Posterior reversible encephalopathy syndrome in preeclampsia and eclampsia: The role of hypomagnesemia

Journal Pre-proof Posterior reversible encephalopathy syndrome in preeclampsia and eclampsia: The role of hypomagnesemia Xiaobo Fang, Haibin Wang, Zifan Liu, Jia Chen, Hu Tan, Yanling Liang, Dunjin Chen

PII:

S1059-1311(19)30676-4

DOI:

https://doi.org/10.1016/j.seizure.2020.01.003

Reference:

YSEIZ 3634

To appear in:

Seizure: European Journal of Epilepsy

Received Date:

3 October 2019

Revised Date:

18 December 2019

Accepted Date:

4 January 2020

Please cite this article as: Fang X, Wang H, Liu Z, Chen J, Tan H, Liang Y, Chen D, Posterior reversible encephalopathy syndrome in preeclampsia and eclampsia: The role of hypomagnesemia, Seizure: European Journal of Epilepsy (2020), doi: https://doi.org/10.1016/j.seizure.2020.01.003

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Posterior reversible encephalopathy syndrome in preeclampsia and eclampsia: the role of hypomagnesemia Xiaobo FANGa,b, Haibin WANGb, Zifan LIUa, Jia CHENa, Hu TANb, Yanling LIANGa,*, Dunjin CHENb*

Xiaobo

Fang,

MD,

PhD

([email protected]);

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Authors: Haibin

Wang,

MD,

PhD

([email protected]), Zifan Liu, MD ([email protected]); Jia Chen, MD,

([email protected]); Hu Tan, MD, PhD ([email protected]); Yanling Liang, MD, PhD

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([email protected]); Dunjin Chen, MD, PhD ([email protected]);

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a. Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, 510150, Guangdong,

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China

b. Department of Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University,

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Guangzhou Medical Center for Critical Pregnant Women, Guangzhou, 510150, Guangdong, China

*Corresponding author:

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Name: Yanling LIANG and Dunjin CHEN Mailing address: No. 63, Duobao Road, Guangzhou, 510150, Guangdong, China;

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Tel:+86 18998321628 or +86 18928916722 E-mail address: [email protected] & [email protected]

Running head: Hypomagnesemia in obstetric PRES.

Highlights: 

hypomagnesemia frequently occurs in the acute phase of obstetric RPLS.



hypomagnesaemia may play a role in triggering obstetric RPLS by regulating blood pressure and inflammation failure.



magnesium supplementation might be helpful for obstetric RPLS patients.

Abstract Purpose: Posterior reversible encephalopathy syndrome (PRES), defined by its clinical

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and imaging manifestations, is a critical maternal complication. The specific pathophysiological mechanism of PRES has not been fully elucidated and remains controversial. Recently, several case studies reported that hypomagnesemia is present

in the acute phase of PRES regardless of its etiology. Moreover, magnesium sulfate is

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a conventional treatment for preeclampsia (PE) and eclampsia; therefore, we hypothesized that hypomagnesemia might play an important role in the cascades

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involved in PRES in PE or eclampsia.

Method: We consecutively collected PE and eclampsia patients who were examined via

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magnetic resonance imaging (MRI) and tested for magnesium levels between January 2013 and January 2017. All patients were grouped into PRES and non-PRES groups based on MRI results. Demographic data, magnesium levels and imaging features were

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collected retrospectively.

Results: A total of 72 patients met the inclusion criteria; these participants were sorted

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into PRES (n=38) and non-PRES (n=34) groups. Twenty-four patients (63%) in the PRES group and 2 patients (6%) in the non-PRES group presented hypomagnesemia.

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Moreover, magnesium levels were significantly lower in the PRES group during both the acute phase (p<0.001) and the post-phase (p=0.04) than in the non-PRES group. However, there was no correlation between magnesium levels and edema severity during the acute phase. Conclusions: These results demonstrate that hypomagnesemia frequently occurs in the acute phase of obstetric PRES and suggest a potential relationship between them. Such a connection would support the application of magnesium sulfate in PE and eclampsia

patients to prevent PRES. However, additional randomized trials are needed.

Key words: Posterior reversible encephalopathy syndrome; hypomagnesemia; eclampsia; inflammation; seizure Introduction Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a special type of cerebrovascular

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disease defined by its clinical and imaging manifestations[1]. The onset of PRES typically occurs acutely or subacutely and involves a variety of nonspecific symptoms, including headaches, visual changes, seizures, consciousness impairment, mental

disorders, focal neurologic deficits, nausea, and vomiting[2, 3]. MRI is the gold

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standard for the diagnosis and evaluation of PRES[4], and the imaging features of this

condition include vasogenic edema in the subcortical white matter in the majority of

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patients and possible cytotoxic edema in some patients[5].

