Tacrolimus (FK506)-induced severe and late encephalopathy in a renal transplant recipient

Philippe Grimbert1, Christine Azema1, Myriam Pastural1, Djamel Dhamane1, Philippe Remy1, Laurent Salomon2, Fredérique Schortgen3, Christophe Baron1 and Philippe Lang1

1 Department of Nephrology, 2 Department of Urology and 3 Intensive Care Unit, Hôpital Henri Mondor, Creteil, France

Correspondence and offprint requests to: Dr Philippe Lang, Service de Nephrologie, Hôpital Henri Mondor, 51 avenue du Marechal de Lattre de Tassigny, 94010 Creteil, France.

Keywords: neurological complications; renal transplantation; tacrolimus



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Tacrolimus (FK506) is an effective immunosuppressive agent for the prevention of organ transplant rejection. The neurological complications of tacrolimus therapy that have been reported are usually mild, i.e. tremors, paresthesia and mild organic brain syndrome, but occasionally severe, i.e. aphasia, ataxia, severe organic brain syndrome, confusion, seizures and coma [1]. Severe neurological complications have been observed mostly after liver and lung transplantation. They are the result of high plasma FK506 levels or of a predisposing condition [2].

We observed an unusual case of severe encephalopathy which occurred late after renal transplantation in the absence of overdose, metabolic abnormalities or history of neurological disease.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 64-year-old woman underwent renal transplantation in May 1996 for chronic glomerulonephritis. Except for renal disease, she had no other medical history. The immediate post-operative course was uneventful. Immunosuppression included antithymocyte globulin, azathioprine and prednisone. On the eighth post-operative day, cyclosporin was introduced. On the fifteenth post-operative day, the patient had steroid-resistant acute rejection which was treated successfully with a course of monoclonal antibody OKT3. At the same time, cyclosporin was stopped and oral therapy with FK506 was initiated. The patient was discharged with a serum creatinine level of 90 µmol/l, and graft function remained stable for 18 months (Table 1Go).


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Table 1. Graft function and FK506 therapy
 
Renal transplantation was complicated by hyperparathyroidism which required surgical parathyroidectomy in October 1997. Two months later, serum creatinine levels increased to 160 µmol/l and an allograft biopsy was performed. Histological findings showed moderate interstitial fibrosis and a few peritubular calcifications without any signs of rejection.

The FK506 dose was decreased from 6 to 5 mg per day (0.1–0.08 mg/kg/day). However, the serum creatinine progressively reached 280 µmol/l and the patient was admitted to our unit in February 1998. On admission, the patient was receiving FK506 (0.08 mg/ kg/day), azathioprine (50 mg/day) and prednisone (10 mg/day).

She complained of memory loss and depressive ideas. Clinical examination showed the patient to be confused and disoriented but responsive, with normal vital signs including temperature. The neurological examination was normal.

One day after admission, a focal clonic epileptic fit of upper limb occurred, the neurological status worsened and the patient went into a coma. She was transferred to the medical intensive care unit and intubated.

The patient's biochemistry showed serum sodium 139 mmol/l, serum calcium 2 mmol/l, magnesium 0.6 mmol/l, total cholesterol 3.6 mmol/l, glycaemia 12 mmol/l, blood urea nitrogen 18 mmol/l, serum creatinine 280 µmol/l, white blood cell count 4500/mm3, haemoglobin 10 g/dl, platelet count 150 000/mm3 and C-reactive protein 5 mg/l. Liver enzymes were normal. A 12-h trough whole-blood FK506 level was 13 ng/ml by enzyme-linked immunosorbent assay (ELISA) (recommended therapeutic range 5–15 ng/ml). Serological tests for human immunodeficiency virus, human T leukaemia virus 1 and 2, cytomegalovirus (CMV), pp65 antigenaemia assay and the detection of cryptococcal antigen were negative in serum.

Cerebrospinal fluid (CSF) analysis was normal: normal glucose level, protein level 0.75 g/l, normal cell counts. Gram stain and bacterial, mycobacterial, viral and fungal cultures were negative for CSF. Polymerase chain reaction-based testing of CMV, herpes simplex virus type 1 and 2, human herpes simplex virus 6, Epstein–Barr virus, varicella–zoster virus and JC virus were negative for CSF, as was the test for spongiform encephalitis.

On the first day of admission, a computed tomographic (CT) brain scan showed moderate parieto-occipital cerebral atrophy without focal abnormalities. A repeat cranial CT scan and magnetic resonance imaging were performed 2 days later, showing identical results. A first electroencephalogram (EEG) showed generalized slowing with no focal features. After the seizure and coma, the EEG showed persistent epileptiform activity.

On the first day of admission, treatment with tacrolimus was interrupted and the dose of prednisone was increased to 1 mg/kg/day. Repeat CSF FK506 levels were 5.2 and 1.3 ng/ml, respectively at 8 and 72 h after the last dose. Systematic treatment against herpes virus and toxoplasm was initiated with ganciclovir and pyrimethamine. Meanwhile, the patient required prolonged ventilatory support for 21 days and anticonvulsive treatment for convulsive status epilepticus for 15 days.

