Posterior reversible encephalopathy syndrome (PRES): A narrative review of pathophysiology, clinical insights, and advances in management

Abstract

Background

Posterior reversible encephalopathy syndrome (PRES) is an acute neurological condition characterized by a spectrum of clinical and radiological features. It is most often associated with severe hypertension, renal dysfunction, autoimmune disease, sepsis, and exposure to cytotoxic or immunosuppressive agents. Although increasingly recognized in emergency and critical care practice, its pathophysiology remains incompletely understood and diagnostic challenges frequently delay treatment. Reported mortality ranges from 10 to 19%, and up to 40–44% of patients experience persistent neurological deficits or residual radiologic lesions, highlighting its clinical relevance.

Main body

The clinical manifestations of PRES range from seizures, headache, and visual disturbance to confusion and reduced consciousness. Seizures occur in as many as 60–90% of cases, particularly in younger populations. Magnetic resonance imaging is the diagnostic modality of choice, revealing characteristic vasogenic edema, most prominently in the posterior cerebral regions, although atypical patterns are frequently observed. Misdiagnosis remains common due to overlap with stroke, encephalitis, and other acute neurological syndromes. Management is primarily supportive and directed at controlling the underlying precipitant. Blood pressure stabilization, withdrawal or adjustment of offending agents, and short-term antiseizure therapy form the cornerstone of treatment. Although most patients show clinical and radiologic recovery within weeks, complications such as intracranial hemorrhage, infarction, or recurrent PRES may occur. Special populations including pediatric, obstetric, and transplant patients require tailored evaluation and management strategies due to distinct risk profiles. Emerging research highlights endothelial dysfunction, blood–brain barrier disruption, and immune-mediated injury as central mechanisms. Investigations into biomarkers, advanced neuroimaging techniques, and targeted therapeutic approaches are opening opportunities for earlier detection and improved outcomes.

Conclusion

PRES is reversible in many cases yet remains a potentially life-threatening syndrome with substantial morbidity and mortality. Early recognition, systematic neuroimaging, and rapid correction of precipitating factors are essential to optimizing outcomes. Future advances will depend on deeper mechanistic insight, validation of prognostic biomarkers, and development of standardized, evidence-based management protocols to guide care across diverse patient populations.

Introduction

Posterior Reversible Encephalopathy Syndrome (PRES) is a neurologic condition characterized by reversible vasogenic edema, typically involving the subcortical white matter of the posterior cerebral hemispheres. Clinically, it most often presents with seizures, headache, visual disturbances, nausea, and altered mental status, with symptoms evolving over hours to days [1, 2]. PRES affects patients across the lifespan but is more frequently reported in women and in individuals with autoimmune disease, renal dysfunction, malignancy, or exposure to cytotoxic and immunosuppressive agents. Increasing availability of magnetic resonance imaging (MRI) and improved awareness have led to more frequent recognition of PRES; however, contemporary cohorts still report mortality rates up to 19% and long-term functional impairment in over 40% of cases, highlighting its substantial clinical burden [1, 2].

The syndrome is linked to a broad range of precipitating factors, including severe hypertension (HTN), renal failure, autoimmune diseases, sepsis, and the use of antineoplastic and immunosuppressive medications [1, 2]. Preeclampsia and eclampsia, end-stage renal disease (ESRD), and intensive oncologic or transplant regimens are particularly prominent contexts in which PRES arises. Despite a relatively well-described clinical and imaging profile, its precise pathophysiology spanning blood–brain barrier (BBB) disruption, endothelial injury, and dysregulated cerebral autoregulation, remains incompletely understood, and the spectrum of atypical radiologic patterns continues to expand [3, 4].

Although several clinical series and narrative reviews have improved recognition of PRES, existing literature is fragmented across general, pediatric, obstetric, and transplant populations, and standardized, evidence-based management protocols are lacking [4]. Variability in diagnostic thresholds, imaging interpretation, and treatment strategies contributes to under-diagnosis, delayed intervention, and heterogeneous outcomes. The objective of this review is to synthesize recent evidence from the last decade on the pathophysiology, clinical manifestations, imaging features, and management of PRES, with attention to high-risk and special populations. By clarifying current knowledge and highlighting areas of uncertainty, this review aims to support earlier recognition, more consistent diagnostic approaches, and rational, population-specific management strategies.

