What causes Posterior Reversible Encephalopathy Syndrome (PRESS) in middle-aged to older adults with a history of cancer, organ transplantation, or autoimmune disorders?

What Causes Posterior Reversible Encephalopathy Syndrome (PRES)

PRES is caused by endothelial injury and disruption of the blood-brain barrier, triggered by severe hypertension, immunosuppressive medications (especially cyclosporine and tacrolimus), renal disease, autoimmune disorders, eclampsia, and certain chemotherapy agents. 1

Primary Pathophysiologic Mechanism

The fundamental cause involves disruption of the blood-brain barrier due to endothelial injury from abrupt blood pressure changes, leading to vasogenic edema predominantly in the posterior cerebral regions. 1 This occurs when cerebral autoregulation fails in the setting of markedly elevated blood pressure or direct endothelial toxicity. 1

Major Triggering Factors

Immunosuppressive Medications (Most Common Drug Cause)

• Calcineurin inhibitors are the leading pharmaceutical triggers, with cyclosporine and tacrolimus accounting for the highest number of reported cases. 2, 3
• These agents cause direct endothelial dysfunction independent of blood pressure elevation. 1, 3
• The 2023 worldwide pharmacovigilance analysis identified 73 drugs statistically associated with PRES, with only 34% having this warning in their product labeling. 2

Chemotherapy and Immunomodulating Agents

• Bevacizumab, methotrexate, and vincristine are among the most frequently implicated antineoplastic agents. 2
• Anti-TNF therapy (infliximab) has been reported as a cause in patients with inflammatory bowel disease. 1
• Immune checkpoint inhibitors can trigger PRES as part of immune-related adverse events, though this is rare. 4

Hypertensive Crisis

• Severe, acute hypertension remains a classic precipitant, particularly when blood pressure rises rapidly and overwhelms cerebral autoregulation. 1, 5
• Pre-existing arterial hypertension increases susceptibility to PRES development. 1

Renal Disease

• Renal impairment and renal failure are significant risk factors, even without concurrent immunosuppressive therapy. 1, 6, 5
• Focal segmental glomerulosclerosis and other glomerular diseases can precipitate PRES through combined mechanisms of hypertension and endothelial dysfunction. 6
• Nephrotic syndrome has been associated with PRES development. 6

Transplantation

• Allogenic stem-cell transplantation and solid organ transplantation create high-risk scenarios through multiple mechanisms: immunosuppression, hypertension, and systemic inflammation. 1, 7
• The combination of calcineurin inhibitors used post-transplant with underlying metabolic derangements substantially increases risk. 1, 3

Autoimmune and Inflammatory Conditions

• Autoimmune diseases including systemic lupus erythematosus and other connective tissue disorders are established triggers. 1, 5, 3
• The inflammatory state itself, combined with treatment-related factors, contributes to endothelial injury. 5

Pregnancy-Related Causes

• Eclampsia represents a classic obstetric cause of PRES through severe hypertension and endothelial dysfunction. 1, 5

Infectious Triggers

• Varicella-Zoster Virus (VZV) reactivation, particularly in immunocompromised patients, can precipitate PRES even without significant hypertension. 1
• The mechanism involves immune-mediated reaction to viral replication causing direct endothelial dysfunction and blood-brain barrier disruption. 1
• VZV-associated vasculopathy creates multiple insults to cerebral endothelium. 1

Pediatric-Specific Risk Factors

• In children, renal disease, malignancy, sepsis, and exposure to specific medications are the predominant causes. 7
• Hypertension associated with underlying renal parenchymal disease is particularly common in pediatric PRES. 7

Multiple Insult Hypothesis

PRES typically develops when multiple risk factors converge, creating a scenario where the cerebral endothelium faces combined insults from hypertension, direct drug toxicity, inflammatory mediators, and metabolic derangements. 1 This explains why patients with cancer, transplantation, or autoimmune disorders—who often have several concurrent risk factors—are at highest risk.

Critical Clinical Implication

Mortality in drug-associated PRES is 8.1%, underscoring the importance of recognizing potential causative agents and discontinuing them immediately. 2 The reversibility of PRES depends on early identification and removal of the triggering factor, whether it be a medication, uncontrolled hypertension, or another modifiable cause. 1, 5