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

Femke Molema; Monique Williams; Janneke Langendonk; Sarwa Darwish-Murad; Jacqueline van de Wetering; Ed Jacobs; Willem Onkenhout; Esther Brusse; Anke van der Eerden; Margreet Wagenmakers

doi:10.1002/jmd2.12088

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

JIMD Rep. 2020 Jan 22;51(1):89-104. doi: 10.1002/jmd2.12088. eCollection 2020 Jan.

Authors

Affiliations

¹ Department of Pediatrics, Center for Lysosomal and Metabolic Disease Erasmus - Sophia Children's Hospital, University Medical Center Rotterdam The Netherlands.
² Department of Internal Medicine, Erasmus University Medical Center Center for Lysosomal and Metabolic Disease Rotterdam The Netherlands.
³ Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam The Netherlands.
⁴ Department of Internal Medicine Erasmus University Medical Center, Nephrology and Transplantation, Rotterdam Transplant Group Rotterdam The Netherlands.
⁵ Department of Clinical Genetics Erasmus University Medical Center Rotterdam The Netherlands.
⁶ Department of Neurology Erasmus University Medical Center Rotterdam The Netherlands.
⁷ Department of Radiology Erasmus University Medical Center Rotterdam The Netherlands.

Abstract

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.

Keywords: calcineurin inhibitors; liver and/or kidney transplantation; methylmalonic acidemia; neurotoxicity; posterior reversible encephalopathy syndrome/PRES.