Objectives: Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.

Materials and Methods: We retrospectively investigated 205 patients who had a living-donor liver transplantation performed at our institution between August 1998 and October 2008.

Results: Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immuno­suppression after their living-donor liver transplantation. The underlying diseases were alcoholic cirrhosis in 3 cases, viral cirrhosis in 2, biliary atresia in 1, and Wilson disease in 1. Time to clinical onset after tacrolimus medication was 15.6 days (range, 6-30 days). The neurologic symptoms included headache, confusion, myoclonus, seizures, and visual disturbances. The mean serum trough level of tacrolimus at clinical onset was not very high (11.7 ng/mL [range, 6.0-14.2 ng/mL]). T2-weighted magnetic resonance imaging in all cases showed diffuse high signal in the white matter of the frontal, parieto-occipital, and temporal lobes. Treatment with antihypertensives, anticonvulsants, and withdrawal of tacrolimus resulted in amelioration of symptoms and magnetic resonance imaging abnormalities. Six patients showed complete recovery, while the seventh had residual rigidity and cognitive impairment caused by hypoxia during a convulsion.

Conclusions: Tacrolimus neurotoxicity can occur despite low trough levels; it depends on variations in pharmacokinetics, such as absorption and maximum concentration level. Early diagnosis and treatment of leukoencephalopathy syndrome should contribute to complete remission.

Key words : Complication, Liver transplantation, Neurotoxicity, Tacrolimus

The results of deceased-donor and living-donor liver transplantations have improved in recent years. The outcome of living-donor liver transplantation correlates with progress in surgical techniques, perioperative management, and immunosuppressive therapies. Calcineurin inhibitors, cyclosporine, and tacrolimus are effective immunosuppressants, and their use has resulted in rapid improvement in recipient survival.^1-4 However, serious toxic adverse effects of these agents have been reported including neurotoxicity, headaches, tremors, paresthesia, sleep disturbances, and mood changes, with an estimated incidence of 20% to 40% of patients who undergo an organ transplant.^5-8 Transplantation recipients also are reported to develop what is collectively termed immunosuppression-associated leukoencephalopathy syndrome, which is a brain disorder of predominantly subcortical white matter lesions with severe symptoms.^9-11 We investigated the clinical features of leukoencephalopathy after a living-donor liver transplantation.

Patients and Methods

Two hundred five patients underwent a living-donor liver transplantation at our institution between August 1998 and October 2008. There were 172 adult patients and 33 pediatric patients (< 18 years). The indications for transplant included viral liver cirrhosis (n=85), cholestatic cirrhosis (n=56), acute liver failure (n=24), cryptogenic liver failure (n=14), alcoholic cirrhosis (n=12), Wilson disease (n=7), metabolic disorder (n=5), and liver tumor (n=2). Graft types were the right lobe (n=104), the left lobe (n=69), a lateral segment (n=26), a posterior segment (n=5), and a monosegment (n=1).

Surgical procedures, drug monitoring, and assessment of leukoencephalopathy syndrome
Donor hepatectomy and recipient transplant procedures were performed as previously described.^{12, 13} The volume of the resected liver segment was calculated before surgery by computed tomographic volumetry. The choice of resected segments for donation was dictated by the need to maintain a remnant liver volume of more than approximately 35% of the donor’s original liver volume. The resected segments included the left lobe, the extended left lobe (with the left caudate lobe), and the right lobe. Regarding the donor procedure, a parenchymal dissection was performed without inflow occlusion of the Glissonian pedicle of the liver graft. The liver graft was flushed and preserved in cold University of Wisconsin solution. In the recipient, the native liver was resected, preserving the inferior vena cava. After reconstruction of the hepatic and portal veins, the hepatic artery was anastomosed under microscopy or surgical loupe. The biliary tract was reconstructed by a Roux-en-Y hepatico­jejunostomy or a duct-to-duct hepatic­o­choledochostomy.

The initial immunosuppressive regimen consisted of tacrolimus or cyclosporine and a short course of steroids with tapering over 3 to 6 months. Tacrolimus and cyclosporine were started at 0.12 mg/kg/d, or 6 to 8 mg/kg/d, via a nasogastric feeding tube. The dosage was carefully adjusted according to the drug trough level. Mycophenolate mofetil was administered in patients with renal insufficiency. Serum tacrolimus or cyclosporine drug trough levels were measured 12 hours after administration of the drug, and every morning during the postoperative acute phase.

During the postoperative period, the patient’s systolic blood pressure was controlled within 160 mm Hg by an antihypertensive agent, calcium channel blocker. The appearance of neurologic symptoms, such as headache, tremors, paresthesia, seizures, visual abnormalities, or confusion were noted, and magnetic resonance imaging and computed tomography were performed in addition to laboratory tests such as serum electrolytes, NH3, blood sugar level, and arterial gas analysis.

