What is the pathophysiology of posterior reversible encephalopathy syndrome (PRES) in patients with underlying conditions such as hypertension, eclampsia, or those undergoing immunosuppressive therapy?

Pathophysiology of Posterior Reversible Encephalopathy Syndrome (PRES)

PRES pathophysiology centers on endothelial dysfunction and blood-brain barrier disruption leading to vasogenic edema, with two competing but not mutually exclusive mechanisms: hypertension-induced autoregulatory failure versus endothelial injury as the primary insult. 1

Primary Pathophysiological Mechanisms

Endothelial Dysfunction as the Central Pathway

• Endothelial injury serves as the fundamental pathogenic mechanism, where immune system activation triggers a molecular cascade that weakens tight junctions in cerebral blood vessels, allowing fluid extravasation and vasogenic edema formation 2

• This endothelial activation hypothesis explains why PRES occurs in normotensive patients and provides a unifying framework for all PRES-associated conditions including eclampsia, immunosuppression, sepsis, and autoimmune diseases 2

• Direct endothelial damage from cytotoxic agents (chemotherapy, immunosuppressants like cyclosporine), inflammatory mediators (sepsis, autoimmune disease), or metabolic derangements (eclampsia, renal failure) compromises blood-brain barrier integrity independent of blood pressure 1, 3

The Hypertension-Related Mechanisms

Two opposing theories exist regarding hypertension's role, though both may operate simultaneously:

Breakthrough Edema Theory (More Widely Accepted):

• Severe hypertension exceeds cerebral autoregulatory capacity (typically when mean arterial pressure rises above 150-160 mmHg), causing forced vasodilation and hyperperfusion 4
• This breakthrough of autoregulation allows plasma and proteins to leak through the blood-brain barrier into the brain parenchyma, creating vasogenic edema 5, 4
• The posterior circulation (vertebrobasilar system) has less sympathetic innervation than anterior circulation, making it more vulnerable to autoregulatory failure and explaining the characteristic posterior distribution 1

Vasoconstrictive-Ischemic Theory (Original Hypothesis):

• Acute hypertension triggers excessive cerebral autoregulatory vasoconstriction as a protective mechanism 4
• This vasoconstriction leads to cerebral hypoperfusion, ischemia, and subsequent blood-brain barrier breakdown with fluid leakage 4

Critical Insight on Hypertension's Role

• Hypertension may be an epiphenomenon rather than the primary cause, as many PRES patients present without significant blood pressure elevation 2
• The rate of blood pressure rise matters more than absolute values—patients with chronic hypertension tolerate higher pressures than previously normotensive individuals 6

Condition-Specific Pathophysiological Mechanisms

Eclampsia/Pre-eclampsia

• Shallow cytotrophoblast invasion of maternal spiral arteries causes placental hypoxia and ischemia 7
• The hypoxic placenta releases soluble factors (particularly sFlt-1) into maternal circulation that antagonize VEGF and placental growth factor 7
• This creates systemic endothelial dysfunction with reduced nitric oxide and prostacyclin production, impairing cerebral autoregulation 7
• The resulting endotheliopathy combined with hypertension leads to blood-brain barrier breakdown 7

Immunosuppressive Therapy (Especially Calcineurin Inhibitors)

• Cyclosporine and tacrolimus cause direct endothelial toxicity through multiple mechanisms including increased endothelin production, decreased prostacyclin synthesis, and oxidative stress 3
• Cyclosporine carries higher PRES risk than tacrolimus in transplant recipients 3
• These agents disrupt the blood-brain barrier independent of blood pressure effects, though hypertension frequently coexists 1, 3

Infection and Sepsis

• Gram-positive bacteria and severe sepsis trigger systemic inflammatory responses with cytokine release (TNF-α, IL-1, IL-6) 8
• These inflammatory mediators cause widespread endothelial activation and dysfunction throughout cerebral vasculature 8
• Sepsis-associated coagulopathy and microvascular thrombosis may contribute to blood-brain barrier compromise 8

Varicella-Zoster Virus (VZV) in Immunocompromised Patients

• VZV reactivation causes direct endothelial infection and dysfunction even without significant hypertension 1
• The pathogenic process represents immune-mediated reaction to low-level viral replication rather than direct cytopathology 1
• VZV-associated vasculopathy creates multiple insults to cerebral endothelium, particularly in immunocompromised states 1

Anatomical Distribution and Vulnerability

Why the Posterior Circulation?

• The vertebrobasilar system has reduced sympathetic innervation compared to anterior circulation, making it less capable of autoregulatory vasoconstriction 1
• Posterior white matter has higher water content and less compact myelin, making it more susceptible to vasogenic edema accumulation 5
• The parieto-occipital regions are watershed zones with relatively lower perfusion pressure at baseline 5

Atypical Distributions

• Anterior circulation involvement occurs in 30-40% of cases, particularly with severe or prolonged insults 5
• Brainstem, basal ganglia, and deep white matter can be affected, especially in severe cases 5
• Hemorrhagic transformation and cytotoxic edema (indicating irreversible injury) occur when treatment is delayed 5

The Blood-Brain Barrier Disruption Cascade

1. Initial insult (hypertension, endothelial toxin, inflammatory mediators, or metabolic derangement) 1
2. Endothelial activation with upregulation of adhesion molecules and inflammatory pathways 2
3. Tight junction protein disruption (occludin, claudin-5, ZO-1) weakening the blood-brain barrier 2
4. Increased vascular permeability allowing plasma protein and fluid extravasation 1, 5
5. Vasogenic edema formation predominantly in subcortical white matter with cortical involvement 1
6. Potential progression to cytotoxic edema, hemorrhage, or infarction if untreated 5

Common Pitfalls in Understanding PRES Pathophysiology

• Assuming hypertension is always present or causative—many patients have normal or only mildly elevated blood pressure, particularly with immunosuppressant-induced or infection-related PRES 2

• Overlooking the reversibility window—the "reversible" designation depends on prompt recognition and treatment; delayed intervention leads to irreversible cytotoxic edema and permanent injury 4

• Missing the multifactorial nature—most PRES cases involve multiple simultaneous insults (e.g., hypertension + immunosuppression + renal dysfunction), creating additive endothelial stress 1, 3