Methods

This review focused on literature published within the last decade (2014–2024). A structured search was conducted across PubMed, EMBASE, and the Cochrane Library using terms including “posterior reversible encephalopathy syndrome,” “PRES pathophysiology,” “vasogenic edema,” and “PRES management”. Peer-reviewed cohorts, case series, clinical trials, and guidelines addressing epidemiology, imaging, pathophysiology, or treatment were considered. Non-English publications, preclinical studies, and articles unrelated to PRES were excluded.

Because this work was designed as a narrative review, study selection and interpretation were qualitative and descriptive rather than statistical or meta-analytic. Titles and abstracts were screened for relevance, with full texts reviewed when uncertainty remained. Reference lists of key articles were also examined to identify additional pertinent studies. The final body of literature was synthesized to highlight recurring themes, areas of consensus, and gaps requiring further research.

Epidemiology

Since its initial description in 1996, recognition of PRES has increased substantially, largely paralleling wider MRI availability and heightened clinical awareness [5]. PRES occurs across all age groups but is reported more frequently among women and in patients with conditions such as renal disease, autoimmune disorders, and malignancy [6, 7]. Although the true population incidence remains uncertain, cohort data offer insight into high-risk settings: PRES occurs in approximately 0.04% of children overall and 0.4% of pediatric intensive care admissions, while about 0.69% of patients with systemic lupus erythematosus (SLE) develop the syndrome [3, 8, 9].

In a large U.S. inpatient cohort, 39,460 adult hospitalizations for PRES between 2016 and 2019 represented roughly 0.03% of all admissions. HTN was present in nearly 84% of cases, and ischemic stroke occurred in about 10%, reflecting the frequent coexistence of cerebrovascular comorbidity [10].

Diagnostic capacity influences reported rates. In many low- and middle-income countries, limited access to MRI and lower familiarity with PRES contribute to underrecognition and misdiagnosis, whereas high-income settings benefit from earlier detection and more complete case capture [11].

Overall, available data suggest that PRES remains uncommon but is increasingly identified, particularly in medically complex populations, with risk closely tied to HTN, renal dysfunction, autoimmune disease, and exposure to cytotoxic or immunosuppressive therapy.

Pathophysiology

PRES is characterized primarily by vasogenic edema, which most commonly involves the posterior cerebral hemispheres [12, 13]. Central to its development is dysfunction of the BBB, a selective interface that maintains cerebral homeostasis. When the BBB becomes compromised, plasma components leak into the extracellular space, producing cerebral edema. This disruption is strongly linked to endothelial injury and impaired autoregulation of cerebral blood flow [14].

HTN-related autoregulatory failure

Under normal conditions, cerebral autoregulation maintains relatively constant blood flow despite changes in systemic blood pressure. During acute, severe HTN, these mechanisms can be overwhelmed. Hyperperfusion increases capillary hydrostatic pressure, mechanically stretching and disrupting the BBB and promoting vasogenic edema [14]. The posterior circulation is particularly vulnerable because of its relatively sparse sympathetic innervation, which may explain the characteristic parieto-occipital involvement seen in PRES.

Endothelial injury and BBB disruption

Endothelial cells play a critical role in maintaining BBB integrity. In PRES, endothelial dysfunction may result from cytotoxic medications, autoimmune activation, infection, or systemic inflammation [15, 16]. Calcineurin inhibitors such as cyclosporine and tacrolimus are notable examples; they exert direct toxic effects on the vascular endothelium and promote vasoconstriction. In immunosuppressed or septic patients, inflammatory mediators further increase permeability, amplifying vasogenic edema [17].

Special physiologic states

Pregnancy introduces unique hemodynamic and endothelial stresses. Disorders such as preeclampsia and eclampsia combine severe HTN with diffuse endothelial dysfunction, creating a biologic environment highly conducive to PRES development [2]. Similar mechanisms likely contribute in renal failure and autoimmune disease, where vascular injury and impaired autoregulation coexist.

Taken together, PRES appears to arise from the convergence of two major mechanisms, hypertensive autoregulatory failure and endothelial injury, acting on a vulnerable posterior circulation. Their relative contribution varies among patients, which helps explain the syndrome’s heterogeneous clinical and imaging features.

Clinical features of PRES

The acute neurological manifestations of PRES vary widely. The most frequently reported symptoms include headache, seizures, visual disturbances, and altered mental status. Headache is particularly common in pediatric patients, especially in the setting of HTN or nephrotic syndrome [11]. Differences between pediatric and adult presentations are summarized in Fig. 1.

Fig. 1.

