Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature.

Introduction: New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke-like-events. Since calcineurin inhibitors (CNIs) are a well-known cause of new neurological symptoms in non-MMA transplanted patients, we investigated the incidence of CNI-induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post-transplanted MMA patients.
Methods: We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post-transplanted MMA patients and determined if CNI-induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI-induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI-induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)-scan post-transplantation.
Results: Our two MMA patients both developed CNI-induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow-up was reported in 54 of them, of which 24 were excluded from analysis since no anti-rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post-transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post-transplanted MMA patients on CNI.
Conclusion: In MMA post-transplanted patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered. Early recognition of CNI-induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome.
Concise One Sentence Take Home Message: In all post-transplanted MMA patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.
Competing Interests: This research was performed independently of all financial sponsors other than Erasmus MC, University Medical Center
(© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)