Elevation of blood ciclosporin levels by voriconazole leading to leukoencephalopathy
One 18-year-old 46-kg female patient was admitted on the 70th day postoperative with complaints of dizziness, headaches, and blurred vision for 2 days. Her consciousness was distinct without nausea, vomiting, cough, expectoration, urinary, or fecal incontinence on admission. Her vital signs suggested normal body temperature and normal blood pressure with heart rate (HR) of 98 bpm. Examination of ocular fundus was normal. She did not have pre-existing neurological disorders and had not received significant amounts of psychotropic drugs before. Her medication history revealed that she was receiving “CsA (100 mg, q12h, po)-mycophenolate (1g, q12h, po)-methylprednisolone (8 mg, q12h, po)” antirejection therapy, because she had received allogeneic HSCT for myelodysplastic syndromes (MDS) 70 days before. The patient suffered from coughing accompanying expectoration 14 days ago, and the chest computed tomography (CT) showed pulmonary infections in the superior lobe of right lung. Cefaclor sustained release table had been administrated for one week, however symptoms did not improve. Fungus infection was suspected. Tablet voriconazole (400 mg, q12h, po) on the first day, followed by 200 mg every 12 h orally was added for the prophylaxis of IFI one week later. During this period, other medications, including herbal remedies and vitamins, had not been used; her liver function and renal function tests during the past 2 months were normal. After admission carbamazepine, rotundine, and citicoline sodium were administrated immediately for symptomatic treatment and supportive management; however, her condition continued to deteriorate in the next 2 hours, she dropped into locked jaw and convulsion of limbs, presented with epileptiform seizures, which was gradually improved by 10 mg diazepam (once) and 7 days of phenobarbital (0.1 g, bid, im) afterwards.\nA standard fluorescence polarization immunoassay (FPIA) was used to detect the trough blood concentration of CsA before the next administration. Historical trough whole blood concentration of CsA (reference range 150-300 ng/ml) was collected within the past month (average 230 ng/ml) before the combination with voriconazole. On the second day of admission, the blood concentration of CsA was 378 ng/ml. On the same day other examinations such as blood counts, cerebrospinal fluid, and serum chemistries are shown in . Blood smear showed plenty of leukocytes which were well distributed, and the immunochemical assay for cytomegalovirus (CMV) showed negative result on the third day of admission, the chest CT showed inflammation in anterior segment of superior lobe and median lobe in the right lung on the same day. Magnetic resonance imaging (MRI) of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4th day of admission.\nAccording to the clinical symptoms, laboratory examinations, and imaging examinations, the interaction between CsA and voriconazole was suspected. The concentration of CsA had risen slowly to 378 ng/ml during the past 7 days of co-administration with voriconazole. So voriconazole was suspended, and alprostadil, clopidogrel, and atorvastatin were administered from the second day of hospital stay to improve microcirculation and decrease hyperlipemia. From the third day of hospital stay, cefoperazone sodium and sulbactam sodium for injection were added to control the inflammation in the right lung. Her condition improved gradually. Because of the phenobarbital's induction of enzymes, the blood concentration of CsA dropped to 57 ng/ml on the 8th day of hospital stay; therefore, phenobarbital was suspended after 7 days’ medication under the circumstances of improved neurologic signs. On the 9th day of admission, the CT in chest showed amelioration in superior lobe of right lung comparing to anterior results besides miliary tuberosity in bilateral lungs, probable fungus infection, and the 1-3-β-D polyglucosan elevated to 89.57 pg/ml on the 10th day of admission. Voriconazole treatment was administered again to control fungus infection in bilateral lungs. To prevent drug toxicity, the dose of CsA was adjusted to 3/4 compared to the initial dose. Satisfactory steady-state blood concentration of CsA was achieved (250 ng/ml around). She was discharged 12 days later. The trough concentration of CsA and the important co-administered drugs (including enzyme inhibitors or enzyme inductors) during different time periods are shown in\n.