Key differences in PRES clinical manifestations and imaging features between adults and children. This includes seizures, visual disturbances, altered consciousness, imaging patterns, and HTN

Seizures occur in up to 90% of patients, more often in younger individuals, and are typically generalized tonic–clonic, although focal seizures and status epilepticus may also occur [18]. Visual symptoms range from blurred vision to transient cortical blindness and usually improve with treatment, although persistent deficits may occur in severe cases [19]. Focal neurological deficits such as hemiparesis, dysphasia, or ataxia are less frequent and are often associated with more extensive or anterior involvement on imaging [19].

Overall, the broad symptom spectrum particularly in children requires a high index of suspicion to avoid delayed diagnosis. Figure 2 highlights key early warning signs in pediatric presentations.

Fig. 2.

Early warning signs of PRES in children. This includes seizures, visual disturbances, altered consciousness, headache, and HTN

Imaging findings in pediatric PRES

MRI

Neuroimaging is essential for diagnosis. MRI is most sensitive for detecting the characteristic vasogenic edema, typically appearing as hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, a technique that suppresses cerebrospinal fluid (CSF) signal to better highlight edema in the brain parenchyma. Although often parieto-occipital, pediatric cases more commonly show atypical involvement of the frontal lobes, basal ganglia, or brainstem, complicating recognition [19, 20]. Diffusion-weighted imaging (DWI), which evaluates the movement of water molecules in tissue, helps distinguish vasogenic from cytotoxic edema; restricted diffusion suggests superimposed ischemic injury in severe cases [21].

CT

Computed tomography (CT) may be used when MRI is unavailable or in emergent settings. CT can reveal hypodense areas consistent with edema but may underestimate the extent of disease and cannot reliably differentiate vasogenic from cytotoxic changes. Studies emphasize that CT alone may lead to underdiagnosis, whereas MRI better defines lesion distribution and severity [11, 20–22]. Nonetheless, CT remains valuable as an initial tool when combined with clinical assessment.

In summary, MRI provides the most detailed evaluation of PRES, while CT serves as a practical preliminary modality in resource-limited or urgent contexts.

Differential diagnosis of PRES

PRES must be distinguished from other acute neurological disorders such as stroke, vasculitis, and encephalitis. Neuroimaging, clinical context, and laboratory evaluations are critical for accurate differentiation, especially in pediatric populations where atypical presentations are more prevalent.

PRES and ischemic stroke share symptoms including acute headache, visual disturbances, and altered mental status, but key imaging features help differentiate the two. On T2-weighted and FLAIR MRI sequences, PRES usually shows vasogenic edema in the parieto-occipital white matter, typically without restricted diffusion on DWI [18, 20]. In contrast, ischemic stroke shows cytotoxic edema with restricted diffusion on DWI [23]. In pediatric patients, PRES may involve atypical regions such as the brainstem and basal ganglia, making distinction from stroke more challenging [20].

Magnetic resonance angiography (MRA) is primarily used to evaluate intracranial vessels. In PRES, MRA is often normal or shows only mild reversible vasoconstriction, and its main role is to help exclude alternative diagnoses such as vasculitis or large-vessel stenosis [19]. In some pediatric patients, particularly those undergoing hematopoietic stem cell transplantation, atypical PRES lesions may resemble the patchy distribution of vasculitic changes. In such cases, careful assessment of clinical and laboratory markers, including autoantibodies and inflammatory cytokines, is essential [19].

PRES also overlaps clinically with infectious or autoimmune encephalitis, sharing features such as seizures and altered mental status. Encephalitis more often involves the hippocampus and gray matter and may show hemorrhagic lesions or inflammatory changes, whereas PRES classically demonstrates reversible white matter–predominant edema with relative cortical sparing [20, 22]. When imaging findings in pediatric PRES are equivocal, additional laboratory testing for infectious or autoimmune markers is recommended [18].

Advanced neuroimaging remains central to differentiating PRES from these mimics. Symmetrical vasogenic edema in the parieto-occipital regions on MRI is a key marker of PRES, and adjunct sequences such as DWI and MRA help exclude ischemic or vasculitic processes and better characterize the nature of the lesions [18, 19]. For a comprehensive overview of the diagnostic criteria for pediatric PRES, refer to Table 1. Additionally, Table 2 summarizes the differential diagnoses of PRES, highlighting the distinguishing clinical and radiological characteristics of each condition.

Table 1.

