Ischemic Strokes Threaten Patients With Reversible Cerebral Vasoconstriction Syndrome
Overview
Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) can lead to ischemic stroke and intracranial hemorrhage. This study aimed to evaluate the incidence of these outcomes. Methods included a PROSPERO-registered systematic review and meta-analysis (CRD42022355704), utilizing PubMed up to November 7, 2022. Criteria for inclusion were: (1) original research articles, (2) adult participants (≥18 years), (3) studies including patients with PRES and/or RCVS, (4) publications in English, and (5) available outcome data. Outcomes assessed were the frequency of (1) ischemic stroke and (2) intracranial hemorrhage, further categorized into subarachnoid hemorrhage (SAH) and intraparenchymal hemorrhage (IPH). The Cochrane Risk of Bias tool was employed for quality assessment.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a neurovascular condition marked by several key angiographic and clinical features: (1) diffuse, reversible, segmental, and multifocal vasoconstriction of cerebral arteries, (2) severe, sudden-onset headaches known as “thunderclap headaches,” (3) the possible presence of focal neurological deficits or seizures, and (4) an absence of inflammatory causes, such as vasculitis. RCVS can affect individuals aged 10 to 76 years, with a peak incidence around 42 years, and a higher prevalence in women. Diagnosis is based on angiographic evidence of segmental arterial narrowing and dilation. The pathophysiology involves a transient disturbance in cerebral arterial tone regulation. RCVS may occur spontaneously or be triggered by factors such as vasoactive substances or postpartum status. Most patients (over 90%) experience a self-limiting course, resolving within a few days to three months. However, a significant number may develop intracranial hemorrhage or ischemic stroke. Neuroimaging, including MRI, can show white matter hyperintensities on FLAIR sequences, indicating cortical and subcortical damage. Perfusion-weighted imaging may reveal hypoperfusion indicative of cerebral infarction. Due to RCVS’s dynamic nature, repeated angiograms are often necessary. The prevention of lesions and the utility of monitoring vasoconstriction remain unclear.
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Posterior reversible encephalopathy syndrome (PRES) is characterized by a range of clinical symptoms, which may include headaches, altered mental status (from confusion to coma), visual disturbances (ranging from vision loss to visual hallucinations), and seizures, along with characteristic neuroimaging findings. Neuroimaging typically reveals vasogenic edema in a bilateral pattern in the parieto-occipital regions, though it can also appear in the frontal or temporal lobes, brainstem, basal ganglia, or cerebellum. FLAIR sequences often detect the characteristic lesion pattern of PRES. The differential diagnosis includes various conditions such as infections, autoimmune disorders, or malignancies. Triggers like pre-eclampsia, eclampsia, or severe hypertension are frequently identified. The pathophysiology involves disruptions in cerebrovascular autoregulation and blood-brain barrier integrity, with the posterior brain regions being particularly vulnerable due to reduced sympathetic innervation. Most cases resolve within a few days to weeks, but there is a risk of developing intracranial hemorrhage or ischemic stroke. Diffusion-weighted imaging (DWI) can reveal ischemic infarctions.
PRES and RCVS share overlapping risk factors and clinical features, suggesting a potential common pathophysiological pathway. Misdiagnosis can occur due to their similar clinical and radiological features. PRES can complicate RCVS in 7% to 38% of cases and is associated with an increased risk of ischemic stroke in RCVS patients. This study aims to systematically review and analyze the frequency of ischemic stroke and intracranial hemorrhage, including subarachnoid and intraparenchymal hemorrhage, in patients with RCVS and PRES.
Methods
We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review was pre-registered with PROSPERO (CRD42022355704).
Inclusion and Exclusion Criteria
The inclusion criteria were: (1) original scientific papers, (2) studies involving adult patients (≥18 years), (3) enrollment of patients with PRES and/or RCVS, (4) articles in English, and (5) data on the incidence of ischemic stroke and/or intracranial hemorrhage. Exclusion criteria included: (1) absence of imaging (CT/MRI) verification for ischemic stroke or intracranial hemorrhage, and (2) case reports with three or fewer patients or reviews.
Data Source and Search Strategy
The literature search was conducted using PubMed with the following strategy: ((Posterior reversible encephalopathy syndrome) OR (PRES) OR (Reversible cerebral vasoconstriction syndrome) OR (RCVS)) AND ((Imaging) OR (CT) OR (MRI)) AND (journalarticle[Filter]) NOT (review) NOT (case report)). The search was initially performed by one author (J.K.) from August 26 to August 31, 2022, and independently repeated by a second author (D.S.) on November 7, 2022. Studies meeting the inclusion criteria were selected. Titles were first screened, followed by detailed abstract review, and finally, relevant articles were reviewed in full text. Additionally, references from these articles were examined to identify further relevant literature on these conditions.
