Multidrug resistance protein in recurrent breast cancer.

1885 remained otherwise well until January, 1996, when he developed recurrent biliary stricturing with jaundice and worsening diarrhoea. Trough cyclosporin concentrations were considered sub-therapeutic at 60 ng/mL and so he was converted to Neoral therapy at the same dose. Several 12-h trough whole blood cyclosporin levels were taken over the following 2 months, and did not exceed 125 ng/mL. In March, 1996, he complained of altered colour perception, which improved after empirical parenteral vitamin A therapy. In April, 1996, he was admitted with coma following recent onset of myalgia and dysarthria. On arrival he was unresponsive, restless, and hyperventilating with decorticate movements, extensor plantar responses, and bilateral ankle clonus. Investigations revealed metabolic acidosis and renal impairment; arterial pH 7·1, bicarbonate 8·4 mmol/L, serum creatinine 279 µmol/L (rising from 148 µmol/L 4 weeks previously). Serum sodium level was 135 mmol/L. Cyclosporin level was 52 ng/mL. An electroencephalogram and cerebrospinal fluid examination were normal. Computed tomography and magnetic resonance imaging showed white matter changes consistent with leucoencephalopathy (figure), which had progressed substantially since 1993. He was mechanically ventilated and treated with empirical antimicrobial therapy. Cyclosporin and azathioprine were discontinued. He failed to regain consciousness after withdrawal of sedation and died 20 days after presentation. A screen for viruses taken before death, including PCR analysis of cerebrospinal fluid for JC virus, was negative. Necropsy of the brain revealed axonal degeneration in the areas of white matter abnormality seen on the scans, with associated oedema, scattered lymphocytes, and macrophages localised to the white matter. This case has clinical, radiological, and pathological features consistent with leucoencephalopathy, a rare condition previously described in patients treated with cyclosporin or tacrolimus. However, most previously described leucoencephalopathies associated with immunosuppression occurred early during therapy and were reversible with good recovery. Unusual features in this case included late onset (3 years after starting immunosuppressive therapy), more extensive and fronto-parietal distribution of white matter changes, and deterioration despite withdrawal of cyclosporin, all suggesting an extreme variant of the disease. Neurotoxic side-effects of cyclosporin are more frequently reported in liver transplant recipients than in other organ recipients, which may reflect increased permeability of the blood-brain barrier consequent upon liver failure. 1,3,4 Other risk factors include high trough cyclosporin concentrations, and low serum cholesterol levels, although a causative effect of the latter is not proven. Neoral, the recently introduced microemulsion formulation of cyclosporin, is more bioavailable than Sandimmun. Patients with liver or gut …