Diagnostic criteria for pediatric PRES

Category	Criteria
Clinical Presentation	Acute neurological symptoms including headache, seizures (generalized or focal), visual disturbances (blurred vision, cortical blindness), and altered mental status.
	HTN frequently observed, often above the 99th percentile for age, sex, and height.
	Neurological deficits like hemiparesis or ataxia, though less common, may occur in atypical cases.
Imaging Findings	Symmetrical vasogenic edema predominantly in the parieto-occipital white matter, as seen on T2-weighted and FLAIR MRI sequences.
	Atypical regions in pediatric cases include the frontal lobes, basal ganglia, brainstem, and cerebellum.
	Reversible nature of lesions, sparing of cortical gray matter, and lack of infarction; DWI shows no restricted diffusion, distinguishing PRES from stroke.
	CT imaging may show hypodensities in posterior regions, but MRI remains the gold standard for diagnosis.
Differentiation Criteria	Exclusion of stroke: PRES lesions show vasogenic (not cytotoxic) edema, with normal diffusion patterns on DWI.
	Exclusion of vasculitis: MRI lacks vessel wall abnormalities; inflammatory markers (e.g., CRP, ESR) are not elevated as in vasculitis.
	Exclusion of encephalitis: PRES spares the cortical gray matter; CSF analysis typically negative for infection or inflammation.
	Exclusion of metabolic encephalopathy: PRES imaging findings are not diffuse and systemic metabolic abnormalities are absent.
Additional Diagnostics	MRI as the primary diagnostic tool; CT is secondary and less sensitive but may show early hypodense lesions in affected regions.
	Laboratory evaluation for potential triggers: HTN, renal dysfunction, sepsis, cytotoxic agents, and organ transplantation.

Table 2.

Summarizing differential diagnoses of PRES based on clinical and imaging features

Condition	Clinical Features	Key Imaging Findings
Stroke	Sudden-onset focal deficits, hemiparesis, or aphasia; may involve visual disturbances	Cytotoxic edema; restricted diffusion on DWI; infarct patterns; localized ischemic lesions​​
Vasculitis	Multi-system involvement; persistent neurological symptoms; elevated inflammatory markers	Patchy or diffuse lesions; vessel wall abnormalities on MRA; inflammatory markers elevated​​
Encephalitis	Fever, seizures, confusion, and altered mental status; often progresses over hours to days	Gray matter involvement; hippocampal lesions; possible hemorrhagic changes​​
Metabolic Encephalopathy	Non-focal deficits, confusion, and altered consciousness; systemic metabolic imbalance	Diffuse brain edema; sparing of localized regions; systemic lab abnormalities​​
Toxic or Drug-Induced Encephalopathy	Altered consciousness, seizures, and potential multiorgan involvement	Diffuse edema on imaging; no restricted diffusion; bilateral patterns involving white matter​​

Etiology and risk factors of PRES

Reversible subcortical vasogenic edema is the hallmark clinical and radiological feature of PRES, and accurate diagnosis and treatment depend on an understanding of its underlying etiologies [9]. The syndrome arises from the convergence of systemic disorders and direct injuries to the central nervous system that disrupt cerebral autoregulation and compromise the BBB.

Primary causes, such as hypertensive encephalopathy, typically involve sudden elevations in blood pressure that exceed autoregulatory capacity, resulting in vasogenic edema and BBB disruption [24]. Secondary causes include systemic disorders that indirectly compromise cerebrovascular integrity. Endothelial dysfunction is central in eclampsia and preeclampsia, which are prevalent in obstetric populations. Autoimmune diseases such as SLE and vasculitis promote systemic inflammation and vascular injury, increasing the risk of PRES. Transplant recipients receiving immunosuppressive therapy, particularly calcineurin inhibitors such as cyclosporine and tacrolimus, are at heightened risk due to drug-induced endothelial damage and vasoconstriction. Infectious etiologies, including sepsis, similarly contribute through inflammatory endothelial injury [9, 25].

Risk profiles differ across populations. In pediatric patients, major risk factors include nephrotic syndrome, congenital cardiac disorders, and acute lymphoblastic leukemia (ALL). Chemotherapy-related endothelial injury, particularly from agents such as methotrexate, is a common trigger in this group, and HTN, either primary or secondary to renal disease, remains an important contributor [26]. In obstetric populations, hypertensive disorders of pregnancy, including preeclampsia and eclampsia, dominate the etiological landscape, underpinned by hypercoagulability and systemic endothelial dysfunction. In transplant patients, calcineurin inhibitors are strongly associated with PRES due to their hypertensive and vasoconstrictive effects [24, 27].

