Causes of Posterior Reversible Encephalopathy Syndrome (PRES)
PRES is triggered by conditions that cause endothelial dysfunction and blood-brain barrier disruption, with the most common causes being severe hypertension, immunosuppressive medications (particularly calcineurin inhibitors like cyclosporine), renal impairment, autoimmune diseases, eclampsia/pre-eclampsia, cancer chemotherapy, and solid organ or stem cell transplantation. 1
Primary Pathophysiological Categories
The underlying mechanism involves either hypertension-induced autoregulatory failure or direct endothelial injury, with most cases involving multiple simultaneous insults creating additive endothelial stress. 2 The posterior circulation's reduced sympathetic innervation makes it particularly vulnerable to autoregulatory failure, explaining the characteristic posterior distribution of edema. 2
Medication-Related Causes
Immunosuppressive Agents
- Calcineurin inhibitors, especially cyclosporine, are among the most common medication triggers due to direct endothelial toxicity. 1, 2
- Immunosuppressive therapy used in transplantation settings significantly increases PRES risk. 1
Chemotherapy and Biological Agents
- High-dose antineoplastic therapy is a well-established trigger. 1
- Anti-TNF therapy, specifically infliximab, has been reported to cause PRES in patients with Crohn's disease. 1
- Anti-amyloid monoclonal antibody therapy can produce PRES-like imaging abnormalities (ARIA). 3
Hypertension-Related Causes
- Pre-existing arterial hypertension and acute severe hypertension are major triggers, with the rate of blood pressure rise mattering more than absolute values. 1, 2
- Accelerated hypertension can exceed cerebral autoregulatory capacity, leading to breakthrough edema. 4, 5
- Patients with chronic hypertension may tolerate higher pressures than previously normotensive individuals. 2
Renal and Metabolic Causes
- Renal impairment and acute kidney diseases are frequent precipitants. 1, 4, 5
- Electrolyte imbalances can contribute to PRES development. 1
Pregnancy-Related Causes
- Eclampsia and pre-eclampsia represent classic PRES triggers, where shallow cytotrophoblast invasion causes placental hypoxia, leading to systemic endothelial dysfunction and impaired cerebral autoregulation. 1, 2, 5
Transplantation-Related Causes
- Allogeneic stem cell transplantation creates high risk through multiple mechanisms including immunosuppression and immune activation. 1, 6, 5
- Solid organ transplantation similarly increases risk through immunosuppressive medication exposure and systemic inflammatory states. 1, 5
Autoimmune and Inflammatory Causes
- Autoimmune diseases create chronic endothelial stress and inflammation. 1, 5, 7
- T-cell and endothelial cell activation may drive leukocyte trafficking and cerebral vasoconstriction. 6
Infectious Causes
- Severe infection and sepsis, particularly with gram-positive bacteria, can trigger PRES through endothelial damage and inflammatory mediators. 8, 7
- Varicella-Zoster Virus (VZV) reactivation in immunocompromised patients causes direct endothelial infection and dysfunction, even without significant hypertension. 1, 2
- The pathogenic process involves immune-mediated reaction to viral replication and direct endothelial dysfunction with blood-brain barrier disruption. 1
Malignancy-Related Causes
- Cancer itself and associated treatments create multiple risk factors. 7
- The combination of chemotherapy, potential hypertension, and systemic inflammation creates cumulative endothelial stress. 1
Critical Clinical Pitfall
Most PRES cases involve multiple simultaneous insults rather than a single cause. 2 Failing to identify all contributing factors—such as overlooking concurrent sepsis, metabolic disturbances, or medication effects while focusing solely on hypertension—can lead to incomplete treatment and prolonged illness. 1 The key is recognizing that these triggers create additive endothelial stress, and all offending agents must be addressed simultaneously for optimal recovery. 1