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Semin Neurol 2012; 32(05): 517-524
DOI: 10.1055/s-0033-1334471
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Calcineurin Inhibitor Encephalopathy

Aaron Mammoser
1   Neuro-Oncology/Department of Neurology, University of Michigan, Ann Arbor, Michigan
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Publication History

Publication Date:
15 May 2013 (online)

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Abstract

Calcineurin inhibitor encephalopathy (CIE) is a rare condition occurring in patients who are undergoing treatment with drugs from the calcineurin inhibitor (CI) family of immunosuppressants, either cyclosporine (CsA) or tacrolimus (TAC, FK506). Generally acute in onset, the symptoms are commonly reversible if properly managed in a timely fashion. The differential diagnosis is broad and an evaluation should include toxic, metabolic, infectious and ischemic causes, with abnormal cerebrospinal fluid (CSF) results (aside from elevated protein concentration in isolation), suggesting an etiology other than CIE. Neurologic deficits are generally reversible; however, the risk of permanent deficits or poor outcomes increases the longer the condition goes unrecognized.

Keywords

calcineurin inhibitor encephalopathy
 

  • References

  • 1 Gijtenbeek JMM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999; 246 (5) 339-346
    CrossrefPubMedGoogle Scholar
  • 2 Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000; 69 (4) 467-472
    CrossrefPubMedGoogle Scholar
  • 3 Eidelman BH, Abu-Elmagd K, Wilson J , et al. Neurologic complications of FK 506. Transplant Proc 1991; 23 (6) 3175-3178
    PubMedGoogle Scholar
  • 4 Ferrari U, Empl M, Kim KS, Sostak P, Förderreuther S, Straube A. Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms. Headache 2005; 45 (3) 211-214
    CrossrefPubMedGoogle Scholar
  • 5 Piilgaard H, Witgen BM, Rasmussen P, Lauritzen M. Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression. J Cereb Blood Flow Metab 2011; 31 (7) 1588-1598
    CrossrefPubMedGoogle Scholar
  • 6 Wijdicks EFM. Neurotoxicity of immunosuppressive drugs. Liver Transpl 2001; 7 (11) 937-942
    CrossrefPubMedGoogle Scholar
  • 7 Hinchey J, Chaves C, Appignani B , et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334 (8) 494-500
    CrossrefPubMedGoogle Scholar
  • 8 Vearrier D, Simpson SE, Greenberg MI. Mutism and persistent dysarthria due to tacrolimus-based immunosuppression following allogeneic liver transplantation. Am J Ther 2011; 18 (6) e274-e276
    CrossrefPubMedGoogle Scholar
  • 9 Bartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW. Posterior reversible encephalopathy syndrome after solid organ transplantation. AJNR Am J Neuroradiol 2008; 29 (5) 924-930
    CrossrefPubMedGoogle Scholar
  • 10 Schwartz RB, Bravo SM, Klufas RA , et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995; 165 (3) 627-631
    CrossrefPubMedGoogle Scholar
  • 11 Lucey MR, Kolars JC, Merion RM, Campbell DA, Aldrich M, Watkins PB. Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA. Lancet 1990; 335 (8680) 11-15
    CrossrefPubMedGoogle Scholar
  • 12 Onizuka M, Kunii N, Toyosaki M , et al. Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients. Bone Marrow Transplant 2011; 46 (8) 1113-1117
    CrossrefPubMedGoogle Scholar
  • 13 Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II. Clin Pharmacokinet 2010; 49 (4) 207-221
    CrossrefPubMedGoogle Scholar
  • 14 Yanagimachi M, Naruto T, Tanoshima R , et al. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. Clin Transplant 2010; 24 (6) 855-861
    CrossrefPubMedGoogle Scholar
  • 15 Balderramo D, Prieto J, Cárdenas A, Navasa M. Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. Transpl Int 2011; 24 (8) 812-819