Across these demographic groups, several triggers are shared. HTN is the most consistent and universal risk factor, with rapid elevations in blood pressure overwhelming cerebral autoregulation. Endothelial dysfunction represents a common pathophysiological pathway linking conditions such as eclampsia, autoimmune disease, sepsis, and chemotherapy-induced vascular damage. Acute or chronic renal dysfunction further predisposes to PRES by exposing the vasculature to uremic toxins and fluid–electrolyte disturbances, while immunosuppressive regimens emphasize the contribution of pharmacologic vascular injury [27, 28].

PRES is therefore a complex condition shaped by a spectrum of etiologies whose relative contributions vary by age and clinical context. HTN and endothelial dysfunction remain central mechanisms, but demographic and comorbid factors modulate presentation and prognosis. A thorough understanding of these variations is essential for prompt recognition, risk stratification, and effective management [29].

Management

Acute management of PRES

Current treatment strategies for PRES are largely based on expert consensus, as randomized clinical trials are lacking [1, 30, 31]. Management focuses on rapid identification and correction of the precipitating factor. Core priorities include blood pressure stabilization, seizure control, treatment of infection (for example, herpes simplex virus type 1 or 2, which can cause herpes simplex encephalitis), withdrawal or substitution of offending medications, correction of metabolic disturbances, renal replacement therapy when indicated, and delivery in obstetric cases [1–3, 9, 32].

Blood pressure control remains central. In patients with acute HTN, gradual reduction is recommended, targeting a mean arterial pressure between 105 and 125 mmHg while avoiding rapid hypotension that may precipitate ischemia [1, 3]. In malignant HTN, controlled reduction of diastolic blood pressure to 100–105 mmHg over several hours is advised [2, 15]. Intravenous titratable agents are preferred. Detailed drug choices, mechanisms, and precautions are summarized in Table 3.

Table 3.

Acute management of PRES

Drug	Mechanism of action	Dose
First-line antihypertensive agents
Labetalol	Alpha-1 blocker/non-selective beta blocker	Initial: 20 mg slow injection over 3 min. Titrate: additional 40 mg at 10 min intervals until achieving the desired BP reduction or until 300 mg has been injected
Nicardipine	Dihydropyridine calcium channel blocker	Initial: 5 mg/hour. Titrate: Increase by 2.5 mg/hour every 5–15 min until achieving the desired BP reduction
Nimodipine	Calcium channel blocker	Initial: 0.5–1 mg/hour (15 mcg/kg/hour). Titrate: increase to 2 mg/hour (30 mg/kg/hour)
Second-line antihypertensive agents
Enalapril	ACE inhibitor	Dose: 1.25 mg intravenously four times per day. Use for less than 48 h, avoid in pregnancy
Hydralazine	Vasodilator by direct relaxation of vascular smooth muscle	Dose: 1.7–3.5 mg/kg divided into four to six doses
Sodium nitroprusside	Direct nitric oxide donor vasodilator	Initial dose: 0.25–0.5 mcg/kg/min. Titrate: increase by 0.2 mcg/kg/min until desired clinical response. Maximum dose: 6 mcg/kg/min
Antiepileptic medications
Sodium valproate	GABA enhancer/sodium channel blocker	Initial loading dose: 30–40 mg/kg (maximum dose of 3500 mg). Continuing dose: 400–1000 mg two times per day (maximum dose 2000 mg two times per day)
Phenytoin	Voltage-gated sodium channel blocker	Initial loading dose: 15–20 mg/kg (maximum dose of 1500 mg). Continuing dose: 4–8 mg/kg initially titrating to plasma concentration of 15–20 mg/L Initial infusion rate cannot exceed 50 mg/min.
Levetiracetam	SV2A synaptic vesicle modulator	Initial loading dose: 40–60 mg/kg (maximum dose 6000 mg). Continuing dose: 500–1000 mg two times per day (maximum dose 2000 mg two times per day)

Seizures are frequent in the acute phase, although there are no specific guidelines for non–status epileptic PRES [1, 3]. Status epilepticus is treated using standard protocols with continuous EEG monitoring when available. Antiepileptic selection should consider renal function and adverse-effect profile, and many patients can later be tapered off therapy once PRES resolves [1, 3, 30].

Up to 70% of patients require ICU-level monitoring, with 35–40% needing temporary ventilatory support, particularly in cases of encephalopathy, refractory seizures, or hemodynamic instability [1–3].

Management of associated comorbidities

Patients with cancer, autoimmune disease, and transplant regimens present unique challenges because therapies that treat the underlying disease may also precipitate PRES. Whenever possible, the offending drug should be reduced or replaced, balancing neurologic risk with disease control [1–3, 32]. Plasma exchange may benefit selected patients by reducing inflammatory mediators, although evidence remains limited [32].