Results

Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immunosuppression after their living-donor liver transplantation. On the other hand, none of the patients treated with cyclosporine-based immunosuppression developed leuko­encephalopathy syndrome. The 7 patients consisted of 5 adults and 2 children (< 10 years of age; 2 males and 5 females). The mean age was 40.7 years (range, 6-57 years). The model for end-stage liver disease (MELD) score, a marker of the general preoperative status of the recipient, was 18.3 (range, 10-32). The underlying disease necessitating a living-donor liver transplantation was alcoholic cirrhosis in 3 cases, viral hepatitis in 2 cases, biliary atresia in 1 case, and Wilson disease in 1 case. Interestingly, 43% of the patients with leukoencephalopathy syndrome (3/7) had alcoholic cirrhosis, and they formed 25% of the alcohol-related living-donor liver transplant patients (3/12). Operating time, blood loss, graft-to-recipient body weight ratio, and total ischemic time were 10 h 29 m, 92 mL/kg, 1.12 minutes, and 107 minutes. With regard to the diagnosis of leukoencephalopathy syndrome, the time to clinical onset was 15.6 days (range, 6-21 days), which was equivalent to the duration of the tacrolimus medication. The neurologic symptoms were confusion in 85% of the patients (6/7), myoclonus/seizure in 43% of the patients (3/7), and cortical blindness in 14% of the patients (1/7). One patient, a 55-year-old man with hepatitis C, required pulmonary resuscitation because he was found hypopneic due to a tonic convulsion attack.

The serum trough level of tacrolimus on the day of clinical onset was 11.7 ng/mL (range, 6.0-14.2 ng/mL). The results of other laboratory tests such as liver function tests, serum electrolytes, NH3, blood sugar level, and total cholesterol showed no abnormalities. Furthermore, the results of fungal and human herpes viral infection tests were negative. Not all patients showed hypertension owing to maintenance by antihypertensive agents after transplantation. However, all 7 patients were examined by magnetic resonance imaging and computed tomography for further investigation of the central nervous system. The T2-weighted magnetic resonance imagings showed diffuse high signal in the white matter of the parieto-occipital and temporal lobes in all patients (Figure 1), although a computed tomographic scan showed no abnormalities. Treatment with antihypertensive agents, anticonvulsants, the immediate withdrawal of tacrolimus, and a switch to low-dose cyclosporine reversed the symptoms. This was associated with a disappearance of the magnetic resonance imaging abnormalities. It took 8 days ± 3.5 (range, 6-14 days) for the neurologic symptoms and neuroimaging abnormalities to disappear after ceasing tacrolimus. There were no deaths. Regarding long-term effects, 6 patients showed complete recovery, while the last patient had residual rigidity and cognitive impairment because of hypoxia during a convulsion (Table 1).

Discussion

Leukoencephalopathy syndrome was reported as a disease in 1996.¹⁴ It encompasses a reversible syndrome of headaches, the sudden onset of seizures, visual abnormalities, and hemiparesis. These appear after immunosuppressive therapy used after surgery or as a treatment for aplastic anemia including interferon for melanoma, eclampsia, and acute hypertensive encephalopathy.

Several studies have investigated immuno­suppressive-associated leukoencephalopathy syndrome. Although the most-common cause of leukoencephalopathy syndrome is the use of immunosuppressants such as tacrolimus and cyclosporine, other causes have been reported.¹⁵ The overall incidence of leukoencephalopathy syndrome after organ transplantation has been reported to be 20% to 40%,^5-8 with 12% to 27% showing central nervous complications.^{16, 17} The reported incidence of leukoencephalopathy syndrome in liver transplants is 0.4% to 6%.^{9, 10, 18, 19} Time to onset of leukoencephalopathy syndrome in liver transplantation tends to be shorter than in other organ transplantations, and in most cases, it occurs within 30 days of the transplantation.²⁰ This study showed that the incidence of leukoencephalopathy syndrome in living-donor liver transplantation was 3.9% (7/205), and leukoencephalopathy syndrome in all cases developed within 3 weeks of the transplantation.

Clinically, leukoencephalopathy syndrome is associated with various neurologic symptoms. The most notable are visual abnormalities (cortical blindness, homonymous hemianopsia, blurred vision, and unspecified visual changes), seizures, hemiplegia, hemiparesis, mental status changes, and speech disturbances.^{5-11, 14-17, 20} Mental status changes are important symptoms consisting of confusion, disorientation, lethargy, and irritability.²⁰ The diagnosis of leukoencephalopathy syndrome is usually made by magnetic resonance imaging or computed tomography. A T2-weighted spin-echo magnetic resonance imaging scan will show scattered high-signal intensity in the occipital, parietal, and temporal white matter. On the other hand, a computed tomography scan will show white matter edema as low-attenuation or lucencies.^21-23 Comparison of the diagnostic use of the 2 imaging modalities indicates that the sensitivity of the magnetic resonance imaging is higher than that of computed tomography.^{20, 24} A magnetic resonance image is the preferred imaging modality for diagnosing leukoencephalopathy syndrome. Although computed tomography does not detect early-phase leukoencephalopathy syndrome, it is simple and necessary for the differential diagnosis of leukoencephalopathy syndrome from other central nervous system disorders. As hypertensive encephalopathy could show similar magnetic resonance imaging findings, existing hypertension should be excluded for diagnosing leuko­encephalopathy syndrome.

