Posterior Reversible Encephalopathy Syndrome in Critical Care: A Comprehensive Review for the Intensivist

Dr Neeraj Manikath , claude.ai

Abstract

Background: Posterior Reversible Encephalopathy Syndrome (PRES) is a clinico-radiological syndrome characterized by acute neurological symptoms and distinctive neuroimaging findings. While initially considered rare, PRES is increasingly recognized in critical care settings, particularly in association with hypertensive crises, eclampsia, and immunosuppressive therapy.

Objective: To provide critical care physicians with a comprehensive understanding of PRES pathophysiology, clinical triggers, diagnostic imaging pearls, and evidence-based management strategies.

Methods: Comprehensive literature review of PRES in critical care contexts, with emphasis on recent advances in pathophysiology, diagnostic criteria, and therapeutic interventions.

Results: PRES manifests across a spectrum of severity from mild cognitive impairment to status epilepticus and coma. Early recognition through characteristic MRI findings and prompt management of underlying triggers can lead to complete neurological recovery in most cases.

Conclusions: PRES represents a medical emergency requiring immediate recognition and intervention. Understanding key clinical triggers and imaging patterns enables timely diagnosis and optimization of outcomes in critically ill patients.

Keywords: Posterior reversible encephalopathy syndrome, hypertensive encephalopathy, eclampsia, calcineurin inhibitors, neurointensive care

Introduction

Posterior Reversible Encephalopathy Syndrome (PRES), first described by Hinchey et al. in 1996, represents a distinctive clinico-radiological entity characterized by acute-to-subacute neurological deterioration accompanied by characteristic neuroimaging findings¹. Originally termed "reversible posterior leukoencephalopathy syndrome," the condition has undergone nomenclature evolution as our understanding of its pathophysiology and clinical spectrum has expanded.

The syndrome gained particular relevance in critical care medicine due to its association with common ICU precipitants including hypertensive emergencies, eclampsia, sepsis, and immunosuppressive medications. Recognition of PRES has increased substantially over the past two decades, partly due to improved neuroimaging accessibility and heightened clinical awareness among intensivists.

Despite its designation as "reversible," PRES can result in permanent neurological sequelae or death if not promptly recognized and appropriately managed. This review synthesizes current understanding of PRES pathophysiology, clinical presentations, diagnostic challenges, and evidence-based management strategies specifically relevant to critical care practice.

Pathophysiology

Classical Hypothesis: Hypertensive Breakthrough

The traditional pathophysiological model proposes that PRES results from failure of cerebrovascular autoregulation in the setting of acute severe hypertension². The posterior circulation, particularly the parieto-occipital regions, demonstrates relative paucity of sympathetic innervation compared to anterior territories, rendering these areas more susceptible to hypertensive injury.

When mean arterial pressure exceeds the upper limit of autoregulation (typically >150-160 mmHg), arteriolar dilatation occurs, leading to:

Increased capillary hydrostatic pressure
Breakdown of blood-brain barrier integrity
Vasogenic edema formation
Subsequent neurological dysfunction

Contemporary Understanding: Endothelial Dysfunction Model

Recent evidence suggests a more complex pathophysiology centered on endothelial dysfunction rather than purely mechanical blood-brain barrier failure³. This model proposes:

Primary endothelial injury from various triggers (hypertension, toxins, inflammation)
Dysregulation of nitric oxide and endothelin pathways
Increased vascular permeability independent of pressure effects
Complement activation and inflammatory cascades
Resultant vasogenic edema with potential for cytotoxic components

This paradigm better explains PRES occurrence in normotensive patients and the variable clinical presentations observed across different patient populations.

Clinical Pearl: The "Two-Hit" Hypothesis

Many PRES cases result from multiple concurrent insults (e.g., hypertension + immunosuppression + renal dysfunction), suggesting a "two-hit" mechanism where individual factors may be subclinical but synergistically trigger the syndrome.