In severe renal dysfunction, early dialysis is often necessary. Fenoldopam mesylate may be useful in this population because of its renal vasodilatory properties, but data remain largely observational [3].

Biologic agents targeting inflammatory cascades (e.g., anti-C5, anti-TNF-α, anti-IL-6) are promising in experimental settings but lack clinical validation in PRES [32].

Management of PRES in pregnancy

Management parallels established protocols for pre-eclampsia, eclampsia, and HELLP syndrome. Stabilization includes antihypertensive therapy (such as labetalol or nifedipine) and management of seizures. Standard antiepileptic drugs (for example, phenytoin or levetiracetam) may be used when seizures occur, while magnesium sulfate is the preferred agent for seizure prophylaxis and treatment in eclampsia and also contributes to improved endothelial stability [3, 30]. ACE inhibitors are avoided, and escalation to delivery remains the definitive intervention when maternal or fetal risk persists [1, 2].

Choice of anesthesia depends on coagulopathy and neurologic status, with postpartum ICU monitoring recommended in complicated cases. Steroid therapy may occasionally worsen PRES [31].

Management of malignant PRES

Malignant PRES, characterized by coma or deterioration despite medical therapy with radiographic edema or hemorrhage, requires aggressive neurocritical care. Measures include mechanical ventilation, intracranial pressure control, treatment of coagulopathy, and surgical decompression when indicated. Although severe, favorable functional outcomes have been reported with timely intervention [1, 3].

Long-term follow-up of PRES

Serial neuroimaging helps document resolution and detect complications [30]. Most patients do not require prolonged antiepileptic therapy, as long-term epilepsy is uncommon (1–3.9%) [1, 3]. Ongoing management should reassess immunosuppressive or chemotherapeutic regimens and maintain strict blood pressure control to prevent recurrence.

Outcomes and prognosis

PRES is a neurotoxic condition in which prognosis is closely tied to the underlying cause [3]. Although many patients experience clinical and radiologic reversibility, permanent tissue damage may occur in a subset of cases [30]. Discrepancies between apparent radiologic recovery and persistent neurological deficits have also been reported, particularly in patients with significant comorbid illnesses [15, 30]. Gewirtz et al. reported complete recovery in 75–90% of patients within one week, whereas 10–20% developed residual neurological sequelae [31]. Figure 3 shows the long-term outcomes observed in pediatric PRES.

Fig. 3.

Long-term outcomes of pediatric PRES

Several clinical and radiologic factors have been associated with poor prognosis. Clinically, severe encephalopathy, hyperglycemia, malignancy, delayed correction of the underlying trigger, multiple comorbidities, elevated C-reactive protein (CRP), coagulopathy, and abnormalities such as low CSF glucose or elevated creatinine, uric acid, and LDH levels are important predictors [3]. Radiologically, atypical MRI findings such as corpus callosum involvement, progressive cerebral edema, intracerebral or subarachnoid hemorrhage, and restricted diffusion correlate with worse outcomes [1]. High DWI signal intensity with low or normal apparent diffusion coefficient (ADC) values suggests evolving infarction and can help anticipate tissue injury [15, 30]. Although debate remains regarding contrast enhancement, hemorrhagic complications and cytotoxic edema consistently portend poorer outcomes. Brainstem edema or hemorrhage is particularly ominous [15]. The impact of hemorrhage appears dose-dependent: small bleeds may be clinically silent, whereas multiple or extensive hemorrhages significantly worsen prognosis [3]. Interestingly, HTN itself is not independently associated with poor prognosis, and patients with pre-eclampsia/eclampsia or seizure-dominant presentations often recover well [3].

Taken together, prognosis is strongly influenced by factors that are both intrinsic and modifiable. Early recognition, prompt control of blood pressure, rapid withdrawal of offending medications, and aggressive management of seizures and renal/metabolic disturbances appear to limit irreversible injury. Conversely, delayed treatment, uncontrolled systemic disease, and complications such as hemorrhage or infarction shift outcomes toward long-term disability.

Recurrence rates and predictors

Recurrence highlights the importance of long-term vigilance in patients who survive the acute episode. Recurrent PRES occurs in approximately 4% of cases and is most often associated with persistent or recurrent precipitating factors, including sickle-cell crises, autoimmune disease flares, hypertensive crises, renal failure, mitochondrial disorders, and multi-organ failure [1]. Infections and systemic inflammation may act as recurrent triggers by re-inducing endothelial injury [30].