    CrossrefPubMedGoogle Scholar
  • 16 Bartynski WS, Zeigler ZR, Shadduck RK, Lister J. Pretransplantation conditioning influence on the occurrence of cyclosporine or FK-506 neurotoxicity in allogeneic bone marrow transplantation. AJNR Am J Neuroradiol 2004; 25 (2) 261-269
    PubMedGoogle Scholar
  • 17 Shibasaki F, Hallin U, Uchino H. Calcineurin as a multifunctional regulator. J Biochem 2002; 131 (1) 1-15
    CrossrefPubMedGoogle Scholar
  • 18 Medyouf H, Ghysdael J. The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. Cell Cycle 2008; 7 (3) 297-303
    CrossrefPubMedGoogle Scholar
  • 19 Graef IA, Chen F, Crabtree GR. NFAT signaling in vertebrate development. Curr Opin Genet Dev 2001; 11 (5) 505-512
    CrossrefPubMedGoogle Scholar
  • 20 Kahan BD. Cyclosporine. N Engl J Med 1989; 321 (25) 1725-1738
    CrossrefPubMedGoogle Scholar
  • 21 Tedesco D, Haragsim L. Cyclosporine: a review. J Transplant 2012; 2012: 230386
    PubMedGoogle Scholar
  • 22 Macleod AM, Thomson AW. FK 506: an immunosuppressant for the 1990s?. Lancet 1991; 337 (8732) 25-27
    CrossrefPubMedGoogle Scholar
  • 23 Wasik M, Stepień-Sopniewska B, Lagodziński Z, Górski A. Effect of FK-506 and cyclosporine on human T and B lymphoproliferative responses. Immunopharmacology 1990; 20 (1) 57-61
    CrossrefPubMedGoogle Scholar
  • 24 Fortune K, Couriel D. Tacrolimus in hematopoietic stem cell transplantation. Expert Opin Drug Metab Toxicol 2009; 5 (7) 835-841
    CrossrefPubMedGoogle Scholar
  • 25 Barrett AJ, Le Blanc K. Prophylaxis of acute GVHD: manipulate the graft or the environment? . Best Pract Res Clin Haematol 2008; 21 (2) 165-176
    CrossrefPubMedGoogle Scholar
  • 26 Dezern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev Hematol 2011; 4 (2) 221-230
    CrossrefPubMedGoogle Scholar
  • 27 Meier J, Sturm A. Current treatment of ulcerative colitis. World J Gastroenterol 2011; 17 (27) 3204-3212
    PubMedGoogle Scholar
  • 28 Barshes NR, Goodpastor SE, Goss JA. Pharmacologic immunosuppression. Front Biosci 2004; 9: 411-420
    CrossrefPubMedGoogle Scholar
  • 29 Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008; 29 (6) 1043-1049
    CrossrefPubMedGoogle Scholar
  • 30 Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J 2001; 77 (903) 24-28
    CrossrefPubMedGoogle Scholar
  • 31 Kaminska B, Figiel I, Pyrzynska B, Czajkowski R, Mosieniak G. Treatment of hippocampal neurons with cyclosporin A results in calcium overload and apoptosis which are independent on NMDA receptor activation. Br J Pharmacol 2001; 133 (7) 997-1004
    CrossrefPubMedGoogle Scholar
  • 32 Lee SH, Kim BC, Yang DH , et al. Calcineurin inhibitor-mediated bilateral hippocampal injury after bone marrow transplantation. J Neurol 2008; 255 (6) 929-931
    CrossrefPubMedGoogle Scholar
  • 33 Rinne A, Banach K, Blatter LA. Regulation of nuclear factor of activated T cells (NFAT) in vascular endothelial cells. J Mol Cell Cardiol 2009; 47 (3) 400-410
    CrossrefPubMedGoogle Scholar
  • 34 Scherrer U, Vissing SF, Morgan BJ , et al. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 1990; 323 (11) 693-699
    CrossrefPubMedGoogle Scholar
  • 35 Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol 2008; 29 (6) 1036-1042
    CrossrefPubMedGoogle Scholar
  • 36 Bartynski WS, Zeigler Z, Spearman MP, Lin L, Shadduck RK, Lister J. Etiology of cortical and white matter lesions in cyclosporin-A and FK-506 neurotoxicity. AJNR Am J Neuroradiol 2001; 22 (10) 1901-1914
    PubMedGoogle Scholar
  • 37 Aydin K, Donmez F, Tuzun U, Minareci O, Atamer T. Diffusion MR findings in cyclosporin-A induced encephalopathy. Neuroradiology 2004; 46 (10) 822-824
    CrossrefPubMedGoogle Scholar