Clinical Presentations

Cardinal Symptoms

PRES typically presents with an acute-to-subacute constellation of neurological symptoms developing over hours to days:

Primary Manifestations:

Headache (50-80% of cases): Often severe, holocephalic, and refractory to standard analgesics
Seizures (60-75%): May range from focal to generalized tonic-clonic; status epilepticus occurs in 5-15%
Visual disturbances (33-60%): Including cortical blindness, hemianopia, or visual neglect
Altered mental status (50-80%): From mild confusion to coma

Secondary Features:

Nausea and vomiting
Focal neurological deficits
Speech disturbances
Behavioral changes

Severity Spectrum

Recent classifications recognize PRES as existing along a continuum of severity⁴:

Mild PRES:

Subtle cognitive changes
Mild headache
Minimal imaging findings
Rapid reversibility

Severe PRES:

Status epilepticus
Coma
Extensive vasogenic edema
Risk of herniation
Potential for permanent sequelae

Clinical Hack: The "PRES Triad"

Remember the classic triad: Headache + Hypertension + Seizures in the appropriate clinical context. However, absence of any component does not exclude the diagnosis.

ICU-Specific Triggers

Hypertensive Emergencies

Hypertensive crises represent the most common trigger for PRES in critical care settings, accounting for 70-80% of cases⁵. Key considerations include:

Threshold Effects:

PRES can occur with systolic BP >180 mmHg or mean arterial pressure >130 mmHg
Relative hypertension important in patients with baseline hypotension
Rate of BP rise may be more critical than absolute values

High-Risk Scenarios:

Malignant hypertension with end-organ damage
Hypertensive emergency with acute kidney injury
Pheochromocytoma crisis
Drug-induced hypertension (cocaine, amphetamines)

Management Considerations:

Avoid precipitous BP reduction (risk of watershed infarction)
Target 10-20% reduction in first hour
Nicardipine or clevidipine preferred for titratable control

Eclampsia and Preeclampsia

PRES occurs in approximately 10-15% of severe preeclampsia cases and up to 2% of all preeclampsia patients⁶. Unique aspects include:

Pathophysiology:

Impaired placental angiogenesis
Increased anti-angiogenic factors (sFlt-1, soluble endoglin)
Enhanced susceptibility to endothelial dysfunction

Clinical Features:

May occur antepartum, intrapartum, or postpartum
Can develop with only moderately elevated BP
Often associated with HELLP syndrome

Obstetric Pearls:

PRES can occur up to 4-6 weeks postpartum
Consider in any postpartum patient with new neurological symptoms
MgSO₄ remains first-line for seizure prophylaxis and treatment

Calcineurin Inhibitor Toxicity

Cyclosporine and tacrolimus represent important iatrogenic causes of PRES in transplant recipients and autoimmune patients⁷. Key points include:

Mechanisms:

Direct endothelial toxicity
Impaired endothelial nitric oxide production
Enhanced vasoconstriction
Dose-dependent and idiosyncratic reactions

Risk Factors:

Recent transplantation with higher drug levels
Concurrent nephrotoxicity
Hypomagnesemia
Concurrent use of other neurotoxic agents

Management Strategy:

Immediate discontinuation or dose reduction
Switch to alternative immunosuppression when possible
Monitor drug levels closely
Consider therapeutic drug monitoring

Oyster: Normotensive PRES

Up to 30% of PRES cases occur without significant hypertension, particularly in the setting of immunosuppressive therapy, sepsis, or autoimmune conditions. Don't let normal blood pressure discourage consideration of the diagnosis.

Diagnostic Imaging

MRI: The Gold Standard

Magnetic resonance imaging remains the cornerstone of PRES diagnosis, with characteristic findings including:

T2/FLAIR Hyperintensities:

Bilateral, symmetric (though asymmetry possible)
Predilection for parieto-occipital regions
Subcortical white matter involvement
"String of pearls" pattern along sulci

DWI/ADC Patterns:

Typically shows facilitated diffusion (increased ADC values)
Indicates vasogenic rather than cytotoxic edema
Restricted diffusion suggests irreversible injury

Distribution Patterns⁸:

Typical posterior pattern (80%): Parieto-occipital predominance
Holohemispheric pattern (23%): Anterior and posterior involvement
Superior frontal sulcal pattern (27%): Parasagittal frontal involvement
Partial expression patterns: Limited regional involvement