While the overall prognosis of PRES is generally favorable, outcome variability remains substantial. Mortality has been reported at approximately 19%, with up to 44% of patients demonstrating functional impairment and 40% retaining residual radiologic lesions at follow-up [1, 3]. Identifying patients at highest risk is therefore essential. ESRD, malignancy, and atrial fibrillation have emerged as strong predictors of mortality. Patients with ESRD experience up to a seven-fold higher mortality risk, likely due to HTN, medication burden, and fluid–electrolyte instability. Individuals with malignancy face additional risk from thrombocytopenia, renal dysfunction, and treatment-induced HTN, while atrial fibrillation confers a four-fold increase and often necessitates ICU admission [3, 6]. Although infections and sepsis are frequently associated with poorer outcomes, some analyses have not demonstrated statistical significance [6]. Figure 4 summarizes factors implicated in PRES recurrence and outcome variability.

Fig. 4.

Factors influencing recurrent PRES

Special populations

The clinical features of PRES in children are often non-specific, overlapping with symptoms seen in other neurological disorders. Typically, symptom onset is rapid, peaking within 12–48 h. Seizures are the most common presentation in pediatric cases, with generalized tonic–clonic seizures occurring in 60–75% of patients [33]. Multiple seizures are common, and status epilepticus may occur. Compared with adults, pediatric PRES tends to present earlier and more frequently with seizures. Altered consciousness is also frequent, though usually less prominent than in adults, where encephalopathy predominates [18].

HTN is a hallmark of PRES, present in 70–80% of pediatric cases, and contributes significantly to its pathophysiology. In children, HTN commonly reflects systemic disorders such as renal parenchymal disease, adrenal pathology, or endocrine abnormalities. Importantly, it may be detected late in the course, highlighting the need for careful blood pressure monitoring in children with neurological symptoms [34, 35].

Managing pediatric PRES centers on addressing underlying risk factors such as HTN, renal dysfunction, or immunosuppressive therapies. Early intervention reduces morbidity, yet permanent neurological deficits may occur in approximately 12% of cases, highlighting the need for vigilant monitoring and supportive care [18, 33]. Obstetric PRES is most frequently associated with eclampsia and postpartum HTN; management focuses on seizure control, blood pressure stabilization, and treatment of the precipitating condition. Transplant-related PRES is closely associated with calcineurin inhibitors such as cyclosporine and tacrolimus, which impair endothelial function and promote vasogenic edema. Management emphasizes dose adjustment or discontinuation of the offending agent and concurrent control of HTN and renal impairment [18, 33, 36].

Neuroimaging remains central to diagnosis, with MRI offering the highest sensitivity and specificity. The hallmark radiologic pattern consists of bilaterally symmetric vasogenic edema, most often involving the parieto-occipital regions [33]. T2-weighted and FLAIR sequences typically show hyperintense lesions consistent with vasogenic edema, while DWI generally demonstrates preserved diffusion. Atypical patterns are more frequent in pediatrics and may involve the frontal lobes, basal ganglia, cerebellum, or brainstem, complicating recognition [37, 38]. Because clinical features are often nonspecific, accurate diagnosis requires integration of history, imaging, and laboratory evaluation [39]. Complications such as cerebral infarction (10–23%) must be rapidly differentiated from ischemic stroke to avoid mismanagement. Although uncommon, cerebral hemorrhage introduces additional diagnostic complexity, particularly in patients on anticoagulation or with conditions such as SLE, where distinguishing PRES from neuropsychiatric lupus is essential because therapeutic approaches differ [15, 18, 33]. Variants of PRES, including spinal cord involvement (PRES-SCI), further illustrate the syndrome’s heterogeneity; in children, this variant may present with milder HTN yet more atypical imaging features [40, 41].

Across pediatric, obstetric, and transplant populations, several themes consistently emerge. HTN, whether chronic, pregnancy-related, or medication-induced, remains the most common precipitating factor. In parallel, therapies that alter endothelial function, particularly calcineurin inhibitors and cytotoxic agents, create a biologic environment highly susceptible to PRES. These shared mechanisms explain why PRES presents across diverse clinical settings and reinforce the importance of early blood pressure control, careful immunosuppressant monitoring, and high clinical suspicion when neurological symptoms arise.

Future directions and research gaps

Emerging research is refining our understanding of PRES, revealing mechanisms and tools that may enable earlier detection and targeted treatment. Key areas include biomarkers of endothelial dysfunction, advances in neuroimaging, and novel therapeutic pathways.

