Management Strategies for Posterior Reversible Encephalopathy Syndrome (PRES) in Patients Receiving Calcineurin-Inhibitor or Sirolimus Therapy for Hematologic Disorders and Allogeneic Transplantation

Background: Posterior reversible encephalopathy syndrome (PRES) is a potentially life-threatening complication of therapy with calcineurin inhibitors (CNI). Medications in this class include tacrolimus (Tac) and cyclosporine A (CSA). Sirolimus (Siro), an inhibitor of the mammalian target of rapamycin (mTOR) complex, may also be associated with PRES. These therapies are generally used in the management of patients with severe aplastic anemia (SAA), to prevent or treat graft-versus-host disease following allogeneic hematopoietic cell transplantation (alloHCT), or to prevent rejection of solid organ allografts. PRES is associated with hypertension and symptomatic features include headaches, seizures, and occasionally, intracranial hemorrhage or ischemic strokes. Classical findings on magnetic resonance imaging (MRI) studies include leukoencephalopathy with vasogenic edema in the occipital cerebrum. Diffusion restriction is observed on diffusion-weighted imaging. Management of CNI/Siro-associated PRES has not been well-studied.

Methods: We performed a single-institution retrospective review of all patients identified to have possible PRES on MRI between October 2000 and February 2014. Patients were identified by searching a database of all neuroimaging studies performed at our institution during this time period for the terms: PRES, posterior reversible encephalopathy, or reversible posterior leukoencephalopathy. Radiography studies were reevaluated for this study to uniformly collect data regarding imaging features. Medical chart review was conducted to determine patient features at diagnosis, management decisions with focus on medication changes, and outcomes.

Results: Our review identified 191 patients who underwent 236 MRI studies that demonstrated findings suggesting a possible diagnosis of PRES. On medical record review, pertinent clinical data were available for 167 patients, of whom 93 (56%) were deemed to have a clinical diagnosis consistent with PRES. Amongst this cohort, 27 patients (29%) were diagnosed with PRES while taking a CNI or Siro – 22 (81%) were receiving Tac, 4 (15%) were receiving CSA, and 1 patient (3.7%) was receiving Siro at diagnosis. The median age at PRES diagnosis was 52 (range 7 - 68), with no apparent association between age and the occurrence of CNI/Siro-associated PRES. Indications for CNI/Siro therapy included: alloHCT (19%), SAA (3.7%), systemic lupus erythematosus (7.4%), and solid organ transplantation (70%). Symptomatic features and physical signs at diagnosis of CNI/Siro-associated PRES included: hypertension (74%), seizure (52%), headache (44%), intracranial hemorrhage (22%), and cerebrovascular accident (15%). Presentation with these symptoms was not significantly different between CNI/Siro-associated PRES and other forms of PRES (p = 0.36, 0.48, 0.88, 0.97, and 0.44, respectively). The median time from initiation of CNI/Siro therapy to onset of PRES was 22 days (range 1 - 1924). Only 3 patients (11%) discontinued CNI/Siro therapy at PRES diagnosis and did not resume, whereas 12 (44%) continued the same medication, 10 (37%) were changed to alternative CNI (Tac-to-CSA or CSA-to-Tac) therapy, and 2 (7.4%) were changed from CNI to Siro. Two patients experienced recurrent PRES following these initial management decisions. All other patients continued therapy without recurrence.

Conclusions: CNI/Siro therapy, mostly in the setting of allogeneic hematopoietic cell or solid organ transplantation, was associated with roughly one-third of PRES cases at our institution. Management of CNI/Siro-associated PRES has not been well studied, and the low incidence of this complication is prohibitive to the implementation of prospective studies. In this retrospective review, we evaluated the management strategies and outcomes of patients who developed PRES while receiving CNI/Siro therapy. The vast majority of patients (77%) tolerated continuation of the same CNI or changing to alternative CNI therapy. An additional 11% tolerated conversion from CNI to Siro. The recurrence rate with continuation of CNI/Siro therapy was low at 2/24 (8.3%) and no patients experienced fatal complications of PRES, suggesting this management strategy is safe. Additional analyses are underway to determine whether clinical or radiographic features may help predict the recurrence of PRES in patients who continue CNI/Siro therapy.