The specific pathophysiological mechanism underlying PRES has not been fully

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elucidated and remains controversial. A variety of pathogeneses account for PRES, and although its common pathologies include severe hypertension, renal dysfunction, chemotherapy and transplantation[6], accumulating evidence reveals that preeclampsia

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(PE) and eclampsia are the leading pathologies among affected female patients[7, 8], with approximately 90%-100% of eclampsia patients and approximately 20% of PE

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patients with neurological symptoms also confirmed to have PRES as a complication[8, 9]. This condition is also defined as obstetric PRES. Normally, the prognosis of PRES

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is favorable; however, without timely treatment, status epilepticus, cerebral ischemia, hemorrhage, intracranial hypertension or even death can occasionally occur[3, 10]. In pregnant women, PRES is a serious maternal complication that can worsen pregnancy outcomes in the acute phase when combined with PE and eclampsia[11]. Furthermore, according to our previous study, the incidence of PRES is high (0.22%) among pregnant women[6]. Therefore, a special focus on obstetric PRES is needed. Recently, several cases have reported that hypomagnesemia was present in the acute

phase of PRES regardless of the etiology[12]. Moreover, a novel hypothesis has suggested that arginine vasopressin (AVP) axis stimulation precipitates PRES development through an increase in AVP secretion or AVP receptor density due to several conditions (eclampsia, inflammatory disorders, hypertension, drug-induced PRES, etc.), leading to cerebral vasoconstriction, endothelial dysfunction and cerebral ischemia that result in PRES[13]. Magnesium, which is one of the most abundant trace elements in the body and has been reported to stabilize blood pressure by regulating vascular function[14], can also exert neuroprotective effects by reducing inflammation

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and decreasing blood-brain barrier permeability[15, 16]. Moreover, magnesium sulfate is a conventional treatment for PE and eclampsia[17, 18]. Therefore, we hypothesized that hypomagnesemia might play an important role in the cascades involved in PRES

in PE or eclampsia, and in the present study, we explored whether hypomagnesemia is

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associated with obstetric PRES.

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Materials and methods

This retrospective study was approved by the institutional ethics committee of the Third

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Affiliated Hospital of Guangzhou Medical University (2017-063) and conducted in

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Guangzhou Medical Centre for Critical Pregnant Women between January 2013 and January 2017. The inclusion criteria were a) patients who were diagnosed with PE or

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eclampsia after 20 weeks of gestation or within 6 weeks postpartum and b) patients in whom serum magnesium levels were measured before the application of magnesium

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sulfate and within 24 h of the appearance of PRES. The consecutively collected patients were grouped into a PRES group and a non-PRES group according to the PRES diagnostic criteria. Demographic data, serum magnesium levels and imaging features were collected retrospectively. In this study, the diagnosis of PRES was based on a combination of clinical symptoms

(headache, vision change, seizure, consciousness disorders or hypertension) and standard radiological criteria (hyperintensities on T2WI and fluid-attenuated inversion recovery [FLAIR] in the subcortical regions and the gyri) as well as the reversibility of symptoms and imaging findings[2, 3]. The clinical and imaging features of a subset of the patients have been previously reported[6]. PE was defined as a disorder of pregnancy associated with new-onset hypertension after the 20th week of gestation and

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frequently near term, often accompanied by maternal organ dysfunction or signs of

uteroplacental dysfunction with or without proteinuria [19]. Eclampsia was defined as PE plus new-onset tonic-clonic, focal, or multifocal seizures in the absence of other

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causative conditions, such as epilepsy, cerebral infarction, intracranial hemorrhage, or

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drug use [18, 20]. HELLP syndrome was defined as elevated liver enzymes (aspartate transaminase [AST] and/or alanine aminotransferase [ALT] level > 70 IU/L) and low

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platelets (platelet count < 100 × 109/L) as a consequence of hemolysis (lactate

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dehydrogenase level > 600 IU/L) [20, 21]. The normal range of serum magnesium levels is 0.75-1.02 mmol/L; accordingly, a concentration below 0.75 mmol/L was

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defined as hypomagnesemia.