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Analysis
Data were entered into MedCalc (Version 20.215) by J.K. for analysis. We employed a proportional meta-analysis to determine the incidence rates reported in the included studies, using a random effects model to account for variability . The extracted proportions are illustrated in the forest plots.
Risk of Bias:
The risk of bias for each study was evaluated using the Cochrane Risk of Bias tool designed for cohort studies. This assessment was independently conducted by two reviewers (J.K. and D.S.), with any disagreements resolved by a third reviewer (P.B.).
Outcomes:
The analysis recorded the frequency of (a) ischemic stroke and (b) intracranial hemorrhage, including overall intracranial hemorrhages as well as subarachnoid hemorrhage (SAH) and intraparenchymal hemorrhage (IPH) separately. Data were extracted from each study, presenting results as the frequency within the study population (nevents/Ntotal population). The results were reported separately for selective populations and non-selective studies, which included all patients with RCVS or PRES. Data for each outcome were pooled and presented distinctly for PRES and RCVS.
Funding:
This study did not receive specific funding.
Ethics:
As this was a systematic review and meta-analysis of existing literature without original data collection, ethics approval was not required.
Data Sharing:
All data utilized in this study are publicly available and can be accessed from the original articles cited in the reference list.
Results
Our searches yielded 848 and 867 results, respectively. After screening titles and abstracts, 760 and 777 articles were excluded as unsuitable for the review. For the remaining 90 articles, full texts were reviewed, leading to the exclusion of 10 studies focused solely on pediatric patients, 13 due to missing imaging details regarding hemorrhage or ischemia, 7 as case reports, 7 for duplicate publications, and 5 due to being non-English. Ultimately, 48 articles were included: 34 on PRES and 14 on RCVS.
Studies Included: General Findings and Imaging Used:
Out of the 48 studies analyzed, 41 (85.4%) utilized a retrospective design. More than a third of these studies were conducted in the past decade (34 of 48, 70.8%). All studies confirmed diagnoses using MRI, and a majority (42.6%) also used CT. Study sizes ranged from 4 to 2020 subjects, with more than half (28 studies, 58.3%) investigating samples of 50 or fewer subjects, while only 7 studies (14.6%) included 100 or more subjects. Ischemic stroke was investigated in 29 studies (60.4%), and intracranial hemorrhage in almost all studies (45 of 48, 93.8%). Specifically, SAH was assessed in 32 (66.7%) and IPH in 31 (64.6%) studies.
The risk of bias was moderate in most studies. While 41 (85.4%) studies drew exposed and non-exposed cohorts from the same population, groups were not matched for outcome-associated variables, and no statistical adjustments were noted. Exposure assessment and follow-up were adequately conducted in all studies, but outcome assessment was rated negatively in 34 (70.8%) studies.
Frequency of Ischemic Stroke and Intracranial Hemorrhage in Patients with RCVS:
Fourteen studies on RCVS were included, 11 of which reported on unselected RCVS patients, and 3 focused on specific complications such as coronavirus disease and intracranial hemorrhage. The 11 studies included 2746 patients, with 487 (15.9%) experiencing ischemic stroke and 181 of 705 (22.1%) having an intracranial hemorrhage. Specifically, 813 (20.3%) patients suffered from SAH and 274 of 2725 (6.7%) from IPH. The frequency of ischemic stroke ranged from 1.5% to 55.6%, and intracranial hemorrhage from 3.1% to 63.3%.
Frequency of Ischemic Stroke and Intracranial Hemorrhage in Patients with PRES:
Thirty-four studies on PRES were included, with 28 investigating unselected patients. Six studies focused on specific conditions such as calcineurin inhibitor use, pre-existing hypertension, liver transplants, bleeding, pregnancy, and coronavirus disease. In 1385 non-selective PRES patients, 232 (16.1%) experienced intracranial hemorrhage. Specifically, 49 (7%) of 680 patients had SAH, and 81 (9.7%) of 628 had IPH. Additionally, 59 (11.2%) of 552 patients suffered from ischemic stroke. The frequency of ischemic stroke varied from 3.3% to 28.6%, and intracranial hemorrhage from 3.8% to 37.4%.
Frequency of Ischemic Stroke and Intracranial Hemorrhage in PRES Associated with RCVS:
Few studies reported on ischemic stroke and hemorrhage in PRES patients with RCVS. Approximately half to two-thirds of patients with ischemic stroke had concomitant PRES. One study noted that PRES was more frequently observed in patients with hemorrhage.
Conclusion
Intracranial hemorrhage and ischemic stroke frequently occur in both PRES and RCVS, with complication rates varying based on the study context and population. This review offers a comprehensive overview of the prevalence of these associated complications, providing valuable insight into their frequency.
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