1. Neurotoxicity of Immunosuppressive drugs 신장내과 R3 김경엽

2.  Early after transplantation  Higher dose of immunosuppressive medications -> ↑ neurotoxicity  Neurotoxicity is particularly prevalent in agents active through the mechanism of calcineurin inhibition Kyungyup Kim, M.D.

3. Prevalence of Neurotoxicity  In the US: Neurologic complications affect up to 30-60% of allograft recipients  Tremor  Approximately 40% of patients on cyclosporine and tacrolimus therapy Kyungyup Kim, M.D.

4. Clinical Features of Neurotoxicity  Tremor  Extreme restlessness  Insomnia  Marked disorientation  Acute manic syndrome  Articulation of speech: less precise  Dysarthria  Blindness  Confabulation  Status epilepticus Kyungyup Kim, M.D.

5. Pathogenesis  Both cyclosporine and tacrolimus  Highly lipophilic drugs  Contain many aliphatic groups  The lipophilic nature of both substances does not imply that they rapidly enter brain tissue  One possible mechanism of entry is at the capillary level Kyungyup Kim, M.D. Reduce polar charges, insoluble in water Injury to brain capillary endothelial cell Inhibit the expression of a p-glycoprotein

6.  Cyclosporine  Enhance nitric oxide production -> dysfunction of the blood-brain barrier  Earliest abnormality in cyclosporine or tacrolimus neurotoxicity  Fluid extravasation (vasogenic edema), not cell destruction (cytotoxic edema) Am J Neuroradiol 1999;8:1507-1510  Cytotoxicity and cytotoxic edema: after prolonged drug exposure Life Sci 2000;23:2255-2260 Kyungyup Kim, M.D.

8. Neuroimaging  Neuroimaging abnormalities with cyclosporine and tacrolimus immunosuppressive toxicity  Posterior leukoencephalopathy on CT scan or MRI  Cortical hyperintensity  Liver transplant recipient with cyclosporine neurotoxicity Kyungyup Kim, M.D.

9.  Abnormalities of white matter, cortex, cerebellum, and such deeper structures as the basal ganglia Kyungyup Kim, M.D.

10. Management  The diagnosis remains tentative in many patients  Consult to neurologist  Confusional state  No evidence of abnormalities on neuroimaging  Increasing cyclosporine or tacrolimus levels  A well-recognized phenomenon  The poor correlation with tacrolimus and cyclosporine trough levels  Consider discontinuation of cyclosporine or tracrolimus therapy (MMF or ↓ target level) Kyungyup Kim, M.D.

11.  Identify  Drugs that may increase levels of immunosuppressive agents and trigger neurotoxicity  Cyclosporine – cephalosporins, diltiazem, verapamil, and high-dose methylprednisolone  Tacrolimus – erythromycin, danazol, and fluconazole  Switching to cyclosporine therapy in patients with tacrolimus and vice versa (two large series)  Resolution of neurotoxicity in vertually all cases  No recurrence of neurotoxicity after restarting the medication  Rejection: approximately 30% in both studies Transplantation 2000;1:172-176 / Transpl Int 2000;1:73-78 Kyungyup Kim, M.D.

12.  Acute confusional state  Haloperidol  Lorazepam  Seizures  Intravenous lorazepam  Electroencephalography: epileptic activity  Add phenytoin for approximately 1 month  Check serum magnesium levels  Cyclosporine neurotoxicity – cyclosporine increases the urinary excretion of magnesium because of its interference with tubular reabsorption Kyungyup Kim, M.D.

13.  Headache  Common symptom, but poorly characterized  Increase in frequency after prolonged exposure  Switching to another immunosuppressive agent can result in dramatic relief Neurology 1996;47:1347-1348  Propranolol (20 mg every 6 to 8 hours)  Verapamil, a drug commonly used for migraine, should be discouraged (verapamil -> ↑ cyclosporine)  Grapefruit juice consumption - discourage Kyungyup Kim, M.D.

14. Conclusion  Clinical features of immunosuppression neurotoxicity -> well understood  The mechanism, predictive factors, and best management of immunosuppression neurotoxicity -> unknown  True relevance  Seizure, cortical blindness, and coma  Failure to recognize its heralding symptoms  Increase morbidity and length of stay in the transplant intensive care unit Kyungyup Kim, M.D.