What is the association between Posterior Reversible Encephalopathy Syndrome (PRES) and methotrexate (MTX) therapy?

From the Guidelines

Posterior reversible encephalopathy syndrome (PRES) is a rare but serious complication of methotrexate therapy that requires immediate discontinuation of the drug and supportive care. If PRES is suspected in a patient receiving methotrexate, the management includes:

• Blood pressure control if hypertension is present
• Anticonvulsants for seizures, such as levetiracetam 500-1000 mg twice daily
• Close neurological monitoring
• Neuroimaging with MRI showing vasogenic edema in the posterior cerebral regions is essential for diagnosis, as stated in the guidelines for diagnosis, prevention, treatment, and follow-up of systemic anticancer therapy-induced peripheral and central neurotoxicity 1. The treatment of PRES is purely symptomatic and includes discontinuation of the offending agent, correction of electrolytes, and symptomatic treatment with benzodiazepines, as recommended by the clinical practice guidelines 1. Most patients recover completely within days to weeks after methotrexate discontinuation, though some may have residual neurological deficits. The mechanism of methotrexate-induced PRES likely involves direct neurotoxicity and endothelial dysfunction leading to blood-brain barrier disruption. After resolution, alternative immunosuppressive or chemotherapeutic agents should be considered based on the original indication for methotrexate. Rechallenge with methotrexate is generally not recommended as recurrence of PRES is possible, but decisions must be individualized based on risk-benefit assessment if no suitable alternatives exist.

From the Research

Definition and Characteristics of PRES

• Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by seizures, severe headache, mental status instability, and visual disturbances, typically accompanied by hypertension 2, 3, 4.
• The syndrome is thought to be caused by a breakdown of the blood-brain barrier and an extravasation of the intravascular fluid, leading to reversible cerebral vasogenic edema 3.
• PRES can present with a wide variety of acute or subacute neurological symptoms, including headache, mental status alteration, seizures, and visual dysfunction 4.

Association with Methotrexate

• There is evidence of PRES occurring after intrathecal methotrexate infusion, as reported in a case study of a 13-year-old boy with Burkitt lymphoma/leukaemia 2.
• The pathophysiology of leukoencephalopathy, a condition associated with PRES, remains unclear, but it is thought to develop within 5-14 days after intrathecal methotrexate and resolve within a week usually without permanent neurological sequelae 2.

Diagnosis and Management

• Diagnosis of PRES is made by a thorough history and physical exam, and cerebral imaging, such as MRI or CT scans 3, 5.
• The mainstay of management is parenteral anti-hypertensives with proper blood pressure monitoring, as well as treatment of underlying causes, such as withdrawal of causative agents 3, 5.
• Early identification and appropriate management of PRES decrease morbidity and mortality without chronic neurologic sequelae 5.

Prognosis and Outcome

• Prognosis is generally benign, but delayed diagnosis and improper management may result in permanent brain insult 2.
• Factors associated with poor outcome include altered sensorium, hypertensive etiology, hyperglycemia, longer time to control the causative factor, elevated C reactive protein, coagulopathy, extensive cerebral edema, and hemorrhage on imaging 6.