Skip to main content

Advertisement

SpringerLink
Log in

Tacrolimus-associated neurotoxicity isolated to the brainstem: two illustrative cases and a systematic review of the literature

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Introduction

Tacrolimus-associated neurotoxicity (TAN) manifests with wide clinical spectrum, ranging from mild tremors to severe encephalopathy. The isolated involvement of the brainstem is a rarely documented presentation of TAN, and its clinical and diagnostic characteristics are unclear.

Methods

We report two cases of brainstem-isolated TAN (bi-TAN). Moreover, we performed a systematic review of the literature on bi-TAN and extracted data concerning demographics, clinical characteristics, radiological features, and management. The systematic literature search followed PRISMA guidelines and a pre-defined protocol.

Results

Eleven patients, including our two, were identified (mean age: 41.3 years, ± 18.8; five males, 45%). Speech disturbance was the most common clinical presentation (45%). The mean latency from Tacrolimus initiation to bi-TAN onset was 26 days (± 30.8). Tacrolimus serum level tested above the reference range in three patients (mean: 26.83 ± 5.48). Brain MRI showed T2-FLAIR hyperintensities; three showed restricted diffusion on ADC maps. Neurological symptoms resolved completely in seven patients (63%) after Tacrolimus withdrawal or dose reduction.

Conclusions

Our findings suggest that bi-TAN could represent a brainstem variant of posterior reversible encephalopathy syndrome. Recognition of bi-TAN as a potential cause of isolated brainstem lesions is crucial to disentangle the diagnostic work-up and ensure prompt withdrawal or reduction of the offending agent.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The corresponding author has full access to all of the data and has the right to publish any and all data separate and apart from any sponsor.

Code availability

Not applicable.

References

  1. Wijdicks EFM, Wiesner RH, Dahlke LJ, Krom RAF (1994) FK506-induced neurotoxicity in liver transplantation. Ann Neurol 35(4):498–501. https://doi.org/10.1002/ana.410350422

    Article  CAS  PubMed  Google Scholar 

  2. Wu Q et al (2010) Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 64(3):169–177. https://doi.org/10.1159/000319032

    Article  CAS  PubMed  Google Scholar 

  3. Furukuwa M, Terae S, Chu BC, Kaneko K, Kamada H, Miyasaka K (2001) MRI in seven cases of tacrolimus (FK-506) encephalopathy: utility of FLAIR and diffusion-weighted imaging. Neuroradiology 43(8):615–621. https://doi.org/10.1007/s002340100545

    Article  Google Scholar 

  4. Hsiao CY, Ho MC, Ho CM, Wu YM, Lee PH, Hu RH (2021) Long-term tacrolimus blood trough level and patient survival in adult liver transplantation. J Pers Med. https://doi.org/10.3390/jpm11020090

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dumont FJ (2012) FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem. https://doi.org/10.2174/0929867003374723

    Article  Google Scholar 

  6. Spencer CM, Goa KL, Gillis JC (1997) Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs. https://doi.org/10.2165/00003495-199754060-00009

    Article  PubMed  Google Scholar 

  7. Bechstein WO (2000) Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int. https://doi.org/10.1111/j.1432-2277.2000.tb01004.x

    Article  PubMed  Google Scholar 

  8. Appignani BA, Bhadelia RA, Blacklow SC, Wang AK, Roland SF, Freeman RB (1996) Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity. Am J Roentgenol 166(3):683–688. https://doi.org/10.2214/ajr.166.3.8623651

    Article  CAS  Google Scholar 

  9. Triplett JD, Kutlubaev MA, Kermode AG, Hardy T (2022) Posterior reversible encephalopathy syndrome (PRES): diagnosis and management. Pract Neurol. https://doi.org/10.1136/practneurol-2021-003194

    Article  PubMed  Google Scholar 

  10. McKinney AM et al (2007) Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. Am J Roentgenol. https://doi.org/10.2214/AJR.07.2024