CT Findings

While less sensitive than MRI, CT may demonstrate:

Bilateral hypodensities in posterior white matter
Cerebral edema with sulcal effacement
Hemorrhagic transformation (10-15% of cases)

Advanced Imaging Techniques

Arterial Spin Labeling (ASL):

Demonstrates hyperperfusion in affected regions
Useful for monitoring treatment response

Susceptibility-Weighted Imaging (SWI):

Detects microhemorrhages
Prognostic implications for recovery

Imaging Pearl: The "Dot Sign"

Look for punctate areas of restricted diffusion within areas of vasogenic edema on DWI - these "dots" may represent small infarcts and correlate with less complete recovery.

Differential Diagnosis

Critical care physicians must distinguish PRES from other acute neurological conditions:

Primary Considerations

Acute Ischemic Stroke:

Usually unilateral
Restricted diffusion on DWI
Vascular territory distribution

Viral Encephalitis:

Fever and CSF pleocytosis
Temporal lobe predilection (HSV)
Different enhancement patterns

CNS Vasculitis:

Multifocal infarcts
Vessel wall enhancement
CSF inflammatory markers

Metabolic Encephalopathy:

Diffuse, non-territorial changes
Correlation with systemic abnormalities
Usually reversible with correction

Diagnostic Hack: The "PRES Checklist"

✓ Appropriate clinical trigger present?
✓ Acute neurological symptoms?
✓ Bilateral posterior white matter changes?
✓ Vasogenic edema pattern on DWI?
✓ Clinical improvement with trigger management?

Management Strategies

Immediate Management

Primary Intervention:

Identify and address underlying trigger
Blood pressure management (avoid precipitous reduction)
Seizure control (standard anticonvulsants)
Supportive care (airway, oxygenation, glucose)

Blood Pressure Management

Target Parameters:

10-20% reduction from baseline in first hour
Avoid reduction >25% in first 24 hours
Target MAP 110-130 mmHg unless contraindicated

Preferred Agents:

Nicardipine: 5 mg/h IV, titrate by 2.5 mg/h q15min (max 15 mg/h)
Clevidipine: 1-2 mg/h IV, double dose q90 seconds PRN
Labetalol: 20 mg IV bolus, then 20-80 mg q10min PRN

Agents to Avoid:

Sublingual nifedipine (unpredictable reduction)
Hydralazine (erratic response)

Seizure Management

First-Line Therapy:

Levetiracetam: 20 mg/kg IV load, then 500-1000 mg BID
Phenytoin: 20 mg/kg IV load (if levetiracetam unavailable)
Lorazepam: 0.1 mg/kg IV for acute seizures

Status Epilepticus Protocol:

Standard institutional protocols apply
Consider continuous EEG monitoring
Address underlying metabolic triggers

Specific Interventions

Calcineurin Inhibitor Toxicity:

Immediate cessation or dose reduction
Alternative immunosuppression (mycophenolate, sirolimus)
Therapeutic drug level monitoring

Eclampsia Management:

Magnesium sulfate: 4-6 g IV load, then 1-2 g/h infusion
Antihypertensive therapy as above
Obstetric consultation for delivery planning

Management Pearl: The "Golden Hour"

Early recognition and prompt intervention within the first few hours of symptom onset correlate with better neurological outcomes and reduced risk of permanent sequelae.

Prognosis and Outcomes

Recovery Patterns

Typical Course:

Symptom improvement: 2-8 days
Radiological resolution: 1-4 weeks
Complete recovery: 85-95% of cases

Factors Associated with Poor Outcome:

Delayed diagnosis (>24-48 hours)
Severe initial presentation
Hemorrhagic transformation
Restricted diffusion on DWI
Concurrent systemic complications

Long-term Sequelae

Permanent neurological deficits occur in 5-15% of cases:

Cortical blindness
Cognitive impairment
Seizure disorder
Motor deficits

Recurrence Risk:

Overall recurrence: 5-10%
Higher risk with ongoing trigger exposure
Preventive strategies important

Special Populations

Pediatric Considerations

PRES in children often presents with:

