell morphology data available at the time of their neurologic events). Whereas the hematocrit (0.36 ± 0.06 vs 0.28 ± 0.10, P = .02) and white blood cell concentration (13.7 x 109/L ± 6.2 vs 9.2 x 109/L ± 2.5, P = .011) were significantly higher in individuals with radiologic abnormalities, there was no difference in platelet counts. No significant differences were present for mean, systolic, or diastolic blood pressures.
Stepwise multiple logistic regression analysis revealed red blood cell morphology to be the strongest predictor of abnormal radiographic findings; it accounted for 25% of the variance in the model that predicted brain edema. No other variables entered into the model.
Comparison of Patients before and after Onset of Neurologic Symptoms
There were eight patients in the group with positive MR imaging findings and three in the group with negative MR imaging findings whose blood pressures were determined and blood was drawn for evaluation of preeclampsia within the week prior to their development of severe neurologic symptoms (Table 3). The only laboratory parameter that was abnormal prior to the development of neurologic symptoms was the serum LDH level, which was higher in the group that later developed hypertensive encephalopathy– related brain edema than in the group that did not develop brain edema (297 U/L ± 59 vs 195 U/L ± 34, respectively; P = .04). The other liver enzyme (AST, ALT, and alkaline phosphatase) levels and all renal function test findings, most notably uric acid and creatinine levels, were not significantly different between these two groups before the onset of symptoms. Red blood cell morphology data and serum magnesium levels were not available prior to the development of symptoms.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have also found that the elevated LDH level in patients who eventually developed brain edema preceded by several days the development of neurologic signs and symptoms at a time when all other laboratory values were normal and blood pressures were only mildly increased. This is consistent with the findings of previous studies (15–17) in which investigators have shown that endothelial damage in patients with preeclampsia-eclampsia is not a result of hypertension but actually precedes substantial blood pressure increases. The endothelial dysfunction experienced by these patients is more likely related to circulating endothelial toxins (12) or antibodies against the endothelium (13).
The radiologic pattern observed in our patients was similar to that observed in patients who were not pregnant and had severe hypertensive encephalopathy (3). Although hypertensive encephalopathy can arise in patients with conditions in which there is acute systemic hypertension alone, it most commonly occurs in patients with conditions in which there is also preexisting endothelial dysfunction or damage, such as systemic lupus erythematosus (3,9), cryoglobulinemia (20), or hemolytic uremic syndrome (9,21), and in patients undergoing cyclosporine (22) and cisplatin (23) therapy. Investigators in studies in which single photon emission computed tomography (SPECT) (3) and diffusion-weighted MR imaging (8,9) have demonstrated that the brain edema in patients with hypertensive encephalopathy does not represent cytotoxic edema. Rather, the combination of acute hypertension and endothelial damage results in hydrostatic edema—a specific form of vasogenic edema characterized by the forced leakage of serum through capillary walls and into the brain interstitium—which, if severe enough, will be radiographically evident.
Cerebrovascular autoregulatory considerations may help to explain the pathogenesis and distribution of abnormalities in patients with hypertensive encephalopathy. Brain perfusion is maintained by an autoregulatory system of the small arteries and arterioles that has myogenic and neurogenic components. Endothelial damage may attenuate or abolish the myogenic response (24). The perivascular sympathetic nerves, which serve to protect the brain if the myogenic response is blunted or overwhelmed (25), travel in the adventitial layer of the cerebral vessels and are relatively protected from agents that cause endothelial damage. Since the vertebrobasilar system and posterior cerebral arteries are sparsely innervated by sympathetic nerves (26), the occipital lobes and other posterior brain regions may be particularly susceptible to breakthrough of autoregulation with elevated systemic pressures. Investigators in recent Doppler ultrasonographic studies have demonstrated elevated cerebral perfusion pressures (27,28) and reduced cerebrovascular resistance (29) in patients with eclampsia, and increased regional cerebral blood flow to the occipital lobes has been documented in these patients who undergo SPECT (3) and xenon computed tomography (30).
Seizures were more frequent in patients with brain edema than in those with normal findings. This most likely reflects the irritative effects of fluid in the subcortical and cortical tissues. Some authors (31,32) have suggested, on the basis of the common association of seizures with hypertensive encephalopathy, that the radiographic findings in patients with hypertensive encephalopathy actually may represent seizure edema. We have shown in this series and in previous studies (3), however, that radiographic abnormalities in patients with hypertensive encephalopathy can occur in the absence of seizures. In fact, since patients with hypertensive encephalopathy who do not experience seizures are less likely to come to neuroradiologic attention, they may be underrepresented in this and other studies. Furthermore, brain edema is not frequently associated with idiopathic seizures, even in patients with status epilepticus; when it occurs, it tends to be unifocal, limited to the cortex (33), and have cytotoxic characteristics at diffusion-weighted imaging (34). Nevertheless, we have noted that the patients in the group with brain edema who developed seizures tended to have more extensive brain edema than those who did not have seizures (Figure). The physical stresses of seizures may have contributed to the leukocytosis (35) and hyperuricemia (36) that were noted in this group. Also, serum magnesium levels were significantly lower in the group with brain edema, as compared with the group with normal MR imaging findings. Magnesium has been shown to be effective in reducing the occurrence of seizures in preeclampsia (37) and may exert this effect by directly decreasing neuronal excitability (38), protecting the endothelium against damage by free radicals (38), or reducing cerebral perfusion pressures (39).
We conclude that brain edema in patients with preeclampsia-eclampsia syndrome is primarily associated with laboratory-based evidence of endothelial damage; blood pressures, although elevated in all patients, are not significantly different in those with or without brain edema. In this study, we used red blood cell morphology and LDH levels as indicators of endothelial dysfunction, since these were routinely available in all patients. Irregularities of the endothelial wall disrupt red blood cells and result in the production of schistocytes, anisocytes, and microspherocytes and in the release of LDH into the serum (11). However, more specific markers of endothelial dysfunction that have also been found to be released in patients with preeclampsia include fibronectin, tissue plasminogen activator, thrombomodulin, endothelin-1, and, in particular, von Willebrand factor (11,12, 40). Measurement of these specific markers may be useful to evaluate endothelial integrity in patients who are preeclamptic, especially patients who are at risk for progression to hypertensive encephalopathy, such as those with severe headaches or other neurologic signs and symptoms (41). If this screening result is abnormal, treatment with appropriate antihypertensives may be initiated before hypertensive encephalopathy can develop.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, R.B.S.; study concepts and design, R.B.S., S.K.F., J.F.P.; definition of intellectual content, R.B.S., S.K.F., J.F.P., J.T.R.; literature research, R.B.S., S.K.F., J.T.R.; clinical studies, R.B.S., S.K.F., R.A.K., U.D., J.T.R.; data acquisition, R.B.S., A.I., K.M.B., R.A.K., S.M.B., R.Y.C.C.; data analysis, R.B.S., J.F.P., A.I., K.M.B., S.M.B., R.Y.C.C.; statistical analysis, J.F.P., R.B.S.; manuscript preparation, R.B.S.; manuscript editing, R.B.S., S.K.F., J.F.P., R.A.K., J.T.R.; manuscript review, R.B.S., S.K.F., J.F.P., A.I., K.M.B., R.A.K., U.D., S.M.B., J.T.R.
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