Tacrolimus encephalopathy

Neurological symptoms were observed in 12-25% of liver-transplant patients and in 29% of bone marrow transplant patients, but severe neurotoxicity occurred only in about 1% (18,19/21). They usually appeared within the first month of treatment, but were sometimes delayed (19). Particular attention should be paid to prompt recognition of severe neurotoxicity, because abnormalities of the white matter can occur. Patients usually improved rapidly after temporary ciclosporin withdrawal or dosage reduction, and tacrolimus has sometimes been used successfully instead (SEDA-21, 383) (18). However, recurrence of seizures and persistent electroencephalographic abnormahties were found in 46 and 70% of pediatric transplant patients respectively who had had ciclosporin acute encephalopathy and seizure syndrome and who were followed-up for 49 months (22). 

When neurological symptoms occur in patients taking tacrolimus they are very similar to those seen in patients taking ciclosporin, with more frequent insomnia, tremor, and headaches, but a similar rate of severe neurological adverse effects, such as acute psychosis, peripheral neuropathy, seizures, encephalopathy, coma, and paralysis. Persistent speech disorders (dysarthria, apraxia, expressive aphasia, akinetic mutism), and visual blurring can also occur (SEDA-21, 391) (SEDA-22, 420) (24). 

The presence of significant tacrolimus concentrations (5.2 and 1.3 ng/ml at 8 and 72 hours after the last dose) in the cerebrospinal fluid of a 64-year-old woman with a renal transplant, who developed an extremely severe form of encephalopathy after 21 months of treatment, suggested that tacrohmus can cross the blood-brain barrier (31). 

In children one advantage of tacrohmus is that it can reduce the dose of glucocorticoids required for immunosuppression. This in turn improves growth. When in one center the immunosuppression protocol was changed to tacrolimus plus mycophenolate mofetU and prednisone, two patients developed transient encephalopathy associated with tacrolimus (35). In both cases, the encephalopathy was managed by treating the associated hypertension and fluid overload tacrolimus was not withdrawn. 

Grimbert P, Azema C, Pastural M, Dhamane D, Remy P, Salomon L, Schortgen F, Baron C, Lang P. Tacrolimus (FK506)-induced severe and late encephalopathy in a renal transplant recipient. Nephrol Dial Transplant 1999 14(10) 2489-91. 

Parvex P, Pinsk M, Bell LE, O Gorman AM, Patenaude YG, Gupta IR. Reversible encephalopathy associated with tacrolimus in pediatric renal transplants. Pediatr Nephrol 2001 16(7) 537 2. 

Furukawa M, Terae S, Chu BC, Kaneko K, Kamada H, Miyasaka K. MRI in seven cases of tacrolimus (FK-506) encephalopathy utility of FLAIR and diffusion-weighted imaging. Neuroradiology 2001 43(8) 615-21. 

A 55-year-old woman who had received a liver transplant developed Hashimoto s encephalopathy after interferon therapy for hepatitis C virus accompanied by a lymphoproliferative disorder related to Epstein-Barr virus infection. Tacrolimus was withdrawn. She developed sudden loss of consciousness, convulsions, and cervical stiffness, which responded to prednisone. 

A 62-year-old, liver transplant recipient developed posterior reversible encephalopathy syndrome after taking tacrolimus 2 mg/day and metoprolol 150 mg/day when her serum tacrolimus concentration fell to 1.5 pg/l she recovered [76 ]. 

Posterior reversible encephalopathy syndrome occurred in an 18-year-old woman who had taken tacrolimus tor 14 days an MRI scan 4 weeks after withdrawal of tacrolimus showed almost complete resolution of all the changes that were noted in a scan that was taken at the time of presentation [77 ]. 

There has also been a report of a progressive necrotic encephalopathy following tacrolimus therapy in a 57-year-old man although there was some improvement after drug withdrawal, he was left with a residual hemiplegia [80" ]. 

Frantzeskaki F, Paramythiotou E, Papathanasiou M, Athanasios G, Gouliamos A, Armaganidis A. Posterior reversible encephalopathy syndrome in an intensive care unit patient receiving tacrolimus. Acta Anaesthesiol Scand 2008 52(8) 1177. 

Hodnett P, Coyle J, O Regan K, Maher MM, Fanning N. PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy. Emerg Radiol 2009 16(6) 493-6. 

P6rez Men6ndez-Conde C, Alvarez Diaz A, Delgado Silveira E, Bermejo Vicedo T. Leucoencefalopatia posterior reversible secundaria al tratamiento con tacrolimus. [Reversible posterior leuko-encephalopathy secondary to treatment with tacrolimus]. Farm Hosp 2008 32(5) 298-9. 

Barbas AS, Rege AS, Castleberry AW, Gommer J, Elhs MJ, Brennan TV, et al. Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation. Am J Transplant March 2013 13(3) 808-10. PubMed PMID 23331705. Epub 2013/01/22. eng. 

Fitzgerald RT, Osorio J, Panigrahy A, Mazariegos GV, ZuccoK G. Isolated leptomeningeal enhancement in tacrolimus-associated posterior reversible encephalopathy syndrome. Pediatr Neurol January 2013 48(l) 76-8. PubMed PMID 23290027. Epub 2013/01/08. eng. 

Hammerstrom AE, Howell J, Gulbis A, Rondon G, Champlin RE, Popat U. Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. Am J Hematol April 2013 88(4) 301-5. PubMed PMID 23460378. Epub... 

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