Our patients developed confusion, myoclonus, seizures, and visual disturbances, with 1 patient having a tonic convulsion that required resuscitation. All cases could be diagnosed immediately by magnetic resonance imaging and treated. Adequate and prompt therapies resulted in clinical improvement in all but 1 case, followed by complete recovery without any after effects. Basically, the prognosis of leukoencephalopathy syndrome is good, because it is reversible and generally shows full recovery after the withdrawal or a dosage modification of the immunosuppressants, and treatment with antihypertensive agents and anticonvulsants. However, we suggest that leukoencephalopathy syndrome can sometimes cause severe convulsions possibly leading to death.

The precise mechanism of leukoencephalopathy syndrome is unknown. It is possible that tacrolimus and cyclosporine pass the blood-brain barrier, based on their lipophilic properties, and directly cause neurotoxicity, especially in the lipid-rich white matter. Histopathologically, cerebral brain white matter lesions consist of demyelination or perivascular macrophages containing lamellar bodies, consistent with myelin debris.^{25, 26} Although the relation between development of leukoencephalopathy syndrome and use of these immunosuppressants has been pointed out,²⁷ the critical dosage and serum concentration in the human body have not yet been reported. Indeed, in our patients, although the serum tacrolimus trough levels were not high (mean 11.7 ng/mL, range, 6.0-14.2 ng/mL), the patients developed leukoencephalopathy syndrome.

Furthermore, withdrawal of immuno­suppressants resulted in an immediate improvement of symptoms and resolution of the magnetic resonance imaging abnormalities. It is possible that development of leukoencephalopathy syndrome in some, but not all, patients depends on differences in pharmacokinetics.

In patients with leukoencephalopathy syndrome, it is possible that the area under concentration time curve or maximum concentration (C_max) of tacrolimus could be higher than that expected from their trough levels. Area under concentration time curve is surely the most appropriate method of determining individual dosage. However, tacrolimus can demonstrate a high degree of both between-individual and within-individual variability, which may result in an increased risk of therapeutic failure. In this regard, interpretation of blood concentration could be confounded by relative differences between assays.^28-30 Not to mention that between-individual and within-individual variability could be another factor based on various physiological and pathological conditions such as bowel movements, absorption speed, meal ingredients, and coexisting drug intake.^30-33

Most clinicians practically refer to serum trough levels for the control of tacrolimus and cyclosporine. The area under concentration time curve and C_max should be more important in predicting development of neurotoxicity, but it is difficult and intricate to examine individual area under concentration time curve and C_max. Settlement of these issues requires further analysis of the pharmacokinetics and the development of new agents with suitable pharmacokinetics, low C_max, adequate area under concentration time curve, and easy control.

Modified tacrolimus is already available as a new agent with effective immunosuppression properties equivalent to the original tacrolimus with a similar area under concentration time curve and a reduced C_max.^34-36 Such modifications could decrease the incidence and severity of neurologic complications. Further studies are necessary to determine if modified tacrolimus could decrease the incidence and severity of neurologic complications.

Conclusions

Leukoencephalopathy syndrome is a rare neurologic complication after a living-donor liver transplantation but generally has a good prognosis. The development of leukoencephalopathy syndrome seems to depend on the dosage of immuno­suppressive agents, but our study revealed that leukoencephalopathy syndrome could also occur despite low trough levels of these agents. Modified tacrolimus may decrease the incidence and severity of neurologic complications with a reduced C_max. Severe neurologic complications can sometimes cause grave consequences, such as sequela and death. Although the clinical features of leukoencephalopathy syndrome vary among patients, it is possible to diagnose the condition during the early reversible stages. For the early diagnosis of leukoencephalopathy syndrome, clinicians should be aware of the clinical features of leukoencephalopathy syndrome and the diagnostic ability of magnetic resonance imaging.

