Severe Tacrolimus Leukoencephalopathy after Liver Transplantation

Case Report

A 12-year-old girl underwent an orthotopic liver transplantation in March 1999 and received tacrolimus 3 mg daily and prednisolon 15 mg daily. For 6 weeks after transplantation, she was hypertensive. Thereafter she remained normotensive with medication. Six months after transplantation, she had a focal, secondary generalizing seizure. Within 2 minutes, the seizure stopped. Blood pressure was normal. Neurologic examination revealed a left-sided hemiplegia including an extensor plantar response and a tremor of both hands. Laboratory findings, including liver and renal function, cholesterol, magnesium, and CSF were normal. Polymerase chain reaction analysis for JC virus in the CSF was negative. Tacrolimus blood level was within therapeutic range; 14.9 ng/mL (normal values 5–20 ng/mL). On the cerebral CT scan, the subcortical white matter was hypoattenuated (Fig 1A). MR imaging 1 day after presentation showed extensive white matter lesions on T2-weighted images, without gadolinium enhancement or decreased signal intensity on T1-weighted images (Fig 1B–F). Because of the late occurrence, the lesion extent, and the possibility that a treatable disorder such as PML might be overlooked, a stereotactic biopsy was performed after 2 weeks. After microscopic examination of the biopsy that did not show features of infection, diagnosis of tacrolimus-induced leukoencephalopathy was made (Fig 2A and B). After a decrease in tacrolimus dosage, the white matter lesions gradually disappeared (Fig 1G–H). Clinical recovery was complete within 5 months. At that time, MR imaging showed only mild cerebral white matter lesions (Fig 1J and K). During 3 years of follow-up, she has had no neurologic sequelae and has retained normal liver function.

• Download figure
• Open in new tab
• Download powerpoint

Fig 1.

Radiographic findings in a 12-year-old girl with a severe, reversible tacrolimus-related leukoencephalopathy.

A, Cerebral CT scan shows extensive subcortical hypoattenuation in both parietal regions (canthus-meatus plane, without contrast).

B, T1-weighted MR image obtained in the acute phase (day 1) shows no gadolinium enhancement or decreased signal intensity (5 mm slices, TR 760, TE 15/1, TA 03:42).

C–F, T2-weighted MR images obtained in the acute phase (day 1) show hyperintense lesions in the parietal white matter (C), periventricular white matter (D), cerebellum (E), and brainstem (F) (5 mm slices, TR 3100, TE 98/2, TA 04:03).

G–I, T2-weighted MR images obtained 18 days later (day 19), after a dose reduction of tacrolimus and stereotactic biopsy 6 days earlier, show a remarkable decrease in the hyperintense lesions in the parietal white matter (G). The hyperintense lesions in the cerebellar white matter and brain stem (H) have disappeared. Note the biopsy lesion (I) (5 mm slices, TR 3100, TE 98/2, TA 04:03).

J and K, T2-weighted MR images obtained 5 months after G–I show only a mild right-sided hyperintense lesion (J). In the left hemisphere, the biopsy lesion resides (K) (5 mm slices, TR 3100, TE 98/2, TA 04:03).

• Download figure
• Open in new tab
• Download powerpoint

Fig 2.

Biopsy specimens.

A, In the biopsy fragments, the cerebral white matter shows a normal aspect with ample staining for myelin, absence of inflammatory infiltrate and (in contrast to PML) absence of enlarged nuclei of glial cells. Occasional perivascular macrophages (arrow), however, contain granular, blue-staining material, consistent with myelin debris. (Combined Luxol Fast Blue and Hematoxylin-Eosin staining; original magnification ×630).

B, Electron microscopy, performed on material retrieved from the paraffin block, reveals multilamellar particles in the perivascular macrophages, corroborating the myelin nature of these granules.

Discussion

Leukoencephalopathy is a complication of tacrolimus use in both adults and children and is usually reversible after dose reduction of tacrolimus in almost all patients when diagnosed promptly (5).

The pathophysiologic basis for tacrolimus neurotoxicity is unknown. Factors that are reported to facilitate neurotoxicity are systemic hypertension, high-dose corticosteroid therapy, serum hypocholesterolemia, hypomagnesemia, aluminum overload, and hepatic encephalopathy (2). In our patient, high-dose corticosteroid therapy might have contributed to the leukoencephalopathy, whereas the contribution of hypertension seems less likely, because it was successfully treated.

Tacrolimus is a lipophilic agent that crosses the blood-brain barrier and, like cyclosporine, may have a direct neurotoxic effect, especially on the lipid-rich white matter (6). Furthermore, cyclosporine is known to cause axonal swelling, but this effect has not yet been described for tacrolimus use (5).

Our patient had one focal, secondary generalizing seizure lasting less than 2 minutes. This was the single epileptic event. Seizures may lead to transient MR signal intensity changes themselves (7, 8). Because of the lack of MR imaging findings of involvement of cortical structures, the extent of the lesions, and the absence of a prolonged epileptic event, we find that the convulsion cannot be responsible for the white matter lesions.

In most patients with tacrolimus-related leukoencephalopathy, a biopsy procedure is not considered to be necessary when after cessation or dose reduction of tacrolimus the clinical condition improves. In our patient, however, the lesions were very extensive and occurred relatively late after transplantation. Therefore other diseases, especially PML, had to be considered. In the only previous histopathologic report of tacrolimus leukoencephalopathy, focal, predominantly perivenous demyelination was found (4). In our patient, stereotactic biopsy findings of cerebral white matter showed, by light microscopy, a normal structure and staining for myelin (Fig 2A), but occasional perivascular macrophages containing lamellar bodies consistent with myelin debris were present (Fig 2A and B).

Conclusion

We conclude that leukoencephalopathy is a serious complication of tacrolimus use that can be completely reversible after dose decrement. Although at the radiologic level a predilection for the posterior cerebral white matter has been reported, the lesions may be much more extensive. The relatively mild histologic findings and the reversibility of the clinical syndrome indicate that these impressive radiologic changes are, at least in an early phase, in large part the result of reversible edema instead of destructive structural alterations.