Prognostic Observation of Posterior Reversible Encephalopathy Syndrome

Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical-radiological entity, which is associated with a variety of clinical conditions. The imaging and clinical findings are typically reversible, but many patients still have permanent neurological sequelae with a fatal outcome. Up to now there are no consistent conclusions about the factors that affecting its prognosis. The objective of our study is to discuss the effects of different causes, different imaging findings and laboratory parameters on the prognosis of PRES and deepen the understanding of the nature of PRES. This will contribute to predict the prognosis of patients with PRES and to further investigate the pathogenesis of PRES so as to guide the clinical treatment and follow-up evaluation. A multi-center retrospective case study will be performed from January 2016 to July 2017 and a total of 400 patients who meet the criteria for PRES diagnosis from 10 sub-centers are anticipated included in this research. Patients will be divided into several subgroups according to the etiology. Date will be collected from the clinical records，imaging and laboratory data of the patients, including demographic data, clinical data, imaging findings, laboratory parameters and follow-up data. During the follow-up, MRI and blood biochemical examination will be performed once more. The imaging findings of the patients will be assessed by two neuroimaging physicians, any difference between them will be agreed upon by consensus. Prognosis of the patients will be assessed by using the modified Rankin scale (mRS) scores. All of the above data is saved into the database. In this study we will review etiologies and imaging findings, laboratory and follow-up data of the patients we selected. Univariate and multivariate analysis will be performed within the group and between groups according to the subgroups. Then we will discuss the connection between different causes, different imaging findings and laboratory parameters and the prognosis of posterior reversible encephalopathy syndrome.

Background and Significance

Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical-radiological syndrome. It was first described by Hinchey et al. in 1996. It is characterized by a variable combination of headaches, seizures, altered mental status, visual impairment, nausea, vomiting and focal neurological signs and accompanied with symmetric vasogenic edema of bilateral posterior cerebral circulation territory. PRES is associated with multiple risk factors, such as renal dysfunction, hypertension, cytotoxic drugs, autoimmune disease and pre-eclampsia or eclampsia, which can occur in a wide range of diseases and predisposing factors. Lesions are usually located in the parietal occipital region. However, lesions may also involve unilateral cerebral hemisphere, anterior circulation area or deep brain structure. According to the location of the lesions, five distribution patterns were described: mainly parietal-occipital pattern, superior frontal sulcus pattern, holo-hemispheric watershed pattern, partial or asymmetric expression of the primary patterns and central pattern. In addition, cytotoxic edema with associated diffusion restriction, abnormal enhancement due to blood brain barrier disruption, hemorrhages, infarction are atypical findings which may be occasionally detected.

PRES is associated with a variety of clinical conditions. The occurrence of PRES is not affected by age and gender, it may present in all age groups. The occurrence of PRES may be a result of either breakdown of cerebral autoregulation and disruption of blood brain barrier, causing vasogenic edema or endothelial dysfunction resulting from circulating toxic mediators, sepsis, autoimmune conditions, or eclampsia. Up to now, the pathophysiological mechanism of PRES is still not clear, but cerebral autoregulation impairment and endothelial dysfunction are considered to be the most important potential mechanisms.

PRES usually has a favourable prognosis. The clinical and imaging findings are often reversible when the underlying causes are eliminated and the blood pressure is controlled. Even so, many patients still have permanent neurological sequelae and have a mortality of 5%-15%. Known risk factors for PRES include hypertension, renal disease and immunosuppressive therapy, and researchers have also found that lymphopenia and dyslipidemia are the potential risk factors for PRES. The prognostic factors of PRES include the presence of PRES risk factors, duration of symptoms, the presence of cytotoxic edema and hemorrhage. Alhilali et al. through the retrospective analysis of the etiologies, imaging findings and cerebrospinal fluid examination of the 47 PRES patients with lumbar puncture showed that clinical factors, imaging findings, cerebrospinal fluid laboratory results all affect the prognosis of PRES, with low CSF glucose, hypertensive encephalopathy, and imaging findings of hemorrhage increasing the risk of fatal outcome, while toxemia of pregnancy was found to have a relatively protective effect. Recent research had shown correlation of MRI findings and LDH and albumin levels, suggesting that these biochemical indices may be used as a prognostic factor. Although the various risk factors of PRES and its related imaging findings are well described, and in previous studies, the relationship between clinical factors, imaging findings, laboratory examination results and prognosis of PRES were analyzed respectively by different investigators, their relative effects on the prognosis are remain unclear and there are no consistent conclusions about it.

Here we use a multi-center approach to conduct this study to ensure a larger patients sample. This proposed multi-center retrospective study will analyze the factors that influence the prognosis of the patients with PRES. The aim of our research is to study the connection between different causes, different imaging findings, laboratory findings and clinical outcome in patients with PRES and deepen the understanding of the nature of PRES. The pathogenesis of PRES will be further discussed based on the results obtained. This will contribute to predict the prognosis of patients with PRES and to further investigate the pathogenesis of PRES so as to guide the clinical treatment and follow-up evaluation.