    Article  Google Scholar 

  11. Saad AF, Chaudhari R, Wintermark M (2019) Imaging of atypical and complicated posterior reversible encephalopathy syndrome. Front Neurol. https://doi.org/10.3389/fneur.2019.00964

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wu Q, Marescaux C, Qin X, Kessler R, Yang J (2014) Heterogeneity of radiological spectrum in tacrolimus-associated encephalopathy after lung transplantation. Behav Neurol 2014(i). https://doi.org/10.1155/2014/931808

  13. Covarrubias DJ, Luetmer PH, Campeau NG (2002) Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. AJNR Am J Neuroradiol. 23(6):1038–1048

    PubMed  PubMed Central  Google Scholar 

  14. Yakel JL (1997) Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. Trends Pharmacol Sci. https://doi.org/10.1016/S0165-6147(97)01046-8

    Article  PubMed  Google Scholar 

  15. Lai MM, Luo HR, Burnett PE, Hong JJ, Snyder SH (2000) The calcineurin-binding protein cain is a negative regulator of synaptic vesicle endocytosis. J Biol Chem. https://doi.org/10.1074/jbc.C000429200

    Article  PubMed  Google Scholar 

  16. Lyson T, Ermel LAD, Belshaw PJ, Alberg DG, Schreiber SL, Victor RG (1993) Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. Circ Res. https://doi.org/10.1161/01.res.73.3.596

    Article  PubMed  Google Scholar 

  17. Meyer N, Brodowski L, von Kaisenberg C, Schröder-Heurich B, von Versen-Höynck F (2021) Cyclosporine a and tacrolimus induce functional impairment and inflammatory reactions in endothelial progenitor cells. Int J Mol Sci. https://doi.org/10.3390/ijms22189696

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhou Q, Liu H, Qiao F, Wu Y, Xu J (2010) VEGF deficit is involved in endothelium dysfunction in preeclampsia. J Huazhong Univ Sci Technol - Med Sci. https://doi.org/10.1007/s11596-010-0359-y

  19. Tlemsani C et al (2011) Posterior reversible encephalopathy syndrome induced by anti-VEGF agents. Target Oncol. https://doi.org/10.1007/s11523-011-0201-x

    Article  PubMed  Google Scholar 

  20. Weiss N et al (2016) Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol. https://doi.org/10.1016/j.jhep.2016.07.046

    Article  PubMed  PubMed Central  Google Scholar 

  21. Weiss N et al (2017) Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis. Metab Brain Dis. https://doi.org/10.1007/s11011-016-9916-9

    Article  PubMed  Google Scholar 

  22. DiMartini A, Fontes P, Dew MA, Lotrich FE, de Vera M (2008) Age, model for end-stage liver disease score, and organ functioning predict posttransplant tacrolimus neurotoxicity. Liver Transplant. https://doi.org/10.1002/lt.21427

    Article  Google Scholar 

  23. Jusko WJ et al (1995) Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther. https://doi.org/10.1016/0009-9236(95)90153-1

    Article  PubMed  Google Scholar 

  24. Wong R et al (2003) Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol 122(1):128–134. https://doi.org/10.1046/j.1365-2141.2003.04447.x

    Article  CAS  PubMed  Google Scholar 

  25. Kino T et al (1987) Fk-506, a novel immunosuppressant isolated from a Streptomyces. J Antibiot (Tokyo). https://doi.org/10.7164/antibiotics.40.1249

    Article  PubMed  Google Scholar 

  26. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS (1997) A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation. https://doi.org/10.1097/00007890-199704150-00013

    Article  PubMed  Google Scholar 

  27. Reyes J, Gayowski T, Fung J, Todo S, Alessiani M, Starzl TE (1990) Expessive dysphasia possibly related to FK506 in two liver transplant recipients. Transplantation. https://doi.org/10.1097/00007890-199012000-00028