More frequent seizures (up to 90%)
Different trigger spectrum (acute glomerulonephritis, hemolytic uremic syndrome)
Generally better recovery rates
Age-appropriate blood pressure targets needed

Immunocompromised Patients

Unique features include:

Higher risk of infectious mimics
Multiple potential triggers
Increased risk of complications
May require modified immunosuppression strategies

Future Directions and Research

Biomarker Development

Emerging research focuses on:

Endothelial dysfunction markers (endothelin-1, VEGF)
Inflammatory mediators (TNF-α, IL-6)
Blood-brain barrier markers (S100β, neuron-specific enolase)

Advanced Therapeutics

Investigational approaches include:

Endothelin receptor antagonists
Anti-VEGF therapies for selected cases
Neuroprotective agents
Targeted anti-inflammatory strategies

Precision Medicine

Future directions may include:

Genetic susceptibility testing
Personalized blood pressure targets
Biomarker-guided therapy selection

Clinical Pearls and Oysters Summary

Pearls:

The "Two-Hit" Rule: Look for multiple concurrent triggers rather than single causes
Relative Hypertension Matters: PRES can occur with modest BP elevation in previously normotensive patients
Don't Forget the Postpartum Period: PRES can occur weeks after delivery
DWI is Your Friend: Facilitates differentiation from stroke and predicts reversibility
The "Golden Hour": Early intervention dramatically improves outcomes

Oysters (Potential Pitfalls):

Normotensive PRES: Up to 30% of cases occur without hypertension
Unilateral Presentations: Don't exclude PRES based on asymmetric findings
The "Reversible" Misnomer: 5-15% develop permanent sequelae
Anterior Involvement: Not just a "posterior" syndrome
Microhemorrhages: Small hemorrhages don't contraindicate the diagnosis

ICU Hacks:

BP Management: Think "gentle slope, not cliff" for pressure reduction
Imaging Timing: Repeat MRI in 24-48 hours if clinical improvement doesn't match initial severity
EEG Monitoring: Consider continuous monitoring in severe cases
Multidisciplinary Approach: Involve neurology, ophthalmology, and pharmacy early
Documentation: Photograph retinal findings and detailed neurological assessments for medicolegal purposes

Conclusion

PRES represents a critical care emergency requiring immediate recognition and intervention. The syndrome's increasing recognition reflects both improved diagnostic capabilities and genuine increased incidence in our aging, more medically complex patient populations. Success in managing PRES relies on understanding its diverse presentations, maintaining high clinical suspicion in at-risk patients, utilizing appropriate imaging modalities, and implementing prompt, evidence-based interventions targeting underlying triggers.

The evolution from purely hypertensive models to contemporary endothelial dysfunction paradigms has improved our therapeutic approach and expanded recognition of normotensive variants. Future advances in biomarker development and precision medicine may further optimize outcomes for this challenging but often reversible condition.

For the practicing intensivist, PRES exemplifies the intersection of critical care medicine and neuroscience, demanding rapid decision-making based on incomplete information while balancing competing risks. Mastery of PRES diagnosis and management represents an essential competency for modern critical care practice.

References

Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494-500.
Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008;29(6):1036-1042.
Muscal E, Traipe E, de Guzman MM, et al. The role of inflammation in the pathogenesis of posterior reversible encephalopathy syndrome. Neurol Clin Pract. 2019;9(2):124-131.
Fugate JE, Claassen DO, Cloft HJ, et al. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc. 2010;85(5):427-432.
Schweitzer AD, Parikh NS, Askin G, et al. Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome. Neuroradiology. 2017;59(4):379-386.
Wagner SJ, Acquah LA, Lindell EP, et al. Posterior reversible encephalopathy syndrome and eclampsia: pressing the case for more aggressive blood pressure control. Mayo Clin Proc. 2011;86(9):851-856.
Ahn KJ, You WJ, Jeong SL, et al. Atypical manifestations of reversible posterior leukoencephalopathy syndrome: findings on diffusion imaging and ADC mapping. Neuroradiology. 2004;46(12):978-983.
Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2007;28(7):1320-1327.

Conflict of Interest: None declared Funding: None

Tuesday, September 9, 2025