Ask the Experts - Cyclosporine Neurotoxicity?
We have a 51-year-old patient with alcoholic cirrhosis, postoperative day 21 after liver transplantation, with cyclosporine (CsA) neurotoxicity (seizures and stupor). CsA levels are therapeutic levels (300-400). How do you decrease the dose, what parameters do you use, and what is the best target range? When do you switch to tacrolimus (TAC)?

Dr. Padilla

Neurologic complications are commonly encountered after liver transplantation, especially in the elderly, cachectic, or encephalopathic recipient.

Calcineurin inhibitors have well known neurotoxicity that is accentuated in the presence of electrolyte shifts, preexisting disease, and poor allograft function. Approximately a quarter of patients on CsA or TAC may experience neurotoxicity. Mild symptoms include tremor, headache, and neuropathy. More severe symptoms include seizure, motor dysfunction, and leukoencephalopathy. White matter is particularly susceptible to toxicity, manifested by characteristic focal lesions on MRI. It is possible that these white matter changes are ischemic in origin, although this is not proven. Calcineurin inhibitors may also exacerbate an underlying seizure focus by enhancing neuronal excitability. In patients with seizure disorder it is therefore important that antiseizure medication be carefully maintained within therapeutic ranges.

Mild symptoms of calcineurin inhibitor toxicity usually respond to dose reduction. Severe symptoms such as leukoencephalopathy require cessation and may be associated with prolonged or even permanent neurologic damage. Calcineurin inhibitor-sparing regimens after liver transplantation may be useful in reducing the incidence of neurotoxicity. In our unit, we delay calcineurin inhibitors and use only mycophenolate mofetil (MMF) and corticosteroids in the immediate posttransplantation period. Calcineurin inhibitors are started when encephalopathy and electrolyte shifts have resolved, usually within 48 hours.

The workup for a patient with posttransplant seizure includes a full metabolic and electrolyte assessment with attention to hypomagnesemia and hypocalcemia.

Early posttransplant seizure (within the first 7 days) in an alcoholic raises the suspicion of alcohol withdrawal. MRI scan is indicated to look for central pontine myelinolysis, leukoencephalopathy, cerebrovascular accident, or mass lesions. EEG will be helpful to identify the seizure focus. Patients with mental status changes should have a lumbar puncture to exclude infectious causes. In our unit, we generally discontinue CsA in a patient with stupor and seizures until the diagnosis is clearer. Meanwhile, the patient can be maintained on MMF and prednisone. I do not see much role for TAC conversion, which has a similar risk of neurotoxicity. If the patient improves with CsA cessation and there are no signs of leukoencephalopathy on MRI, CsA can be slowly reintroduced at low dose after the patient is started on antiseizure medications. Once started, antiseizure medication should probably be continued for at least several months after transplantation.