Calcineurin inhibitor encephalopathy can develop years post lung transplantation

Sirs, Calcineurin inhibitor (CNI) encephalopathy is well described post transplantation. The classical presentation is within days or months of the transplant in the setting of large doses and elevated drug levels. We report a case of a 55-year-old female that developed a rapidly fatal neurodegenerative disease 4 years post lung transplantation. We suggest CNI encephalopathy as the diagnosis and consider the wide spectrum of CNI toxicity. Our patient underwent bilateral sequential lung transplantation for bronchiectasis and advanced emphysema secondary to cigarette smoking and alpha-1 antitrypsin deficiency. Post-transplantation, complications included sternal non-union and reactive pleuritis with a pleural effusion. Her renal, hepatic, magnesium and cyclosporine levels, lipids and blood pressure, were regularly monitored by her respiratory physician and were within normal ranges. Medications included cyclosporine 100 mg BD, azathioprine 50 mg OD, prednisolone 7.5 mg OD with valganciclovir and cotrimoxazole prophylaxis. Co-morbidities included osteoporosis (calcium, cholecalciferol, zolendronate) and controlled hypercholesterolaemia (ezetemibe 10 mg OD). There was no history of alcohol abuse, but a family history of Parkinson’s. One year prior to death, she suffered a fall with head laceration, then over months developed fluctuating memory disturbance, headaches, clumsiness and tremor unresponsive to the addition of carbidopa/levodopa 100/25 mg OD, propranolol 10 mg BD and pizotifene 0.5 mg OD. She presented to a secondary regional hospital in 2011 with a sudden onset headache, generalized seizure and low glasgow coma score requiring brief intubation. Post extubation she developed worsening ataxia and tremor, with new visual hallucinations. Lumbar puncture, CT brain and basic bloods were unremarkable and cyclosporine level was low– normal. On day 16 of her admission, she was transferred to our tertiary hospital for respiratory, infectious disease and neurological opinions. Examination revealed delirium, a fine bilateral resting tremor, diffuse hyperreflexia and plantar withdrawal. Her observations remained within the normal range, but on day 18, her neurology worsened. Levodopa/ carbidopa and pizotifene were ceased. Cyclosporine was changed to everolimus 2 mg BD though CNI toxicity was considered of low likelihood given low serum levels. Quetiapine 12.5 mg BD and midazolam PRN (when necessary) were used for delirium. On day 21, she developed status epilepticus requiring sedation and brief mechanical ventilation. Post extubation she had a few days of stability before deteriorating further. On day 30, all rejection medications were ceased. Despite this, her neurological status continued to worsen and she passed away on day 37. Extensive testing (see Table 1) was undertaken to help exclude the following: Progressive multifocal leukoencephalopathy, Creutzfeldt–Jakob disease, status epilepticus, venous sinus thrombosis, vasculitis, Lewy body dementia, infectious encephalitis, graft versus host disease and rejection. A metabolic or toxic differential remained, though at the time, no reversible cause was found. Autopsy report ultimately revealed posterior encephalopathic changes consistent with the missed diagnosis of CNI encephalopathy. Post organ transplantation, neurological side effects associated with the prescription of the CNIs cyclosporine and tacrolimus are well described. Mild side effects of headache, tremor and peripheral neuropathy occur in 10–40% of patients [1–4]. Severe side effects are less common occurring in up to 5% of patients [1,2]. Symptoms include delirium, psychosis, ataxia, blindness, seizures and paresis. The aetiology of CNI encephalopathy is not fully understood and likely to be multifactorial [1–4]. Toxicity usually occurs within days to months of transplantation when large CNI doses and high serum levels can lead to direct neuronal toxicity, though there are case reports with therapeutic or sub-therapeutic CNI levels [1,5–8]. Given encephalopathy can occur without high levels, other factors have been suggested as mechanisms. Hypocholesterolaemia,