How does cyclophosphamide cause Posterior Reversible Encephalopathy Syndrome (PRES)?

Mechanism of Cyclophosphamide-Induced Posterior Reversible Encephalopathy Syndrome (PRES)

Cyclophosphamide causes PRES primarily through endothelial injury leading to disruption of the blood-brain barrier, resulting in vasogenic edema predominantly affecting the parieto-occipital regions of the brain. 1

Pathophysiological Mechanisms

Primary Mechanism: Endothelial Dysfunction

• Cyclophosphamide directly damages vascular endothelial cells, compromising the integrity of the blood-brain barrier 1
• This endothelial injury leads to:
  • Increased vascular permeability
  • Extravasation of fluid into the brain parenchyma
  • Development of vasogenic edema, particularly in posterior brain regions 2

Contributing Factors in Cyclophosphamide-Induced PRES

1. Blood Pressure Dysregulation

   • Cyclophosphamide can cause abrupt blood pressure changes that exceed cerebral autoregulation limits 2, 1
   • This leads to breakthrough vasogenic edema when autoregulatory mechanisms fail 1

2. Immunosuppressive Effects

   • High-dose antineoplastic therapy, including cyclophosphamide, is a recognized risk factor for PRES 2, 1
   • Cyclophosphamide can induce PRES even in normotensive patients with normal renal function 3

3. Drug Interactions

   • Similar to other immunosuppressants like cyclosporine, cyclophosphamide's neurotoxicity may be enhanced by concurrent medications 4
   • Rapid changes in drug levels may trigger PRES onset, even within therapeutic ranges 4

Clinical Manifestations

Patients with cyclophosphamide-induced PRES typically present with:

• Acute neurological deficits
• Altered consciousness
• Visual disturbances or blindness
• Headaches
• Seizures 2, 1

Radiological Findings

• T2-weighted MRI shows hyperintensities indicating vasogenic edema
• Predominantly affects bilateral parieto-occipital lobes
• White matter is more affected than gray matter 2, 1
• Irregular borders toward white matter with defined borders toward gray cortex 1

Risk Factors for Cyclophosphamide-Induced PRES

• Pre-existing hypertension
• Renal impairment
• Autoimmune diseases (particularly active lupus nephritis)
• High-dose cyclophosphamide therapy
• Fluid overload
• Concurrent use of other immunosuppressants 2, 1, 5

Management Considerations

1. Immediate Intervention

   • Discontinue cyclophosphamide 2, 1
   • Control blood pressure (if elevated) with careful monitoring 1
   • Administer antiepileptic treatment for seizures 2, 1

2. Supportive Care

   • Elevate head of bed to 30 degrees to decrease hydrostatic pressure 1
   • Correct any electrolyte imbalances 2
   • Consider benzodiazepines for symptomatic treatment 2

Prognosis

• PRES is typically reversible with appropriate management within 2 weeks 2, 1
• Early recognition and intervention lead to better outcomes 3
• Delayed diagnosis and treatment may result in permanent neurological sequelae 1

Important Clinical Considerations

• PRES can occur in cyclophosphamide-treated patients even without other known risk factors 3
• Clinicians should maintain high vigilance for PRES in patients receiving cyclophosphamide, especially those with autoimmune conditions 5
• Initial symptoms may be misdiagnosed as ischemic stroke, delaying appropriate management 5
• Regular monitoring of patients on cyclophosphamide therapy is crucial for early detection 1

Understanding this mechanism is essential for early recognition and prompt management of this serious but potentially reversible complication of cyclophosphamide therapy.