    Article  PubMed  PubMed Central  Google Scholar 

  28. Oliverio PJ, Restrepo L, Mitchell SA, Tornatore CS, Frankel SR (2000) Reversible tacrolimus-induced neurotoxity isolated to the brain stem. Am J Neuroradiol 21(7):1251–1254

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ravaioli M et al (2003) Speech disorder related to tacrolimus-induced pontine myelinolysis after orthotopic liver transplantation. Transplant Int Off J Eur Soc Organ Transplant. https://doi.org/10.1007/s00147-003-0620-4

    Article  Google Scholar 

  30. Fukazawa K, Nishida S, Aguina LM, Pretto EA (2011) Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation. Ann Transplant 16(3):139–142. https://doi.org/10.12659/AOT.882008

    Article  CAS  PubMed  Google Scholar 

  31. Bao J, Liang H (2014) Tacrolimus-induced permanent asymptomatic pontine myelinolysis after liver transplantation. Intern Med 53(15):1713–1714. https://doi.org/10.2169/internalmedicine.53.2418

    Article  PubMed  Google Scholar 

  32. Uchida H et al (2014) Central pontine myelinolysis following pediatric living donor liver transplantation: a case report and review of literature. Pediatr Transplant 18(4):18–21. https://doi.org/10.1111/petr.12255

    Article  Google Scholar 

  33. Silva Sieger FA, Serrano-Martínez AM, Castillo A, Vanegas Ballesteros M, Cote Florez TP (2017) Mielinolisis Póntica Central post-trasplante hepático: Reporte de Caso. Acta Neurológica Colomb 33(3):154–159

    Article  Google Scholar 

  34. Saadi A, Schmahmann JD (2016) Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion. Neurology 87(13):1423. https://doi.org/10.1212/WNL.0000000000003196

    Article  PubMed  Google Scholar 

  35. Patel K, Menon J, Shanmugam N, Kalyanasundaram S, Rela M (2022) Tacrolimus-induced central pontine myelinolysis in a pediatric liver transplant recipient. J Clin Exp Hepatol 12(2):714–715. https://doi.org/10.1016/j.jceh.2021.07.011

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UOC Clinica Neurologica - Rete Neurologica Metropolitana (NEUROMET), IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Via Albertoni 15, 40138, Bologna, Italy

    Simone Rossi, Rita Rinaldi, Gian Maria Asioli, Valentina Barone, Pietro Cortelli & Maria Guarino

  2. Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    Paolo Pianta & Maria Cristina Morelli

  3. Hepatobiliary Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Sant’Orsola Hospital, Bologna, Italy

    Matteo Cescon

  4. IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    Luca Faccioli & Luca Spinardi

  5. Dipartimento Di Scienze Biomediche E Neuromotorie, Università Di Bologna, Bologna, Italy

    Pietro Cortelli

Authors
  1. Simone Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gian Maria Asioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina Barone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Pianta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matteo Cescon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Cristina Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luca Faccioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Luca Spinardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pietro Cortelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Guarino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design and conceptualization of the study: S. R., R. R., M. G.

Drafting of the manuscript: S. R., G. M. A., V. B.

Major role in acquisition and interpretation of data: S. R., G. M. A., V. B., L. F., L. S.

Analysis of neuroradiological images: L. F., L. S.

Revision of the manuscript for intellectual content: P. P., M. C. M., M. C., P. C., M. G.

Corresponding author

Correspondence to Simone Rossi.

Ethics declarations

Ethics approval

This is a case series including two patients and a literature review. No ethical approval is required.

Informed consent

The patients included in this study provided written informed consent for the publication of anonymized data in accordance with the declaration of Helsinki.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

The participants have consented to the submission of the case report to the journal.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rossi, S., Rinaldi, R., Asioli, G.M. et al. Tacrolimus-associated neurotoxicity isolated to the brainstem: two illustrative cases and a systematic review of the literature. Neurol Sci (2024). https://doi.org/10.1007/s10072-024-07433-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10072-024-07433-8

Keywords

Search

Navigation