All enrolled patients were examined via whole-brain MRI (Achieva 3.0T, Philips,

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Amsterdam, the Netherlands), including T1WI, T2WI and T2 FLAIR sequencing methods, within 3 days of the onset of clinical symptoms or signs. The assessment of the lesion area scores and the edema scores were reported in a previous study[22]. Briefly, the imaging features were described according to their location, including the frontal, parietal, occipital, or temporal cortex; the cerebellum; the basal ganglia; the

brainstem; the deep white matter and the corpus callosum; with 1 point recorded for each involved location. The extent and severity of the edema observed in the lesion area were graded on a scale of 0-5 by evaluating FLAIR images. MRI diagnosis and confirmation were independently evaluated by two neuroradiologists, and the neuroradiologists then attempted to reach a consensus. The criteria for magnesium sulfate treatment were decided by clinicians in accordance

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with the American College of Obstetricians and Gynecologists Committee Opinion[23]. Data on serum magnesium levels in the acute phase were collected to analyze the difference between the PRES group and the non-PRES group. The serum magnesium

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levels before the application of magnesium sulfate and within 24 h of the appearance

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of PRES were collected to explore whether hypomagnesemia is associated with obstetric PRES in the acute and postacute phases. Serum magnesium levels in the acute

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phase, along with lesion area scores and edema scores, were also collected to explore

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the correlation between them.

All patients underwent a standard treatment protocol that included primary disease

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treatment, blood pressure management, magnesium sulfate injection and sometimes

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even pregnancy termination, all of which was performed by experienced obstetricians.

Statistical analyses Descriptive statistics for continuous variables are presented as the mean ± standard deviation, and categorical variables are presented as frequencies and percentages. To examine the two groups of patients, we used Student’s t-tests for normally distributed

continuous variables, Z tests for non-normally distributed continuous variables, and chisquared tests or Fisher’s exact tests for categorical variables. We used nonparametric Spearman correlation to explore the relationship among lesion area scores, edema severity and magnesium levels. The threshold for statistical significance was set at p < 0.05. We analyzed our data using the SPSS 13.0 statistical software package (SPSS Inc.,

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Chicago, IL, USA) and GraphPad Prism (GraphPad Software, San Diego, CA, USA).

Results

A total of 21,872 women were delivered at our center, of whom 72 women met the

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inclusion criteria and were recruited into the PRES (n=38) or non-PRES (n=34) group according to MRI results (Fig. 1). The demographic information and BP values are

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presented in Table 1. Among the PRES patients, 22 (58%) had PE, 8 (21.05%) had

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HELLP syndrome as a complication, and 33 (87%) received magnesium sulfate treatment. Among the non-PRES patients, 34 (100%) had PE, 1 (0.29%) had HELLP

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syndrome as a complication, and 26 (76%) received magnesium sulfate treatment. The clinical and imaging features of a subset of the patients have been previously

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reported[6]. The rates of complications in the HELLP syndrome and eclampsia patients

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in the PRES group were significantly higher than those found in the non-PRES group (p<0.05). In the PRES group, the systolic blood pressure (SBP, 175±23 mmHg) and diastolic blood pressure (DBP, 112±20 mmHg) were significantly higher in the PRES group than in the non-PRES group (SBP, 159±17 mmHg, and DBP, 102±11 mmHg). In the PRES group, the serum magnesium levels were measured before the application of magnesium sulfate and within 24 h of the appearance of PRES, while in the non-

PRES group, serum magnesium levels were measured only before the application of magnesium sulfate. Among all 72 patients, 24 of the 38 patients (63%) in the PRES group and 2 of the 34 patients (6%) in the non-PRES group presented low serum magnesium levels (normal range: 0.75-1.02 mmol/L); the hypomagnesemia rate was significantly higher in the PRES group than in the non-PRES group (p<0.05). Additionally, serum magnesium levels were significantly lower in the PRES group

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(0.71±0.08 mmol/L) than in the non-PRES group (0.86±0.13 mmol/L, p<0.001, Fig. 2A).

Serum magnesium levels were measured again on the last day of hospitalization, which

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was defined as the beginning of post-phase data. Among all 72 patients, 26 of the

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patients in the PRES group and 17 of the patients in the non-PRES group were measured, and serum magnesium levels were lower in the PRES group (1.1±0.4 mmol/L) than in

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the non-PRES group (1.4±0.6 mmol/L, p=0.040, Fig. 2B). Moreover, we explored the

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relationship between lesion severity and magnesium level in the PRES group. The imagine features of these patients are presented in Figure 3. The average lesion area

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score was 2.5±1.3, and the average severity of edema score was 2.5±1.2. The Spearman correlation results demonstrated that there were no correlations among lesion area

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scores, the severity of edema and magnesium levels (Fig. 2C).