References:

1. Buckels JA. Liver transplantation: current status, complications and prevention. J Antimicrob Chemother. 1995;36(suppl B):39-49.
2. Starzl TE, Iwatsuki S, Esquivel CO, et al. Refinements in the surgical technique of liver transplantation. Semin Liver Dis. 1985;5(4):349-356.
3. Hooks MA. Tacrolimus, a new immunosuppressant--a review of the literature. Ann Pharmacother. 1994;28(4):501-511.
4. Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, T Bustami R, Dyke DB. Immunosuppression: practice and trends. Am J Transplant. 2004;4(suppl 9):38-53.
5. Andrews BT, Hershon JJ, Calanchini P, Avery GJ 2nd, Hill JD. Neurologic complications of cardiac transplantation. West J Med. 1990;153(2):146-148.
6. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc. 1991;23(6):3175-3178.
7. Lee JM, Raps EC. Neurologic complications of transplantation. Neurol Clin. 1998;16(1):21-33.
8. Appignani BA, Bhadelia RA, Blacklow SC, Wang AK, Roland SF, Freeman RB Jr. Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity. AJR Am J Roentgenol. 1996;166(3):683-688.
9. Cilio MR, Danhaive O, Gadisseux JF, Otte JB, Sokal EM. Unusual cyclosporin related neurological complications in recipients of liver transplants. Arch Dis Child. 1993;68(3):405-407.
10. de Groen PC, Wiesner RH, Krom RA. Advanced liver failure predisposes to cyclosporine-induced central nervous system symptoms after liver transplantation. Transplant Proc. 1989;21(1 Pt 2):2456.
11. Bonham CA, Dominguez EA, Fukui MB, et al. Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation. 1998;66(12):1596-1604.
12. Umeda Y, Yagi T, Sadamori H, et al. Effects of prophylactic splenic artery modulation on portal overperfusion and liver regeneration in small-for-size graft. Transplantation. 2008;86(5):673-680.
13. Kawasaki S, Makuuchi M, Matsunami H, et al. Living related liver transplantation in adults. Ann Surg. 1998;227(2):269-274.
14. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494-500.
15. Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J. 2005;35(2):83-90.
16. Goldstein LS, Haug MT 3rd, Perl J 2nd, et al. Central nervous system complications after lung transplantation. J Heart Lung Transplant. 1998;17(2):185-191.
17. Bonham CA, Dominguez EA, Fukui MB, et al. Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation. 1998;66(12):1596-1604.
18. Kim BS, Lee SG, Hwang S, et al. Neurologic complications in adult living donor liver transplant recipients. Clin Transplant. 2007;21(4):544-547.
19. Deierhoi MH, Kalayoglu M, Sollinger HW, Belzer FO. Cyclosporine neurotoxicity in liver transplant recipients: report of three cases. Transplant Proc. 1988;20(1):116-118.
20. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation. 2000;69(4):467-472.
21. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008;29(6):1036-1042.
22. Jarosz JM, Howlett DC, Cox TC, Bingham JB. Cyclosporine-related reversible posterior leukoencephalopathy: MRI. Neuroradiology. 1997;39(10):711-715.
23. Antunes NL, Small TN, George D, Boulad F, Lis E. Posterior leukoencephalopathy syndrome may not be reversible. Pediatr Neurol. 1999;20(3):241-243.
24. Donmez FY, Guvenc Z, Emiroglu FK, Coskun M, Haberal M. Evaluation of neurological complications in pediatric liver transplant recipients: MRI versus CT. J Child Neurol. 2009;24(6):656-663.
25. Kochi S, Takanaga H, Matsuo H, Naito M, Tsuruo T, Sawada Y. Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells. Eur J Pharmacol. 1999;372(3):287-295.
26. Schuuring J, Wesseling P, Verrips A. Severe tacrolimus leukoencephalopathy after liver transplantation. AJNR Am J Neuroradiol. 2003;24(10):2085-2088.
27. Small SL, Fukui MB, Bramblett GT, Eidelman BH. Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506). Ann Neurol. 1996;40(4):575-580.
28. Sakamoto Y, Makuuchi-M, Harihara Y, Imamura H, Sato H. Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats. Biol Pharm Bull. 2000;23(8):1008-1010.
29. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-653.
30. Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009;31(2):139-152.
31. Sato K, Amada N, Sato T, et al. Severe elevations of FK506 blood concentration due to diarrhea in renal transplant recipients. Clin Transplant. 2004;18(5):585-590.
32. Bekersky I, Dressler D, Mekki QA. Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects. J Clin Pharmacol. 2001;41(2):176-182.
33. Kuypers DR, Claes K, Evenepoel P, et al. Time-related clinical determinants of long-term tacrolimus pharmacokinetics in combination therapy with mycophenolic acid and corticosteroids: a prospective study in one hundred de novo renal transplant recipients. Clin Pharmacokinet. 2004;43(11):741-762.
34. First MR, Fitzsimmons WE. New drugs to improve transplant outcomes. Transplantation. 2004;77(suppl 9):S88-S92.
35. First MR, Fitzsimmons WE. Modified release tacrolimus. Yonsei Med J. 2004;45(6):1127-1131.
36. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37(2):867-870.