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Ann Thorac Surg 1997;64:1461-1464
© 1997 The Society of Thoracic Surgeons

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Case Report

FK506-Induced Fulminant Leukoencephalopathy After Single-Lung Transplantation

Division of Cardiopulmonary Surgery and Department of Neurology, Oregon Health Sciences University, Portland, Oregon

Accepted for publication June 14, 1997.

	Abstract

Top Footnotes Abstract Introduction Comment References

 
FK506 is being used increasingly to prevent rejection after organ transplantation. Its use is associated with a wide spectrum of neurotoxicity, which has been described after most solid organ transplantations, but reports after lung transplantation are extremely rare. This is a report of the pathologic correlation of the clinical and radiologic features of delayed FK506-induced fulminant leukoencephalopathy after single-lung transplantation. The patient presented with neurologic symptoms that progressed to seizure activity. Neuroimaging showed diffuse changes in the brain, and results of a brain biopsy were consistent with leukoencephalopathy with microglial and astrocytic activation. The patient had a remarkable improvement in clinical status after discontinuation of FK506 administration, with resolution of the changes seen on neuroimaging.

	Introduction

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The success of solid-organ transplantation depends on the ability of immunosuppressive agents to prevent and treat allograft rejection. FK506 (tacrolimus), a macrolide antibiotic, is being increasingly used and is 10 to 100 times more potent than cyclosporine in its immunosuppressive properties [1, 2]. The advantage of FK506 in reducing the risk of obliterative bronchiolitis after lung transplantation has been shown recently [2]. Neurotoxicity after FK506 use has been documented after liver, kidney, and heart transplantation [3, 4], but reports after lung transplantation are extremely rare.

We report a case of delayed fulminant leukoencephalopathy induced by FK506 after single-lung transplantation. The data presented include neurologic, radiologic, and neuropathologic features of this process, with longitudinal neuroimaging demonstrating the natural history of the process, which includes the spontaneous resolution on withdrawal of FK506.

A 59-year-old woman with chronic obstructive pulmonary disease underwent a right single-lung transplantation on February 25, 1996, and was started on a regimen of cyclosporine, azathioprine, and prednisone for immunosuppression. Multiple episodes of rejection developed during follow-up, which were treated with pulse steroids and then with FK506, mycophenolate, and prednisone. The patient continued to do well until the present admission.

She presented to the hospital on December 24, 1996, with 4 days of confusion, expressive aphasia, memory loss and associated headache, and intermittent fevers reaching 40°C. Her medications on admission included FK506, mycophenolate, prednisone, sulfamethoxazole/trimethoprim, and bronchodilators. On examination, the patient was confused but responsive, with normal vital signs including temperature. Abnormal findings on neurologic examination included difficulty in following directions, mild left-sided weakness, and a wide-based, uncertain gait. Reflexes were brisk and symmetric with a flexor plantar response. There was no clonus. The sensory and the fundoscopic examination results were normal.

The serum chemistries, cerebrospinal fluid chemistry and cell counts, and a computed tomographic scan of the cranium, performed on the first day of this admission, were all within normal limits. Her whole-blood FK506 level was 5.6 ng/mL. However, a week later, while still being worked up, she had multiple tonic-clonic generalized seizures. Her whole-blood FK506 level at this time was 13 ng/mL. An unenhanced cranial computed tomographic scan showed new multiple areas of low attenuation bilaterally, predominantly in the subcortical white matter, including the cerebellar hemispheres. Magnetic resonance imaging, on proton density and T2-weighted images, showed diffuse abnormalities of subcortical white matter and gray matter, including the thalamus, bilaterally with meningeal enhancement after contrast administration (Fig 1).

View larger version (107K): [in this window] [in a new window]   Fig 1. . Axial T2-weighted (A) and post–gadolinium-enhanced T1-weighted (B) magnetic resonance images showing diffuse changes in the subcortical white matter and gray matter bilaterally (thick arrows) with meningeal enhancement (thin arrows).

View larger version (123K): [in this window] [in a new window]   Fig 2. . Immunohistochemical stain for CD 68 antigen, showing profound microglial activation and hypertrophy within the white matter.

View larger version (116K): [in this window] [in a new window]   Fig 3. . Immunohistochemical stain for glial fibrillary acid protein, demonstrating marked increase in the number of activated astrocytes within the white matter.

View larger version (126K): [in this window] [in a new window]   Fig 4. . Axial T2-weighted (A) and post–gadolinium-enhanced T1-weighted (B) magnetic resonance images 2 weeks after the first scan, showing resolution of the changes noted on the first scan (thick arrows) and the development of 1-cm focal hemorrhage from the area where biopsy was performed in the right frontal lobe (thin arrow).