Discussion

To our knowledge, this is the first report to focus on the close relationship between hypomagnesemia and obstetric PRES. More precisely, our study reveals that hypomagnesemia is present in the majority of patients during the acute phase of

obstetric PRES and that magnesium levels are significantly lower in PRES patients than in non-PRES patients during both the acute phase and the chronic phase of obstetric PRES, raising the possibility that hypomagnesemia may play a role in triggering obstetric PRES by regulating blood pressure and inflammation failure. Despite the differences between obstetric PRES and other etiologies of PRES, the specific pathophysiology underlying PRES has not been completely clarified. However, the etiologies share the same pathogenic mechanisms. The current, most well-accepted theory proposes that PRES is associated with cerebral autoregulatory failure and

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breakthrough vasodilatation, which are caused by severe hypertension[4, 24]. Normally, cerebrovascular autoregulation maintains proper cerebral blood flow (50-150 mmHg)

to ensure sufficient supply to the brain independent of BP fluctuations; however, acute

breakthrough

vasodilatation,

resulting

in

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BP fluctuations and severe hypertension can lead to autoregulatory failure and cerebral

ischemia

or

cerebral

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hyperperfusion[2, 4, 25]. This ‘‘hyperperfusion theory’’ is supported by our previous study as well as an increasing number of studies[22, 26]. Additionally, this theory

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explains why posterior areas contain a predominance of these lesions because posterior areas are more vulnerable to hyperperfusion resulting from a reduction in the density of sympathetic innervation. Interestingly, not all PRES patients (nearly 15% - 20%)

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have findings in accordance with the ‘‘hyperperfusion theory’’, suggesting that hypertension alone may not be sufficient to contribute to PRES, and other theories may

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therefore need to account for these patients[8, 10]. Endothelial dysfunction led to a second theory, named “cytotoxic/immunogenic theory”. This theory suggests that

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endothelial dysfunction is caused by cytotoxic factors (chemokines, exogenous toxins or chemotherapy reagents) or immunogenic factors (T-cell activation and inflammatory cytokine release), which lead to vasoconstriction and hypoperfusion and subsequent edema formation[4, 27, 28]. In this scenario, the occurrence of PRES in patients with autoimmune disorders, PE/eclampsia, chemotherapy or sepsis may be explained by this theory[29], as could atypical lesion involvement [8]. Magnesium is one of the most abundant microelements in the body and is involved in

numerous physiological, biochemical and cellular processes, especially in the cardiovascular system[14]. The level of serum magnesium is closely associated with the regulation of blood pressure, and it has been reported that almost 15% of patients in the normal population and up to 65% of patients with severe diseases present hypomagnesemia[30]. Experimental data and clinical studies have revealed that hypomagnesemia may contribute to hypertension and that magnesium supplementation can lower blood pressure by increasing nitric oxide and improving endothelial dysfunction

to

antagonize

calcium

channels[30].

When

considering

the

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“hyperperfusion theory”, it is understandable that hypomagnesemia could contribute to PRES via a failure to regulate BP, and obstetric PRES patients may therefore benefit from magnesium supplementation.

In addition to regulating blood pressure, magnesium also exhibits anti-inflammatory

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functions and a neuroprotective effect[15, 31]. Accumulating evidence demonstrates that magnesium exerts a neuroprotective effect by passing through the blood-brain

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barrier to directly attenuate neuronal death and brain edema[16, 32]. Moreover, magnesium can attenuate neuroinflammation by ameliorating blood-brain barrier

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permeability to prevent microglial activation[33]. The supporting evidence indicates that magnesium deficiency results in a more sensitive inflammatory response to

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endotoxin and that magnesium pretreatment alleviates the severity of eclampsia seizures[33, 34]. However, PE and eclampsia patients as well as obstetric PRES patients exhibit a severe inflammatory response to circulating cytokines (tumor necrosis factor-

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α, IL-1β, etc.)[35]. Given that magnesium sulfate is currently the most effective and conventional treatment for PE and eclampsia patients, hypomagnesemia may contribute PRES

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to

via

inflammatory

suppression

failure

according

to

the

“cytotoxic/immunogenic theory”, and obstetric PRES patients may therefore also benefit from magnesium supplementation. Several reasons could account for the hypomagnesemia observed in PE/eclampsia patients; these include inadequate intake of magnesium and renal wasting[30]. PE/eclampsia patients have one of the most severe obstetric diseases that involves multiple systems (e.g., the brain, kidney, cardiovascular system and liver)[36]. Recently,

a case was reported in which magnesium supplementation prevented obstetric PRES and was also associated with improvement of neurological function[37]. In our study, hypomagnesemia was present in the majority of patients in the acute phase of PRES. Moreover, magnesium levels were significantly lower in the PRES group than in the non-PRES group (p<0.001), consistent with a previous study that showed that hypomagnesemia was present in the acute phase of PRES [1, 12] and that pregnancy outcomes are favorable in the presence of magnesium sulfate treatment. Some limitations of this study should be acknowledged. First, due to the nature of this