Biomarkers and endothelial injury

Animal and translational studies increasingly highlight BBB disruption as a central mechanism in the development of vasogenic edema during acute HTN. The BBB normally restricts the passage of plasma proteins and injurious molecules into the brain parenchyma, and its breakdown highlights the pivotal role of endothelial dysfunction in PRES pathogenesis [42, 43].

This recognition has stimulated interest in molecular biomarkers of endothelial injury, including vascular endothelial growth factor (VEGF), circulating endothelial cells, and matrix metalloproteinases (MMPs). These markers hold promise as early indicators of risk and disease activity, potentially allowing intervention before irreversible injury occurs. However, validation in clinical cohorts is still required before routine bedside application can be recommended [44].

Imaging innovations

Neuroimaging remains fundamental to diagnosis, but newer modalities are extending insights beyond structural edema patterns. Conventional MRI sequences such as T2-weighted and FLAIR remain highly sensitive for identifying vasogenic edema. More advanced techniques, including DWI and susceptibility-weighted imaging (SWI), can detect subtle microhemorrhages and early cytotoxic injury that may not be visible on routine sequences [45, 46].

Functional approaches, such as perfusion MRI and magnetic resonance spectroscopy (MRS), further characterize alterations in cerebral blood flow and metabolism, offering a dynamic view of PRES pathophysiology. Despite their potential, widespread implementation remains limited by cost, accessibility, and the need for specialized expertise [18, 47].

Therapeutic pathways under investigation

A growing body of work suggests that modulation of vascular and inflammatory signaling may provide targeted treatment strategies. Interventions directed at the renin–angiotensin–aldosterone system (RAAS) appear capable of reducing vascular permeability and preventing BBB disruption in experimental models, raising interest in angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) as potential therapeutic adjuncts [48].

Likewise, therapies aimed at dampening inflammatory cascades, ranging from corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) to biologics targeting specific cytokines, are being explored for their ability to limit endothelial injury [49]. A newer conceptual framework focuses on arginine vasopressin (AVP) pathways; AVP receptor antagonists (vaptans) may theoretically mitigate vasoconstriction and edema and have been proposed as investigational therapy [50, 51].

Major unanswered questions include the role of genetic predisposition, inter-individual variability in treatment response, and the development of etiology-specific therapy, such as strategies tailored to transplant-associated or obstetric PRES, where mechanisms differ significantly [52].

Collectively, these research directions suggest a shift from supportive care toward mechanism-guided prevention and treatment. Validated biomarkers could permit risk stratification and earlier recognition; advanced imaging may refine prognostication; and targeted therapies hold potential to limit injury rather than merely responding to it. Bridging these scientific advances into clinical protocols will require coordinated prospective studies, standardized definitions, and integration across neurology, critical care, obstetrics, pediatrics, and transplant medicine.

Conclusion

PRES is a complex neurological syndrome with heterogeneous clinical presentations and multifactorial etiologies. Early recognition and rapid correction of precipitating factors remain central to preventing irreversible injury and improving outcomes. Advances in neuroimaging, particularly MRI, have enhanced diagnostic accuracy, yet variability in clinical expression and overlapping radiologic patterns continue to complicate timely diagnosis. Special populations, including pediatric, obstetric, and transplant patients, require tailored strategies aligned with their distinct risk profiles.

Despite important progress, critical gaps persist. The precise mechanisms linking endothelial injury, cerebral autoregulation failure, and brain edema remain incompletely defined, and reliable biomarkers capable of predicting disease course are lacking. Equally, variation in diagnostic thresholds and treatment practices across centers highlights the need for standardized diagnostic criteria, prognostic tools, and evidence-based management protocols that can be applied consistently across diverse clinical settings.

By synthesizing current knowledge, this review highlights the importance of heightened clinical awareness, systematic neuroimaging, and coordinated multidisciplinary care. Continued collaborative research aimed at mechanism-driven therapies and standardized clinical pathways will be essential to improving outcomes for patients with PRES.

Author contributions

Marina Ramzy Mourid and Majd Oweidat share first authorship. Marina Ramzy Mourid contributed to the study conception and literature screening. Majd Oweidat led the manuscript writing, drafting, critical review, revision, validation, and finalization. Eslam Abady, Muhammad Azan Shahid, Israa Magdy Ata, Noha Salaheldeen Shaban, Olalekan John Okesanya, and Eric Lusinski contributed to the initial drafting of the manuscript. Mohammed Alsabri contributed to the study conception and provided overall supervision. All authors read and approved the final manuscript.

Funding

No funding was received for this research.

Data availability

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.