The patient's evolution was complicated by Pseudomonas pneumonia treated with cefotaxim and vancocine. Severe neutropenia with an absolute neutrophil count of 250 mm3 occurred, and normalized in a few days with recombinant human granulocyte colony-stimulating factor. Serum creatinine progressivly decreased to 60 µmol/l. After extubation, back in the medical unit, the patient had (i) residual proximal and distal myopathy, which improved slowly with physical therapy, and (ii) severe alopecia which improved spontaneously in 3 months. Six months later, clinical examination was completely normal and serum creatinine remained at 90 µmol/l.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Neurological complications in transplant patients treated with tacrolimus (FK506) have been well documented, especially after liver transplantation [1]. The incidence of FK506-induced neurotoxicity varies from 5 to 30% in the literature [2,3]. It may occur early (<2 weeks) or late (>2 months) [2]. After renal transplantation, neurological complications are mostly benign [3,4].

This case of extremely severe encephalopathy which occurred following renal transplantation is unusual because it occurred late after the administration of FK506 (21 months) without any biological overdose, metabolic abnormality or any prior history of neurological incidents.

Similar cases have been described in liver and lung [3,5,6] transplant patients. This was associated with leucoencephalopathy with unspecific demyelinization identified in two cerebral biopsies [5,6]. Radiological abnormalities (cerebral CT scan and MRI) were located mainly in the parietal-occipital regions of the white matter, i.e. diffuse hypodense foci on CT scan, hyperintense lesions with MRI without enhancement after gadolinium injection, and a slow diffuse wave or an epileptogenic wave on the EEG. This was not noted in our case, however. FK506 levels were not determined in the CSF in any of the previously reported cases. The fact that we found significant FK506 levels in the CSF suggests that this molecule can cross the intact blood–brain barrier.

The factor which triggered encephalopathy in this case is not clear. The trough levels of FK506 were always within the therapeutic range (5–15 ng/ml), but nephrotoxicity was suggested by a progressive decrease in renal function and by rapidly progressive alopecia as described in 20% of liver transplantations [2].

The present case is exceptional for the severity of the clinical presentation, and its persistence even after FK506 had been discontinued. In most other cases, clinical symptoms disappeared rapidly within several days or weeks. Nevertheless, as in other cases (except one death of a liver transplant patient), the evolution of the patient was favourable, and the symptoms disappeared.

The physiopathological mechanism causing neurotoxicity of FK506 has not been clarified. Numerous studies showed signs of neurotoxicity even at therapeutic trough levels [1,5,7]. Certain authors suggested that factors such as hypocholesterolaemia or hypomagnesaemia may predispose, as is well known for cyclosporin A [8]. No such factors were identified in the present case. With regard to the nephrotoxicity of FK506, vasoconstriction and ischaemia have been suggested in one case of cortical blindness [9]. Other authors [10] suggested that FK506 inhibits cistrans peptidyl propyl isomerase receptors.

The fact that we identified significant FK506 levels in the CSF in the present case indicates that the molecule can cross the blood–brain barrier and probably attaches to myelin which is rich in lipids, permitting FK506 to exert a direct toxic effect. FK506 is selectively toxic for cultured glial cells. However, the mechanism which triggers demyelinization has still to be determined.



   References
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 Introduction
 Case
 Discussion
 References
 

  1. Eidelman BH, Abu-Elmagd K, Wilson J et al. Neurologic complications of FK 506. Transplant Proc 1991; 23: 3175–3178[ISI][Medline]
  2. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110–1115[Abstract/Free Full Text]
  3. Appignani B, Bhadelia R, Blacklow S, Wang A, Roland S, Freeman R. Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity. Am J Roentgenol 1996; 166: 683–688[Abstract]
  4. Pirsch JD, Miller J, Deierhoi M, Vicenti F, Filo R. A comparison of tacrolimus and cyclosporin for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977–983[ISI][Medline]
  5. Small L, Fukui M, Branblett G, Eidelman B. Immunosupression-induced leucoencephalopathy from tacrolimus. Ann Neurol 1996; 40: 575–580[ISI][Medline]
  6. Thyagarajan G, Cobanoglu A, Johnston W. FK506-induced fulminant leukoencephalopathy after single-lung transplantation. Ann Thorac Surg 1997; 64: 1461–1464[Abstract/Free Full Text]
  7. Mueller AR, Platz KP, Bechstein WO et al. Neurotoxicity after orthotopic liver transplantation. Transplantation 1994; 58: 155–170[ISI][Medline]
  8. De Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RAF. Central nervous system toxicity after liver transplantation: the role of cyclosporine and cholesterol. N Engl J Med 1987; 317: 861–866[Abstract]
  9. Shutter LA, Green JP, Newman NJ, Hooks MA, Gordon RD. Cortical blindness and white matter lesions in a patient receiving FK506 after liver transplantation Neurology 1993; 43: 2417–2418[ISI][Medline]
  10. Reyes J, Gayowski T, Fung J, Todo S, Alessiani M, Starzl TE. Expressive dysphasia, possibly related to FK506 in two liver transplant recipients. Transplantation. 1990; 50: 1043–1045[ISI][Medline]
Received for publication: 16. 4.99
Accepted in revised form: 28. 5.99





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