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retrospective study, the data were collected from medical records and are therefore subject to the availability, integrity and accuracy of those records. Second, PE and

eclampsia are severe conditions, as up to 65% of patients with severe disease present with hypomagnesemia. We doubt that there is a causative relationship between

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hypomagnesemia and the chronic state of this disease. However, all patients in our

study were PE and eclampsia patients, and we can therefore draw conclusions based on

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these homogeneous patients despite this bias. Third, as the study was conducted in a single center with a relatively small sample size, our conclusions are purely descriptive

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and merely reveal that there is a potential relationship between acute hypomagnesemia and PRES rather than indicating a causative link.

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In summary, the present study suggests that hypomagnesemia is present in the majority of patients during the acute phase of obstetric PRES and that magnesium levels are significantly lower in obstetric PRES patients during both the acute phase and the

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chronic phase than in non-PRES patients, raising the possibility that hypomagnesemia may play a role in triggering obstetric PRES by regulating blood pressure and

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inflammation failure. Hence, magnesium supplementation might be beneficial in obstetric PRES patients. However, additional prospective or randomized trials are required to further explore this issue.

Declarations of interest Declarations of interest: none

Conflict of interest The authors declare that they have no conflict of interest.

Acknowledgement: This study was supported by grants from the National Natural Science Foundation of China (81571518, 81830045); Social Development Planning Project of Science and Technology Department of Guangdong Province (2014A020212348); Innovative Team for the Major Obstetric Disease Prevention and Control of Education Department of Guangdong Province (2015KCXTD020). The funders had no role in study design, data collection and analysis, decision to publish, or

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preparation of the manuscript.

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References

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Use in Obstetrics. Obstet Gynecol. 2016;127:e52-3. [24] Shankar J, Banfield J. Posterior Reversible Encephalopathy Syndrome: A Review. Can Assoc Radiol J. 2017;68:147-53. [25] Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. Blood Pressure Fluctuations in Posterior Reversible Encephalopathy Syndrome. J Stroke Cerebrovasc Dis. 2012;21:254-8. [26] Tetsuka S, Ogawa T. Posterior reversible encephalopathy syndrome: A review with emphasis on neuroimaging characteristics. J Neurol Sci. 2019;404:72-9. [27] Granata G, Greco A, Iannella G, Granata M, Manno A, Savastano E, et al. Posterior reversible encephalopathy syndrome – insight into pathogenesis, clinical variants and treatment approaches.

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Figure Caption

Figure 1. Patient flow diagram. Figure 2. Serum magnesium levels were significantly lower in the PRES group than in the non-PRES group during the acute phase (0.71±0.08 mmol/L vs. 0.86±0.13 mmol/L, p=0.000, A) and the post-phase (1.10±0.38 mmol/L vs. 1.40±0.56 mmol/L, p=0.04, B);

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C). There was no correlation among lesion area scores or the severity of edema and magnesium levels according to Spearman correlation analysis.

Figure 3. The imaging features of a 36-year-old preeclampsia patient with PRES.

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Lesions showing hypointensity on T1WI (A), hyperintensity on T2WI (B) and FLAIR

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(C), and no enhancement on enhancer sequence (D). Isointensity was observed on DWI (E), and hyperintensity was observed on apparent diffusion coefficient maps (F),

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on MRV (G) or MRA (H).

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indicating that the lesion showed vasogenic edema. No obvious abnormality was found

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Table 1. Comparison of general information and BP between the PRES group and the non-PRES group. non-PRES group(n = 34)

X2or t value

p value

30±6

31±5

0.730

0.468

HELLP （n,%）

8（21）

1（0.3）

-

0.006

Hypomagnesemia rate（n,%）

24（63）

2（6）

23.293

0.000

Immune diseases（n,%）

6（16）

2（6）

-

0.267

PE（n,%）

22（58）

34（100）

Eclampsia（n,%）

16（42）

0（0.00）

31.5±5.1

30.6±4.9

Gestational length（week）

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Age（year）

Blood pressure

112±20

159±17

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DBP（mmHg）

175±23

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SBP（mmHg）

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PRES group (n = 38)

Variable

102±11

18.406

0.000

18.406

0.000

0.811

0.420

3.390

0.001

2.6685

0.009