Research Design and Methods

1. Overall Design of The Research

   A multi-center retrospective case study, after securing required Institutional Review Board approval, will be performed from January 2016 to July 2015 and the patients with complete inpatient clinical records who meet the criteria from 10 sub-centers will be included. Patients' demographic data, clinical data, auxiliary examination, imaging findings and follow-up data will be collected and summarized. The imaging findings of the patients will be assessed by two neuroimaging physicians, any difference between them will be agreed upon by consensus. Following this, the connection between the different causes, different imaging findings, laboratory findings and clinical outcome of posterior reversible encephalopathy syndrome will be analyzed.
2. Patients and Grouping

   A total of 400 patients with complete inpatient clinical records who meet the criteria from 10 sub-centers will be included in this research. The patients above will be divided into several subgroups according to the causes of the disease, including hypertensive encephalopathy, cytotoxic drugs, toxemia of pregnancy (pre-eclampsia or eclampsia), autoimmune diseases and other diseases (anemia, hypomagnesemia, infection, sepsis, etc.).
3. Data Acquisition

   The following information will be collected by reviewing the medical records and follow-up of the patients who met the inclusion criteria:

   Basic information: demographic and sociological characteristics of patients, such as name, gender, age and so on; Clinical date: including the history of past illness, etiology, symptoms (headache, seizures, visual disturbances, nausea and vomiting, altered mental status, focal neurological signs, etc.), blood pressure/MAP at the time of attack, therapeutic measure, time from symptom onset to control of the causative factor, hospitalization, etc.

   Examination to identify cause of PRES: including blood biochemical examination (enzymes, metabolites, minerals, blood protein, etc.), lumbar puncture cerebrospinal fluid examination, EEG, blood gas analysis, etc.

   Imaging examination: including the time from PRES onset to MRI examination, location of lesion , the distribution pattern of edema, degree of edema, cytotoxic edema appears or not, abnormal enhanced appears or not, hemorrhage appears or not, MRA or DSA examination, perfusion weighted imaging, etc.

   Follow-up:

   Time interval from PRES onset to MRI follow-up; Follow up imaging findings; Prognosis observation: discharge status, including the partial or complete recovery of abnormal imaging, hemorrhagic and ischemic complications appear or not ,continue medication treatment or not (antihypertensive drugs, anticonvulsant drugs, etc.), death; time from symptoms onset to recovery of image abnormalities; recurrence and interval time; increased patient's current MRI and blood biochemical examination; the patients' mRS score at the time of onset, discharge and follow-up were achieved by review cases and follow-up.
4. Data Analysis

   All of the above data is saved into the database. In this study we will review etiologies and imaging findings, laboratory and follow-up data of the patients we selected. Univariate and multivariate analysis will be performed within the group and between groups according to the subgroups. In this research prognosis of the patients will be assessed by using the modified Rankin scale (mRS) scores. Single PRES related factors will be tested with Chi-square test. Intergroup comparison will be performed by using student t-test for normally distributed variables and Mann-Whitney U test for variables not normally distributed. In binary variable analysis, logistic regression analysis will be used to analysis factors related PRES. In polytomous variable analysis, multivariate logistic regression analysis will be performed to analyze factors related to PRES.
5. Quality Control

The patients will be identified strictly in accordance with the established inclusion and exclusion criteria. The imaging findings of the patients will be assessed by 2 neuroimaging physicians and the consensus will be reached through consultation when there were differences. The members of the group who assess the prognosis of PRES should be unified training.

Timeline of Events

Patients screening and data acquisition phase. The project is scheduled to initiate in April 2016 and complete all data collection in July 2016.

Data analysis phase. We plan to complete the data analysis in about 4 months after the data acquisition is completed.

Paper publishing stage. We plan to complete the paper publishing in about 6 months after the data analysis is finished.

Data opening phase. We plan to open the data to the society in stages after paper publishing is completed.

Eligibility Criteria:
Inclusion Criteria:

1. Patients who meet the criteria for PRES diagnosis:(1)typical symptoms and signs consistent with PRES, such as headache, seizures, mental status changes, visual disturbances or focal neurological deficits;(2)patients with typical or atypical imaging manifestations of PRES;(3)patients who have known risk factors of PRES.
2. Patients with definite prognosis will be included.
3. Patients with complete inpatient medical records will be included.

Exclusion Criteria:

1. Patients with edema secondary to ischemia, hemorrhage, infection, inflammation, or space occupying lesions will be excluded.
2. Patients with absent or non-diagnostic MRI will be excluded.