	Comment

Top Footnotes Abstract Introduction Comment References

The incidence of FK506-induced neurotoxicity, which may be early (<2 weeks) or late (>2 months) [3], varies from 5% to 30% in the literature [3–5]. The spectrum of neurologic complications may range from mild (tremors, paresthesias, and mild organic brain syndromes) to severe (aphasia, ataxia, severe organic brain syndromes, confusion, seizures, and coma) [3, 4].

The clinical features of the FK506-induced leukoencephalopathy in our patient are similar to those previously described [6]. The onset is with mild symptoms that progress rapidly to generalized seizures in a short time. After the seizure, patients usually have a postictal phase with a normal or an abnormal neurologic examination. They have a normal fundoscopic examination, and analysis of the cerebrospinal fluid does not reveal an infective or metabolic cause for the symptoms.

The syndrome usually reverses on decreasing or stopping administration of FK506 [3, 5, 6]. The absolute FK506 levels associated with imaging findings have been inconsistent in the literature [6]. However, variability in the FK506 levels is a feature of the clinical syndrome [7]. The dosage of FK506 must be tailored for each patient, as the toxicity across individuals is not dose related.

In many cases of toxicity, trough serum or whole-blood levels of FK506 are elevated [3, 5]. The neurologic recovery usually lags behind the declining FK506 levels by several days [5], and the neurologic picture may actually deteriorate after discontinuation of FK506 administration before any improvement is observed.

The precise mechanism of FK506-induced neurotoxicity remains unknown. Toxicity has most frequently been observed in organs with high cyclophilin concentrations, such as kidney, brain, and liver [3]. Selective glial cell toxicity in culture has correlated with typical reversible changes in the white matter revealed by computed tomographic scanning and magnetic resonance imaging [3].

The radiographic findings of our patient are consistent with those previously described. White matter changes with FK506, observed on magnetic resonance imaging, have been described in case reports [8, 9]; however, in a report of 14 patients with FK506 neurotoxicity after liver transplantation, no structural abnormalities could be imaged, unlike the well-described white matter changes that occur with cyclosporine toxicity [7].

The differential diagnosis of this syndrome includes bacterial and viral infections as well as vascular, metabolic, and neoplastic processes. A combination of clinical picture, computed tomographic or magnetic resonance imaging findings, and no clinical or laboratory evidence of infection or metabolic abnormality should alert the physician to the diagnosis.

If the patient is clinically stable, it is prudent to stop giving FK506 and wait as the signs and symptoms resolve with reduction in the dose or after discontinuation of FK 506 administration. A brain biopsy should not be necessary for the diagnosis, although one may be warranted, if the patient does not improve, to rule out a neoplastic process or an opportunistic infection. It is unclear at this time if the intermittent fever and the meningeal enhancement on magnetic resonance imaging that were present concurrently with the rest of the clinical picture represent a part of this syndrome.

There appears to be similarity in the toxic effects of FK506 and related compounds, including cyclosporine [10], but the precise mechanism causing this syndrome has yet to be defined.

	Footnotes

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Address reprint requests to Dr Cobanoglu, Division of Cardiopulmonary Surgery, Oregon Health Sciences University, Mail Code L-353, 3181 SW Sam Jackson Park Rd, Portland, OR 97201.

	References

Top Footnotes Abstract Introduction Comment References

 

1. Tzakis AG, Fung JJ, Todo S, et al. Use of FK 506 in pediatric patients. Transplant Proc 1991;23:924–7.[Medline]
2. Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995;60:580–5.
3. Mueller AR, Platz KP, Bechstein WO, et al. Neurotoxicity after orthotopic liver transplantation. Transplantation 1994;58:155–70.[Medline]
4. Fung JJ, Alessiani M, Abu-Elmagd K, et al. Adverse effects associated with the use of FK506. Transplant Proc 1991;23:3105–8.[Medline]
5. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991;23:3175–8.[Medline]
6. Small SL, Fukui MB, Bramblett GT, Eidelman BH. Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506). Ann Neurol 1996;40:575–80.[Medline]
7. Wijdicks EFM, Weisner RH, Dahlke RN, Krom RA. FK 506 induced neurotoxicity in liver transplantation. Ann Neurol 1994;35:498–501.[Medline]
8. Reyes J, Gayowski T, Fung J, Todo S, Alessiani M, Starzl TE. Expressive dysphasia possibly related to FK 506 in two liver transplant recipients. Transplantation 1990;50:1043–5.[Medline]
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;43:2417–8.[Free Full Text]
10. Dumont FJ, Staruch MJ, Koprak SL, et al. The immunosuppressive and toxic effects of FK506 are mechanistically related: pharmacology of a novel antagonist of FK506 and rapamycin. J Exp Med 1992;176:751–60.[Abstract/Free Full Text]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ganeshakrishnan K. Thyagarajan Adnan Cobanoglu Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thyagarajan, G. K. Articles by Johnston, W. Search for Related Content PubMed PubMed Citation Articles by Thyagarajan, G. K. Articles by Johnston, W.