Research

High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome

Anna Noè^1* , Barbara Cappelli^1,2* , Alessandra Biffi^1,2 , Robert Chiesa^1,2 , Ilaria Frugnoli¹ , Erika Biral¹ , Valentina Finizio¹ , Cristina Baldoli³ , Paolo Vezzulli³ , Fabio Minicucci⁴ , Giovanna Fanelli⁴ , Rossana Fiori⁵ , Fabio Ciceri⁶ , Maria Grazia Roncarolo^1,2,7 and Sarah Marktel^1,2

¹  Pediatric Immunohaematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy

²  San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy

³  Deparment of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy

⁴  Deparment of Clinical Neurophysiology, San Raffaele Scientific Institute, Milan, Italy

⁵  Department of Anesthesia and Intensive Care, San Raffaele Scientific Institute, Milan, Italy

⁶  Haematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy

⁷  Vita-Salute San Raffaele University Medical School, Milan, Italy

author email corresponding author email* Contributed equally

Italian Journal of Pediatrics 2010, 36:14doi:10.1186/1824-7288-36-14

Published:	6 February 2010

Abstract

Background

Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%.

Methods

We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG.

Results

All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065).

Conclusions

Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.